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MRC Epidemiology Unit

Unit Publications

Duell, E. J.; Travier, N.; Lujan-Barroso, L.; Boutron-Ruault, M. C.; Clavel-Chapelon, F.; Palli, D.; Krogh, V.; Mattiello, A.; Tumino, R.; Sacerdote, C.; Rodriguez, L.; Sanchez-Cantalejo, E.; Navarro, C.; Barricarte, A.; Dorronsoro, M.; Khaw, K. T.; Wareham, N.; Allen, N. E.; Tsilidis, K. K.; Bueno-de-Mesquita, H. B.; Jeurnink, S. M.; Numans, M. E.; Peeters, P. H.; Lagiou, P.; Valanou, E.; Trichopoulou, A.; Kaaks, R.; Lukanova-McGregor, A.; Bergman, M. M.; Boeing, H.; Manjer, J.; Lindkvist, B.; Stenling, R.; Hallmans, G.; Dahm, C. C.; Overvad, K.; Olsen, A.; Tjonneland, A.; Bakken, K.; Lund, E.; Jenab, M.; McCormack, V.; Rinaldi, S.; Michaud, D.; Mouw, T.; Nesi, G.; Carneiro, F.; Riboli, E.; Gonzalez, C. A. (2010) Menstrual and Reproductive Factors, Exogenous Hormone Use, and Gastric Cancer Risk in a Cohort of Women From the European Prospective Investigation Into Cancer and Nutrition Am J Epidemiol, , [] Online
Abstract: The worldwide incidence of gastric adenocarcinoma (GC) is lower in women than in men. Furthermore, cancer patients treated with estrogens have been reported to have a lower subsequent risk of GC. The authors conducted a prospective analysis of menstrual and reproductive factors, exogenous hormone use, and GC in 335,216 women from the European Prospective Investigation Into Cancer and Nutrition, a cohort study of individuals aged 35-70 years from 10 European countries. After a mean follow-up of 8.7 years (through 2004), 181 women for whom complete exposure data were available developed GC. Adjusted hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards models. All statistical tests were 2-sided. Women who had ovariectomy had a 79% increased risk of GC (based on 25 cases) compared with women who did not (hazard ratio = 1.79, 95% confidence interval: 1.15, 2.78). Total cumulative years of menstrual cycling was inversely associated with GC risk (fifth vs. first quintile: hazard ratio = 0.55, 95% confidence interval: 0.31, 0.98; P(trend) = 0.06). No other reproductive factors analyzed were associated with risk of GC. The results of this analysis provide some support for the hypothesis that endogenous ovarian sex hormones lower GC incidence in women.
PubMed Accession Number :: 21051447.

Ridgway, C. L.; Brage, S.; Anderssen, S.; Sardinha, L. B.; Andersen, L. B.; Ekelund, U. (2010) Fat-free mass mediates the association between birth weight and aerobic fitness in youth Int J Pediatr Obes, , [Journal Article] Online
Abstract: Abstract Objective. To investigate whether birth weight acts as a biological determinant of later aerobic fitness, and whether fat-free mass may mediate this association. Methods. The European Youth Heart Study (EYHS) is a population-based cohort of two age groups (9 and 15 years) from Denmark, Portugal, Estonia and Norway. Children with parentally reported birth weight >1.5 kg were included (n = 2 749). Data were collected on weight, height, and skinfold measures to estimate fat mass and fat-free mass. Aerobic fitness (peak power, watts) was assessed using a maximal, progressive cycle ergometer test. Physical activity was collected in a subset (n = 1 505) using a hip-worn accelerometer and defined as total activity counts/wear time, all children with >600 minutes/day for >/=3 days of wear were included. Results. Lower birth weight was associated with lower aerobic fitness, after adjusting for sex, age group, country, sexual maturity and socio-economic status (ss = 5.4; 95% CI: 3.5, 7.3 W per 1 kg increase in birth weight, p < 0.001). When fat-free mass was introduced as a covariate in the model, the association between birth weight and aerobic fitness was almost completely attenuated (p = 0.7). Birth weight was also significantly associated with fat-free mass (ss = 1.4; 95% CI: 1.1, 1.8, p < 0.001) and fat-free mass was significantly associated with aerobic fitness (ss = 3.6; 95% CI: 3.4, 3.7, p < 0.001). Further adjustment for physical activity did not alter the findings. Conclusion. Birth weight may have long-term influences on fat-free mass and differences in fat-free mass mediate the observed association between birth weight and aerobic fitness.
PubMed Accession Number :: 21050079.

Tillin, T.; Forouhi, N. G.; McKeigue, P. M.; Chaturvedi, N. (2010) Southall And Brent REvisited: Cohort profile of SABRE, a UK population-based comparison of cardiovascular disease and diabetes in people of European, Indian Asian and African Caribbean origins Int J Epidemiol, , [Journal Article] Online
PubMed Accession Number :: 21044979.

Leufkens, A. M.; van Duijnhoven, F. J.; Siersema, P. D.; Boshuizen, H. C.; Vrieling, A.; Agudo, A.; Gram, I. T.; Weiderpass, E.; Dahm, C.; Overvad, K.; Tjonneland, A.; Olsen, A.; Boutron-Ruault, M. C.; Clavel-Chapelon, F.; Morois, S.; Palli, D.; Grioni, S.; Tumino, R.; Sacerdote, C.; Mattiello, A.; Herman, S.; Kaaks, R.; Steffen, A.; Boeing, H.; Trichopoulou, A.; Lagiou, P.; Trichopoulos, D.; Peeters, P. H.; van Gils, C. H.; van Kranen, H.; Lund, E.; Dumeaux, V.; Engeset, D.; Rodriguez, L.; Sanchez, M. J.; Chirlaque, M. D.; Barricarte, A.; Manjer, J.; Almquist, M.; van Guelpen, B.; Hallmans, G.; Khaw, K. T.; Wareham, N.; Tsilidis, K. K.; Straif, K.; Leon-Roux, M.; Vineis, P.; Norat, T.; Riboli, E.; Bueno-de-Mesquita, H. B. (2010) Cigarette Smoking and colorectal cancer risk in the EPIC study Clin Gastroenterol Hepatol, , [Journal Article] Online
Abstract: BACKGROUND & AIMS:: There has been consistent evidence for a relationship between smoking and colorectal cancer (CRC), although it is not clear whether the colon or rectum is more sensitive to the effects of smoking. We investigated the relationships between cigarette smoking and risk of CRC and tumor location. METHODS:: We analyzed data from 465,879 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study; 2,741 developed CRC during the follow-up period (mean 8.7 years). Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS:: The risk of colon carcinoma was increased among ever smokers (HR 1.18, 95%CI 1.06-1.32) and former cigarette smokers (HR 1.21, 95%CI 1.08-1.36), compared with never smokers; the increased risk for current smokers was of borderline significance (HR 1.13, 95%CI 0.98-1.31). When stratified for tumor location, the risk of proximal colon cancer was increased for former (HR 1.25, 95%CI 1.04-1.50) and current smokers (HR 1.31, 95%CI 1.06-1.64), but the risks for cancers in the distal colon or rectum were not. Subsite analyses showed a non-significant difference between the proximal and distal colon (p=0.45) for former smokers and a significant difference for current smokers (p=0.02). For smokers that had stopped smoking for at least 20 years, the risk of developing colon cancer was similar to that of never smokers. CONCLUSIONS:: Ever smokers have an increased risk of colon cancer, which appeared to be more pronounced in the proximal than the distal colon location.
PubMed Accession Number :: 21029790.

Buchner, F. L.; Bueno-de-Mesquita, H. B.; Ros, M. M.; Kampman, E.; Egevad, L.; Overvad, K.; Tjonneland, A.; Roswall, N.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Touillaud, M.; Kaaks, R.; Chang-Claude, J.; Boeing, H.; Weikert, S.; Trichopoulou, A.; Naska, A.; Benetou, V.; Palli, D.; Sieri, S.; Vineis, P.; Tumino, R.; Panico, S.; van Duijnhoven, F. J.; Peeters, P. H.; van Gils, C. H.; Lund, E.; Gram, I. T.; Sanchez, M. J.; Jakszyn, P.; Larranaga, N.; Ardanaz, E.; Navarro, C.; Rodriguez, L.; Manjer, J.; Ehrnstrom, R.; Hallmans, G.; Ljungberg, B.; Key, T. J.; Allen, N. E.; Khaw, K. T.; Wareham, N.; Slimani, N.; Jenab, M.; Boffetta, P.; Kiemeney, L. A.; Riboli, E. (2010) Variety in vegetable and fruit consumption and risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition Int J Cancer, , [Journal Article] Online
Abstract: Recent research does not show an association between fruit and vegetable consumption and bladder cancer risk. None of these studies investigated variety in fruit and vegetable consumption, which may capture different aspects of consumption. We investigated whether a varied consumption of vegetables and fruits is associated with bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Detailed data on food consumption and complete follow-up for cancer incidence were available for 452,185 participants, who were recruited from ten European countries. After a mean follow-up of 8.7 years, 874 participants were diagnosed with bladder cancer. Diet diversity scores (DDSs) were used to quantify the variety in fruit and vegetable consumption. Multivariable Cox proportional hazard models were used to assess the effect of the DDSs on bladder cancer risk. There was no evidence of a statistically significant association between bladder cancer risk and any of the DDSs when these scores were considered as continuous covariates. However, the hazard ratio (HR) for the highest tertile of the DDS for combined fruit and vegetable consumption was marginally significant compared to the lowest (HR = 1.30, 95% confidence interval: 1.00-1.69, p-trend = 0.05). In EPIC, there is no clear association between a varied fruit and vegetable consumption and bladder cancer risk. This finding provides further evidence for the absence of any strong association between fruit and vegetable consumption as measured by a food frequency questionnaire and bladder cancer risk.
PubMed Accession Number :: 20979109.

Simmons, R. K.; Rahman, M.; Jakes, R. W.; Yuyun, M. F.; Niggebrugge, A. R.; Hennings, S. H.; Williams, D. R.; Wareham, N. J.; Griffin, S. J. (2010) Effect of population screening for type 2 diabetes on mortality: long-term follow-up of the Ely cohort Diabetologia, , [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The aim of this study was to assess the impact of invitation to screening for type 2 diabetes and related cardiovascular risk factors on population mortality. METHODS: This was a parallel-group population-based cohort study including all men and women aged 40-65 years, free of known diabetes, registered with a single practice in Ely, UK (n = 4,936). In 1990-1992, approximately one-third (n = 1,705) were randomly selected to receive an invitation to screening for diabetes (with an OGTT) and related cardiovascular risk factors. In the remaining two-thirds of the population, 1,705 individuals were randomly selected for invitation to screening in 2000-2003 and 1,526 were not invited at any point during the follow-up period. All individuals were flagged for mortality until January 2008. RESULTS: There were 345 deaths between 1990 and 1999 (median 10 years follow-up). Compared with those not invited, individuals who were invited to the 1990-1992 screening round had a non-significant 21% lower all-cause mortality (HR 0.79 [95% CI 0.63-1.00], p = 0.05) after adjustment for age, sex and deprivation. There were 291 deaths between 2000 and 2008 (median 8 years follow-up), with no significant difference in mortality between invited and non-invited participants in 2000-2003. Compared with the non-invited group, participants who attended for screening at any time point had a significantly lower mortality and those who did not attend had a significantly higher mortality. CONCLUSIONS/INTERPRETATION: Invitation to screening was associated with a non-significant reduction in mortality in the Ely cohort between 1990 and 1999, but this was not replicated in the period 2000-2008. This study contributes to the evidence concerning the potential benefits of population screening for diabetes and related cardiovascular risk factors.
PubMed Accession Number :: 20978739.

Gkrania-Klotsas, E.; Ye, Z.; Cooper, A. J.; Sharp, S. J.; Luben, R.; Biggs, M. L.; Chen, L. K.; Gokulakrishnan, K.; Hanefeld, M.; Ingelsson, E.; Lai, W. A.; Lin, S. Y.; Lind, L.; Lohsoonthorn, V.; Mohan, V.; Muscari, A.; Nilsson, G.; Ohrvik, J.; Chao Qiang, J.; Jenny, N. S.; Tamakoshi, K.; Temelkova-Kurktschiev, T.; Wang, Y. Y.; Yajnik, C. S.; Zoli, M.; Khaw, K. T.; Forouhi, N. G.; Wareham, N. J.; Langenberg, C. (2010) Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies PLoS One, 5 (10),e13405 [Journal Article] Online
Abstract: OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated. RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored. RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference. CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.
PubMed Accession Number :: 20976133.

Hochberg, Z.; Feil, R.; Constancia, M.; Fraga, M.; Junien, C.; Carel, J. C.; Boileau, P.; Le Bouc, Y.; Deal, C. L.; Lillycrop, K.; Scharfmann, R.; Sheppard, A.; Skinner, M.; Szyf, M.; Waterland, R. A.; Waxman, D. J.; Whitelaw, E.; Ong, K.; Albertsson-Wikland, K. (2010) Child Health, Developmental Plasticity, and Epigenetic Programming Endocr Rev, , [Journal Article] Online
Abstract: Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.
PubMed Accession Number :: 20971919.

Campa, D.; Husing, A.; Chang-Claude, J.; Dostal, L.; Boeing, H.; Kroger, J.; Tjonneland, A.; Roswall, N.; Overvad, K.; Dahm, C. C.; Rodriguez, L.; Sala, N.; Perez, M. J.; Larranaga, N.; Chirlaque, M. D.; Ardanaz, E.; Khaw, K. T.; Wareham, N.; Allen, N. E.; Travis, R. C.; Trichopoulou, A.; Naska, A.; Bamia, C.; Palli, D.; Sieri, S.; Tumino, R.; Sacerdote, C.; van Kranen, H. J.; Bas Bueno-de-Mesquita, H.; Stattin, P.; Johansson, M.; Chajes, V.; Rinaldi, S.; Romieu, I.; Siddiq, A.; Norat, T.; Riboli, E.; Kaaks, R.; Canzian, F. (2010) Genetic variability of the fatty acid synthase pathway is not associated with prostate cancer risk in the European Prospective Investigation on Cancer (EPIC) Eur J Cancer, , [Journal Article] Online
Abstract: A western lifestyle, characterised by low rates of energy expenditure and a high-energy diet rich in animal protein, saturated fats and refined carbohydrates, is associated with high incidence of prostate cancer in men. A high-energy nutritional status results in insulin/IGF signalling in cells, which in turn stimulates synthesis of fatty acids. We investigated whether the genetic variability of the genes belonging to the fatty acid synthesis pathway is related to prostate cancer risk in 815 prostate cancer cases and 1266 controls from the European Prospective Investigation on Cancer (EPIC). Using a tagging approach and selecting 252 SNPs in 22 genes, we covered all the common genetic variation of this pathway. None of the SNPs reached statistical significance after adjusting for multiple comparisons. Common SNPs in the fatty acid synthase pathway are not major contributors to prostate cancer risk.
PubMed Accession Number :: 20965718.

Sivapalaratnam, S.; Boekholdt, S. M.; Trip, M. D.; Sandhu, M. S.; Luben, R.; Kastelein, J. J.; Wareham, N. J.; Khaw, K. T. (2010) Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study Heart, , [Journal Article] Online
Abstract: Objective The value of a family history for coronary heart disease (CHD) in addition to established cardiovascular risk factors in predicting an individual's risk of CHD is unclear. In the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort, the authors tested whether adding family history of premature CHD in first-degree relatives improves risk prediction compared with the Framingham risk score (FRS) alone. Methods and results This study comprised 10 288 men and 12 553 women aged 40-79&emsp14;years participating in the EPIC-Norfolk cohort who were followed for a mean of 10.9+/-2.1 years (mean+/-SD). The authors computed the FRS as well as a modified score taking into account family history of premature CHD. A family history of CHD was indeed associated with an increased risk of future CHD, independent of established risk factors (FRS-adjusted HR of 1.74 (95% CI 1.56 to 1.95) for family history of premature CHD). However, adding family history of CHD to the FRS resulted in a negative net reclassification of 2%. In the subgroup of individuals estimated to be at intermediate risk, family history of premature CHD resulted in an increase in net reclassification of 2%. The sensitivity increased with 0.4%, and the specificity decreased 0.8%. Conclusion Although family history of CHD was an independent risk factor of future CHD, its use did not improve classification of individuals into clinically relevant risk categories based on the FRS. Among study participants at intermediate risk of CHD, adding family history of premature CHD resulted in, at best, a modest improvement in reclassification of individuals into a more accurate risk category.
PubMed Accession Number :: 20962344.

Ong, K. K.; Elks, C. E.; Wills, A. K.; Wong, A.; Wareham, N. J.; Loos, R. J.; Kuh, D.; Hardy, R. (2010) Associations between the Pubertal Timing-Related Variant in LIN28B and BMI Vary Across the Life Course J Clin Endocrinol Metab, , [Journal Article] Online
Abstract: Context: The common C allele of rs314276 in LIN28B has been robustly associated with earlier age at menarche in girls and associated with earlier timing of other pubertal traits in both sexes. Objective: Our objective was to explore the associations between rs314276, as a marker of earlier pubertal timing, and body mass index (BMI), weight, and height across the life course. Methods: The rs314276 in LIN28B was genotyped in 1242 men and 1209 women born in 1946 and participating in the Medical Research Council National Survey of Health and Development. Birth weight was recorded, and height and weight were measured or self-reported repeatedly at 11 time points between ages 2 and 53 yr. Polynomial mixed models were used to test whether additive genetic associations with SD scores (SDS) for BMI and height changed with age between 0 and 53 yr. Results: Longitudinal analyses revealed age-dependent associations between rs314276 genotype and BMI (P < 0.001 for genotype-by-age(2) interaction) and body weight (P < 0.001 for genotype-by-age(2) interaction) in women, but not in men. In women only, the C allele at rs314276 was associated with higher BMI SDS from ages 15-43 yr. In contrast, C allele associations with shorter height SDS were apparent in both men and women and did not vary with age. Conclusion: A common genetic variant in LIN28B that confers earlier puberty was associated with a prolonged increase in BMI during adolescence and early to mid-adulthood in women only. Such genetic associations may provide insights into the direct effects of pubertal timing on obesity risk.
PubMed Accession Number :: 20962026.

Allen, N. E.; Tsilidis, K. K.; Key, T. J.; Dossus, L.; Kaaks, R.; Lund, E.; Bakken, K.; Gavrilyuk, O.; Overvad, K.; Tjonneland, A.; Olsen, A.; Fournier, A.; Fabre, A.; Clavel-Chapelon, F.; Chabbert-Buffet, N.; Sacerdote, C.; Krogh, V.; Bendinelli, B.; Tumino, R.; Panico, S.; Bergmann, M.; Schuetze, M.; van Duijnhoven, F. J.; Bas Bueno-de-Mesquita, H.; Charlotte Onland-Moret, N.; van Gils, C. H.; Amiano, P.; Barricarte, A.; Chirlaque, M. D.; Molina-Montes, M. E.; Redondo, M. L.; Duell, E. J.; Khaw, K. T.; Wareham, N.; Rinaldi, S.; Fedirko, V.; Mouw, T.; Michaud, D. S.; Riboli, E. (2010) Menopausal Hormone Therapy and Risk of Endometrial Carcinoma Among Postmenopausal Women in the European Prospective Investigation into Cancer and Nutrition Am J Epidemiol, , [Journal Article] Online
Abstract: Estrogen-only menopausal hormone therapy (HT) increases the risk of endometrial cancer, but less is known about the association with other types of HT. Using Cox proportional hazards regression, the authors examined the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women recruited into the European Prospective Investigation into Cancer and Nutrition between 1992 and 2000. After a mean follow-up period of 9 years, 601 incident cases of endometrial cancer were identified. In comparison with never users of HT, risk of endometrial cancer was increased among current users of estrogen-only HT (hazard ratio (HR) = 2.52, 95% confidence interval (CI): 1.77, 3.57), tibolone (HR = 2.96, 95% CI: 1.67, 5.26), and, to a lesser extent, estrogen-plus-progestin HT (HR = 1.41, 95% CI: 1.08, 1.83), although risks differed according to regimen and type of progestin constituent. The association of HT use with risk was stronger among women who were older, leaner, or had ever smoked cigarettes. The finding of a strong increased risk of endometrial cancer with estrogen-only HT and a weaker association with combined HT supports the hypothesis that progestins have an attenuating effect on endometrial cancer risk. The increased risk associated with tibolone use requires further investigation.
PubMed Accession Number :: 20961969.

Yang, L.; Sahlqvist, S.; McMinn, A.; Griffin, S. J.; Ogilvie, D. (2010) Interventions to promote cycling: systematic review Bmj, 341 ,c5293 [Journal Article] Online
Abstract: OBJECTIVES: To determine what interventions are effective in promoting cycling, the size of the effects of interventions, and evidence of any associated benefits on overall physical activity or anthropometric measures. DESIGN: Systematic review. DATA SOURCES: Published and unpublished reports in any language identified by searching 13 electronic databases, websites, reference lists, and existing systematic reviews, and papers identified by experts in the field. Review methods Controlled "before and after" experimental or observational studies of the effect of any type of intervention on cycling behaviour measured at either individual or population level. RESULTS: Twenty five studies (of which two were randomised controlled trials) from seven countries were included. Six studies examined interventions aimed specifically at promoting cycling, of which four (an intensive individual intervention in obese women, high quality improvements to a cycle route network, and two multifaceted cycle promotion initiatives at town or city level) were found to be associated with increases in cycling. Those studies that evaluated interventions at population level reported net increases of up to 3.4 percentage points in the population prevalence of cycling or the proportion of trips made by bicycle. Sixteen studies assessing individualised marketing of "environmentally friendly" modes of transport to interested households reported modest but consistent net effects equating to an average of eight additional cycling trips per person per year in the local population. Other interventions that targeted travel behaviour in general were not associated with a clear increase in cycling. Only two studies assessed effects of interventions on physical activity; one reported a positive shift in the population distribution of overall physical activity during the intervention. CONCLUSIONS: Community-wide promotional activities and improving infrastructure for cycling have the potential to increase cycling by modest amounts, but further controlled evaluative studies incorporating more precise measures are required, particularly in areas without an established cycling culture. Studies of individualised marketing report consistent positive effects of interventions on cycling behaviour, but these findings should be confirmed using more robust study designs. Future research should also examine how best to promote cycling in children and adolescents and through workplaces. Whether interventions to promote cycling result in an increase in overall physical activity or changes in anthropometric measures is unclear.
PubMed Accession Number :: 20959282.

Campa, D.; Husing, A.; McKay, J. D.; Sinilnikova, O.; Vogel, U.; Tjonneland, A.; Overvad, K.; Stegger, J.; Clavel-Chapelon, F.; Chabbert-Buffet, N.; Fagherazzi, G.; Trichopoulou, A.; Zylis, D.; Oustoglou, E.; Rohrmann, S.; Teucher, B.; Fisher, E.; Boeing, H.; Masala, G.; Krogh, V.; Sacerdote, C.; Panico, S.; Tumino, R.; Onland-Moret, N. C.; van Gils, C. H.; Bueno-de-Mesquita, H. B.; Lund, E.; Chirlaque, M. D.; Sala, N.; Quiros, J. R.; Ardanaz, E.; Amiano, P.; Molina-Montes, E.; Hallmans, G.; Lenner, P.; Travis, R. C.; Key, T. J.; Wareham, N.; Khaw, K. T.; Rinaldi, S.; Slimani, N.; Chajes, V.; Siddiq, A.; Riboli, E.; Kaaks, R.; Canzian, F. (2010) The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk BMC Cancer, 10 (1),563 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: The single nucleotide polymorphism rs7566605, located in the promoter of the INSIG2 gene, has been the subject of a strong scientific effort aimed to elucidate its possible association with body mass index (BMI). The first report showing that rs7566605 could be associated with body fatness was a genome-wide association study (GWAS) which used BMI as the primary phenotype. Many follow-up studies sought to validate the association of rs7566605 with various markers of obesity, with several publications reporting inconsistent findings. BMI is considered to be one of the measures of choice to evaluate body fatness and there is evidence that body fatness is related with an increased risk of breast cancer (BC). METHODS: we tested in a large-scale association study (3,973 women, including 1,269 invasive BC cases and 2,194 controls), nested within the EPIC cohort, the involvement of rs7566605 as predictor of BMI and BC risk. RESULTS AND CONCLUSIONS: In this study we were not able to find any statistically significant association between this SNP and BMI, nor did we find any significant association between the SNP and an increased risk of breast cancer overall and by subgroups of age, or menopausal status.
PubMed Accession Number :: 20955599.

Lamb, K. E.; Ferguson, N. S.; Wang, Y.; Ogilvie, D.; Ellaway, A. (2010) Distribution of physical activity facilities in Scotland by small area measures of deprivation and urbanicity Int J Behav Nutr Phys Act, 7 (1),76 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: The aim of this study was to examine the distribution of physical activity facilities by area-level deprivation in Scotland, adjusting for differences in urbanicity, and exploring differences between and within the four largest Scottish cities. METHODS: We obtained a list of all recreational physical activity facilities in Scotland. These were mapped and assigned to datazones. Poisson and negative binomial regression models were used to investigate associations between the number of physical activity facilities relative to population size and quintile of area-level deprivation. RESULTS: The results showed that prior to adjustment for urbanicity, the density of all facilities lessened with increasing deprivation from quintiles 2 to 5. After adjustment for urbanicity and local authority, the effect of deprivation remained significant but the pattern altered, with datazones in quintile 3 having the highest estimated mean density of facilities. Within-city associations were identified between the number of physical activity facilities and area-level deprivation in Aberdeen and Dundee, but not in Edinburgh or Glasgow. CONCLUSIONS: In conclusion, area-level deprivation appears to have a significant association with the density of physical activity facilities and although overall no clear pattern was observed, affluent areas had fewer publicly owned facilities than more deprived areas but a greater number of privately owned facilities.
PubMed Accession Number :: 20955548.

Speliotes, E. K.; Willer, C. J.; Berndt, S. I.; Monda, K. L.; Thorleifsson, G.; Jackson, A. U.; Allen, H. L.; Lindgren, C. M.; Luan, J.; Magi, R.; Randall, J. C.; Vedantam, S.; Winkler, T. W.; Qi, L.; Workalemahu, T.; Heid, I. M.; Steinthorsdottir, V.; Stringham, H. M.; Weedon, M. N.; Wheeler, E.; Wood, A. R.; Ferreira, T.; Weyant, R. J.; Segre, A. V.; Estrada, K.; Liang, L.; Nemesh, J.; Park, J. H.; Gustafsson, S.; Kilpelainen, T. O.; Yang, J.; Bouatia-Naji, N.; Esko, T.; Feitosa, M. F.; Kutalik, Z.; Mangino, M.; Raychaudhuri, S.; Scherag, A.; Smith, A. V.; Welch, R.; Zhao, J. H.; Aben, K. K.; Absher, D. M.; Amin, N.; Dixon, A. L.; Fisher, E.; Glazer, N. L.; Goddard, M. E.; Heard-Costa, N. L.; Hoesel, V.; Hottenga, J. J.; Johansson, A.; Johnson, T.; Ketkar, S.; Lamina, C.; Li, S.; Moffatt, M. F.; Myers, R. H.; Narisu, N.; Perry, J. R.; Peters, M. J.; Preuss, M.; Ripatti, S.; Rivadeneira, F.; Sandholt, C.; Scott, L. J.; Timpson, N. J.; Tyrer, J. P.; van Wingerden, S.; Watanabe, R. M.; White, C. C.; Wiklund, F.; Barlassina, C.; Chasman, D. I.; Cooper, M. N.; Jansson, J. O.; Lawrence, R. W.; Pellikka, N.; Prokopenko, I.; Shi, J.; Thiering, E.; Alavere, H.; Alibrandi, M. T.; Almgren, P.; Arnold, A. M.; Aspelund, T.; Atwood, L. D.; Balkau, B.; Balmforth, A. J.; Bennett, A. J.; Ben-Shlomo, Y.; Bergman, R. N.; Bergmann, S.; Biebermann, H.; Blakemore, A. I.; Boes, T.; Bonnycastle, L. L.; Bornstein, S. R.; Brown, M. J.; Buchanan, T. A.; Busonero, F.; Campbell, H.; Cappuccio, F. P.; Cavalcanti-Proenca, C.; Chen, Y. D.; Chen, C. M.; Chines, P. S.; Clarke, R.; Coin, L.; Connell, J.; Day, I. N.; Heijer, M. D.; Duan, J.; Ebrahim, S.; Elliott, P.; Elosua, R.; Eiriksdottir, G.; Erdos, M. R.; Eriksson, J. G.; Facheris, M. F.; Felix, S. B.; Fischer-Posovszky, P.; Folsom, A. R.; Friedrich, N.; Freimer, N. B.; Fu, M.; Gaget, S.; Gejman, P. V.; Geus, E. J.; Gieger, C.; Gjesing, A. P.; Goel, A.; Goyette, P.; Grallert, H.; Grassler, J.; Greenawalt, D. M.; Groves, C. J.; Gudnason, V.; Guiducci, C.; Hartikainen, A. L.; Hassanali, N.; Hall, A. S.; Havulinna, A. S.; Hayward, C.; Heath, A. C.; Hengstenberg, C.; Hicks, A. A.; Hinney, A.; Hofman, A.; Homuth, G.; Hui, J.; Igl, W.; Iribarren, C.; Isomaa, B.; Jacobs, K. B.; Jarick, I.; Jewell, E.; John, U.; Jorgensen, T.; Jousilahti, P.; Jula, A.; Kaakinen, M.; Kajantie, E.; Kaplan, L. M.; Kathiresan, S.; Kettunen, J.; Kinnunen, L.; Knowles, J. W.; Kolcic, I.; Konig, I. R.; Koskinen, S.; Kovacs, P.; Kuusisto, J.; Kraft, P.; Kvaloy, K.; Laitinen, J.; Lantieri, O.; Lanzani, C.; Launer, L. J.; Lecoeur, C.; Lehtimaki, T.; Lettre, G.; Liu, J.; Lokki, M. L.; Lorentzon, M.; Luben, R. N.; Ludwig, B.; Manunta, P.; Marek, D.; Marre, M.; Martin, N. G.; McArdle, W. L.; McCarthy, A.; McKnight, B.; Meitinger, T.; Melander, O.; Meyre, D.; Midthjell, K.; Montgomery, G. W.; Morken, M. A.; Morris, A. P.; Mulic, R.; Ngwa, J. S.; Nelis, M.; Neville, M. J.; Nyholt, D. R.; O'Donnell, C. J.; O'Rahilly, S.; Ong, K. K.; Oostra, B.; Pare, G.; Parker, A. N.; Perola, M.; Pichler, I.; Pietilainen, K. H.; Platou, C. G.; Polasek, O.; Pouta, A.; Rafelt, S.; Raitakari, O.; Rayner, N. W.; Ridderstrale, M.; Rief, W.; Ruokonen, A.; Robertson, N. R.; Rzehak, P.; Salomaa, V.; Sanders, A. R.; Sandhu, M. S.; Sanna, S.; Saramies, J.; Savolainen, M. J.; Scherag, S.; Schipf, S.; Schreiber, S.; Schunkert, H.; Silander, K.; Sinisalo, J.; Siscovick, D. S.; Smit, J. H.; Soranzo, N.; Sovio, U.; Stephens, J.; Surakka, I.; Swift, A. J.; Tammesoo, M. L.; Tardif, J. C.; Teder-Laving, M.; Teslovich, T. M.; Thompson, J. R.; Thomson, B.; Tonjes, A.; Tuomi, T.; van Meurs, J. B.; van Ommen, G. J.; Vatin, V.; Viikari, J.; Visvikis-Siest, S.; Vitart, V.; Vogel, C. I.; Voight, B. F.; Waite, L. L.; Wallaschofski, H.; Walters, G. B.; Widen, E.; Wiegand, S.; Wild, S. H.; Willemsen, G.; Witte, D. R.; Witteman, J. C.; Xu, J.; Zhang, Q.; Zgaga, L.; Ziegler, A.; Zitting, P.; Beilby, J. P.; Farooqi, I. S.; Hebebrand, J.; Huikuri, H. V.; James, A. L.; Kahonen, M.; Levinson, D. F.; Macciardi, F.; Nieminen, M. S.; Ohlsson, C.; Palmer, L. J.; Ridker, P. M.; Stumvoll, M.; Beckmann, J. S.; Boeing, H.; Boerwinkle, E.; Boomsma, D. I.; Caulfield, M. J.; Chanock, S. J.; Collins, F. S.; Cupples, L. A.; Smith, G. D.; Erdmann, J.; Froguel, P.; Gronberg, H.; Gyllensten, U.; Hall, P.; Hansen, T.; Harris, T. B.; Hattersley, A. T.; Hayes, R. B.; Heinrich, J.; Hu, F. B.; Hveem, K.; Illig, T.; Jarvelin, M. R.; Kaprio, J.; Karpe, F.; Khaw, K. T.; Kiemeney, L. A.; Krude, H.; Laakso, M.; Lawlor, D. A.; Metspalu, A.; Munroe, P. B.; Ouwehand, W. H.; Pedersen, O.; Penninx, B. W.; Peters, A.; Pramstaller, P. P.; Quertermous, T.; Reinehr, T.; Rissanen, A.; Rudan, I.; Samani, N. J.; Schwarz, P. E.; Shuldiner, A. R.; Spector, T. D.; Tuomilehto, J.; Uda, M.; Uitterlinden, A.; Valle, T. T.; Wabitsch, M.; Waeber, G.; Wareham, N. J.; Watkins, H.; Wilson, J. F.; Wright, A. F.; Zillikens, M. C.; Chatterjee, N.; McCarroll, S. A.; Purcell, S.; Schadt, E. E.; Visscher, P. M.; Assimes, T. L.; Borecki, I. B.; Deloukas, P.; Fox, C. S.; Groop, L. C.; Haritunians, T.; Hunter, D. J.; Kaplan, R. C.; Mohlke, K. L.; O'Connell, J. R.; Peltonen, L.; Schlessinger, D.; Strachan, D. P.; van Duijn, C. M.; Wichmann, H. E.; Frayling, T. M.; Thorsteinsdottir, U.; Abecasis, G. R.; Barroso, I.; Boehnke, M.; Stefansson, K.; North, K. E.; M, I. McCarthy; Hirschhorn, J. N.; Ingelsson, E.; Loos, R. J. (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index Nat Genet, 39 , [Journal Article] Online
Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
PubMed Accession Number :: 20935630.

Heid, I. M.; Jackson, A. U.; Randall, J. C.; Winkler, T. W.; Qi, L.; Steinthorsdottir, V.; Thorleifsson, G.; Zillikens, M. C.; Speliotes, E. K.; Magi, R.; Workalemahu, T.; White, C. C.; Bouatia-Naji, N.; Harris, T. B.; Berndt, S. I.; Ingelsson, E.; Willer, C. J.; Weedon, M. N.; Luan, J.; Vedantam, S.; Esko, T.; Kilpelainen, T. O.; Kutalik, Z.; Li, S.; Monda, K. L.; Dixon, A. L.; Holmes, C. C.; Kaplan, L. M.; Liang, L.; Min, J. L.; Moffatt, M. F.; Molony, C.; Nicholson, G.; Schadt, E. E.; Zondervan, K. T.; Feitosa, M. F.; Ferreira, T.; Allen, H. L.; Weyant, R. J.; Wheeler, E.; Wood, A. R.; Estrada, K.; Goddard, M. E.; Lettre, G.; Mangino, M.; Nyholt, D. R.; Purcell, S.; Smith, A. V.; Visscher, P. M.; Yang, J.; McCarroll, S. A.; Nemesh, J.; Voight, B. F.; Absher, D.; Amin, N.; Aspelund, T.; Coin, L.; Glazer, N. L.; Hayward, C.; Heard-Costa, N. L.; Hottenga, J. J.; Johansson, A.; Johnson, T.; Kaakinen, M.; Kapur, K.; Ketkar, S.; Knowles, J. W.; Kraft, P.; Kraja, A. T.; Lamina, C.; Leitzmann, M. F.; McKnight, B.; Morris, A. P.; Ong, K. K.; Perry, J. R.; Peters, M. J.; Polasek, O.; Prokopenko, I.; Rayner, N. W.; Ripatti, S.; Rivadeneira, F.; Robertson, N. R.; Sanna, S.; Sovio, U.; Surakka, I.; Teumer, A.; van Wingerden, S.; Vitart, V.; Zhao, J. H.; Cavalcanti-Proenca, C.; Chines, P. S.; Fisher, E.; Kulzer, J. R.; Lecoeur, C.; Narisu, N.; Sandholt, C.; Scott, L. J.; Silander, K.; Stark, K.; Tammesoo, M. L.; Teslovich, T. M.; Timpson, N. J.; Watanabe, R. M.; Welch, R.; Chasman, D. I.; Cooper, M. N.; Jansson, J. O.; Kettunen, J.; Lawrence, R. W.; Pellikka, N.; Perola, M.; Vandenput, L.; Alavere, H.; Almgren, P.; Atwood, L. D.; Bennett, A. J.; Biffar, R.; Bonnycastle, L. L.; Bornstein, S. R.; Buchanan, T. A.; Campbell, H.; Day, I. N.; Dei, M.; Dorr, M.; Elliott, P.; Erdos, M. R.; Eriksson, J. G.; Freimer, N. B.; Fu, M.; Gaget, S.; Geus, E. J.; Gjesing, A. P.; Grallert, H.; Grassler, J.; Groves, C. J.; Guiducci, C.; Hartikainen, A. L.; Hassanali, N.; Havulinna, A. S.; Herzig, K. H.; Hicks, A. A.; Hui, J.; Igl, W.; Jousilahti, P.; Jula, A.; Kajantie, E.; Kinnunen, L.; Kolcic, I.; Koskinen, S.; Kovacs, P.; Kroemer, H. K.; Krzelj, V.; Kuusisto, J.; Kvaloy, K.; Laitinen, J.; Lantieri, O.; Lathrop, G. M.; Lokki, M. L.; Luben, R. N.; Ludwig, B.; McArdle, W. L.; McCarthy, A.; Morken, M. A.; Nelis, M.; Neville, M. J.; Pare, G.; Parker, A. N.; Peden, J. F.; Pichler, I.; Pietilainen, K. H.; Platou, C. G.; Pouta, A.; Ridderstrale, M.; Samani, N. J.; Saramies, J.; Sinisalo, J.; Smit, J. H.; Strawbridge, R. J.; Stringham, H. M.; Swift, A. J.; Teder-Laving, M.; Thomson, B.; Usala, G.; van Meurs, J. B.; van Ommen, G. J.; Vatin, V.; Volpato, C. B.; Wallaschofski, H.; Walters, G. B.; Widen, E.; Wild, S. H.; Willemsen, G.; Witte, D. R.; Zgaga, L.; Zitting, P.; Beilby, J. P.; James, A. L.; Kahonen, M.; Lehtimaki, T.; Nieminen, M. S.; Ohlsson, C.; Palmer, L. J.; Raitakari, O.; Ridker, P. M.; Stumvoll, M.; Tonjes, A.; Viikari, J.; Balkau, B.; Ben-Shlomo, Y.; Bergman, R. N.; Boeing, H.; Smith, G. D.; Ebrahim, S.; Froguel, P.; Hansen, T.; Hengstenberg, C.; Hveem, K.; Isomaa, B.; Jorgensen, T.; Karpe, F.; Khaw, K. T.; Laakso, M.; Lawlor, D. A.; Marre, M.; Meitinger, T.; Metspalu, A.; Midthjell, K.; Pedersen, O.; Salomaa, V.; Schwarz, P. E.; Tuomi, T.; Tuomilehto, J.; Valle, T. T.; Wareham, N. J.; Arnold, A. M.; Beckmann, J. S.; Bergmann, S.; Boerwinkle, E.; Boomsma, D. I.; Caulfield, M. J.; Collins, F. S.; Eiriksdottir, G.; Gudnason, V.; Gyllensten, U.; Hamsten, A.; Hattersley, A. T.; Hofman, A.; Hu, F. B.; Illig, T.; Iribarren, C.; Jarvelin, M. R.; Kao, W. H.; Kaprio, J.; Launer, L. J.; Munroe, P. B.; Oostra, B.; Penninx, B. W.; Pramstaller, P. P.; Psaty, B. M.; Quertermous, T.; Rissanen, A.; Rudan, I.; Shuldiner, A. R.; Soranzo, N.; Spector, T. D.; Syvanen, A. C.; Uda, M.; Uitterlinden, A.; Volzke, H.; Vollenweider, P.; Wilson, J. F.; Witteman, J. C.; Wright, A. F.; Abecasis, G. R.; Boehnke, M.; Borecki, I. B.; Deloukas, P.; Frayling, T. M.; Groop, L. C.; Haritunians, T.; Hunter, D. J.; Kaplan, R. C.; North, K. E.; O'Connell, J. R.; Peltonen, L.; Schlessinger, D.; Strachan, D. P.; Hirschhorn, J. N.; Assimes, T. L.; Wichmann, H. E.; Thorsteinsdottir, U.; van Duijn, C. M.; Stefansson, K.; Cupples, L. A.; Loos, R. J.; Barroso, I.; McCarthy, M. I.; Fox, C. S.; Mohlke, K. L.; Lindgren, C. M. (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution Nat Genet, 49 ,949-960 [Journal Article] Online
Abstract: Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 x 10(-9) to P = 1.8 x 10(-40)) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 x 10(-3) to P = 1.2 x 10(-13)). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
PubMed Accession Number :: 20935629.

Marteau, T. M.; French, D. P.; Griffin, S. J.; Prevost, A. T.; Sutton, S.; Watkinson, C.; Attwood, S.; Hollands, G. J. (2010) Effects of communicating DNA-based disease risk estimates on risk-reducing behaviours Cochrane Database Syst Rev, 10 ,CD007275 [Journal Article] Online
Abstract: BACKGROUND: There are high expectations regarding the potential for the communication of DNA-based disease risk estimates to motivate behaviour change. OBJECTIVES: To assess the effects of communicating DNA-based disease risk estimates on risk-reducing behaviours and motivation to undertake such behaviours. SEARCH STRATEGY: We searched the following databases using keywords and medical subject headings: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4 2010), MEDLINE (1950 to April 2010), EMBASE (1980 to April 2010), PsycINFO (1985 to April 2010) using OVID SP, and CINAHL (EBSCO) (1982 to April 2010). We also searched reference lists, conducted forward citation searches of potentially eligible articles and contacted authors of relevant studies for suggestions. There were no language restrictions. Unpublished or in press articles were eligible for inclusion. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials involving adults (aged 18 years and over) in which one group received actual (clinical studies) or imagined (analogue studies) personalised DNA-based disease risk estimates for diseases for which the risk could plausibly be reduced by behavioural change. Eligible studies had to include a primary outcome measure of risk-reducing behaviour or motivation (e.g. intention) to alter such behaviour. DATA COLLECTION AND ANALYSIS: Two review authors searched for studies and independently extracted data. We assessed risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. For continuous outcome measures, we report effect sizes as standardised mean differences (SMDs). For dichotomous outcome measures, we report effect sizes as odds ratios (ORs). We obtained pooled effect sizes with 95% confidence intervals (CIs) using the random effects model applied on the scale of standardised differences and log odds ratios. MAIN RESULTS: We examined 5384 abstracts and identified 21 studies as potentially eligible. Following a full text analysis, we included 14 papers reporting results of 7 clinical studies (2 papers report on the same trial) and 6 analogue studies.Of the seven clinical studies, five assessed smoking cessation. Meta-analyses revealed no statistically significant effects on either short-term (less than 6 months) smoking cessation (OR 1.35, 95% CI 0.76 to 2.39, P = 0.31, n = 3 studies) or cessation after six months (OR 1.07, 95% CI 0.64 to 1.78, P = 0.80, n = 4 studies). Two clinical studies assessed diet and found effects that significantly favoured DNA-based risk estimates (OR 2.24, 95% CI 1.17 to 4.27, P = 0.01). No statistically significant effects were found in the two studies assessing physical activity (OR 1.03, 95% CI 0.59 to 1.80, P = 0.92) or the one study assessing medication or vitamin use aimed at reducing disease risks (OR 1.26, 95% CI 0.58 to 2.72, P = 0.56). For the six non-clinical analogue studies, meta-analysis revealed a statistically significant effect of DNA-based risk on intention to change behaviour (SMD 0.16, 95% CI 0.04 to 0.29, P = 0.01).There was no evidence that communicating DNA-based disease risk estimates had any unintended adverse effects. Two studies that assessed fear arousal immediately after the presentation of risk information did, however, report greater fear arousal in the DNA-based disease risk estimate groups compared to comparison groups.The quality of included studies was generally poor. None of the clinical or analogue studies were considered to have a low risk of bias, due to either a lack of clarity in reporting, or where details were reported, evidence of a failure to sufficiently safeguard against the risk of bias. AUTHORS' CONCLUSIONS: Mindful of the weak evidence based on a small number of studies of limited quality, the results of this review suggest that communicating DNA-based disease risk estimates has little or no effect on smoking and physical activity. It may have a small effect on self-reported diet and on intentions to change behaviour. Claims that receiving DNA-based test results motivates people to change their behaviour are not supported by evidence. Larger and better-quality RCTs are needed.
PubMed Accession Number :: 20927756.

Ridgway, C. L.; Brage, S.; Anderssen, S. A.; Sardinha, L. B.; Andersen, L. B.; Ekelund, U. (2010) Does physical activity and aerobic fitness moderate the association between birth weight and metabolic risk in youth? The European Youth Heart Study Diabetes Care, , [Journal Article] Online
Abstract: AbstractObjective: Lower birth weight has been associated with greater risk of metabolic diseases. This study aimed to examine whether physical activity and aerobic fitness may modify associations between birth weigh and metabolic risk. Research Design and Methods: The European Youth Heart Study is a population based study of 9 and 15 year olds (n=1,254). Birth weight was maternally reported. Skin fold measures were used to calculate body fat and Fat Mass Index (FMI=fat mass(kg)/height(2)). Insulin was measured using fasting blood samples. Physical activity was measured using a hip worn accelerometer (MTI Actigraph) for >600 minutes/day for >/=3 days, and expressed as 'average activity' (counts per minute) and time spent in above moderate intensity activity (MVPA, >2000 cpm). Aerobic fitness was assessed using a maximal cycle ergometry test (watts/kg FFM). Results: Higher birth weight was associated with higher FMI (ss=0.49, 95%CI: 0.21, 0.80, p=0.001) and greater waist circumference (ss=0.90, 95%CI: 0.32, 1.47, p<0.001), adjusted for sex, age group, sexual maturity, height and SES. Lower birth weight was associated with higher fasting insulin only after further adjustment for adolescent waist circumference and height (ss=-0.059, 95%CI: -0.107, -0.011 p=0.016). There was no evidence for any modification of the associations following adjustment for physical activity or aerobic fitness. Conclusions: The present study did not find any evidence that physical activity or aerobic fitness can moderate the associations between higher birth weight and increased fat mass and greater waist circumference, or between lower birth weight and insulin resistance, in healthy children and adolescents.
PubMed Accession Number :: 20921217.

Simmons, R. K.; Echouffo-Tcheugui, J. B.; Griffin, S. J. (2010) Screening for type 2 diabetes: an update of the evidence Diabetes Obes Metab, 12 (10),838-44 [Journal Article] Online
Abstract: A growing body of evidence on diabetes screening has been published during the last 10 years. Type 2 diabetes meets many but not all of the criteria for screening. Concerns about potential harms of screening have largely been resolved. Screening identifies a high-risk population with the potential to gain from widely available interventions. However, in spite of the findings of modelling studies, the size of the benefit of earlier initiation of treatment and the overall cost-effectiveness remains uncertain, in contrast to other screening programmes (such as for abdominal aortic aneurysms) that are yet to be fully implemented. There is also uncertainty about optimal specifications and implementation of a screening programme, and further work to complete concerning development and delivery of individual- and population-level preventive strategies. While there is growing evidence of the net benefit of earlier detection of individuals with prevalent but undiagnosed diabetes, there remains limited justification for a policy of universal population-based screening for type 2 diabetes at the present time. Data from ongoing studies should inform the key assumptions in existing modelling studies and further reduce uncertainty.
PubMed Accession Number :: 20920035.

Lakshman, R.; McConville, A.; How, S.; Flowers, J.; Wareham, N.; Cosford, P. (2010) Association between area-level socioeconomic deprivation and a cluster of behavioural risk factors: cross-sectional, population-based study J Public Health (Oxf), , [Journal Article] Online
Abstract: BACKGROUND: The Commission on Social Determinants of Health has urged governments across the world to promote health equity by reducing the gap between the most and least deprived individuals in society. Some of this gap can be bridged by promoting healthy lifestyles through targeted Public Health policy and interventions. METHODS: Cross-sectional analyses of data on behavioural risk factors, individual socioeconomic factors and neighbourhood deprivation score collected from 26 290 adults aged over 16 years who participated in the 2008 East of England Lifestyle Survey. RESULTS: After adjustment for individual socioeconomic factors, across quintiles of increasing neighbourhood deprivation, participants were more likely to smoke and less likely to consume five portions of fruit and vegetables on five or more days of the week (least deprived versus most deprived quintile: odds ratios for not smoking 0.45 (0.41-0.50); and fruit and vegetable consumption 0.70 (0.64-0.76), P-trend <0.0001). Greater neighbourhood deprivation and lower occupational social class were independently associated with a lower summary healthy lifestyle score (both P-trend <0.0001). CONCLUSIONS: Public health interventions aimed at reducing health inequalities by targeting behavioural risk factors may focus in particular on reducing smoking and increasing fruit and vegetable consumption in more deprived communities.
PubMed Accession Number :: 20884643.

Lango Allen, H.; Estrada, K.; Lettre, G.; Berndt, S. I.; Weedon, M. N.; Rivadeneira, F.; Willer, C. J.; Jackson, A. U.; Vedantam, S.; Raychaudhuri, S.; Ferreira, T.; Wood, A. R.; Weyant, R. J.; Segre, A. V.; Speliotes, E. K.; Wheeler, E.; Soranzo, N.; Park, J. H.; Yang, J.; Gudbjartsson, D.; Heard-Costa, N. L.; Randall, J. C.; Qi, L.; Vernon Smith, A.; Magi, R.; Pastinen, T.; Liang, L.; Heid, I. M.; Luan, J.; Thorleifsson, G.; Winkler, T. W.; Goddard, M. E.; Sin Lo, K.; Palmer, C.; Workalemahu, T.; Aulchenko, Y. S.; Johansson, A.; Carola Zillikens, M.; Feitosa, M. F.; Esko, T.; Johnson, T.; Ketkar, S.; Kraft, P.; Mangino, M.; Prokopenko, I.; Absher, D.; Albrecht, E.; Ernst, F.; Glazer, N. L.; Hayward, C.; Hottenga, J. J.; Jacobs, K. B.; Knowles, J. W.; Kutalik, Z.; Monda, K. L.; Polasek, O.; Preuss, M.; Rayner, N. W.; Robertson, N. R.; Steinthorsdottir, V.; Tyrer, J. P.; Voight, B. F.; Wiklund, F.; Xu, J.; Hua Zhao, J.; Nyholt, D. R.; Pellikka, N.; Perola, M.; Perry, J. R.; Surakka, I.; Tammesoo, M. L.; Altmaier, E. L.; Amin, N.; Aspelund, T.; Bhangale, T.; Boucher, G.; Chasman, D. I.; Chen, C.; Coin, L.; Cooper, M. N.; Dixon, A. L.; Gibson, Q.; Grundberg, E.; Hao, K.; Juhani Junttila, M.; Kaplan, L. M.; Kettunen, J.; Konig, I. R.; Kwan, T.; Lawrence, R. W.; Levinson, D. F.; Lorentzon, M.; McKnight, B.; Morris, A. P.; Muller, M.; Suh Ngwa, J.; Purcell, S.; Rafelt, S.; Salem, R. M.; Salvi, E.; Sanna, S.; Shi, J.; Sovio, U.; Thompson, J. R.; Turchin, M. C.; Vandenput, L.; Verlaan, D. J.; Vitart, V.; White, C. C.; Ziegler, A.; Almgren, P.; Balmforth, A. J.; Campbell, H.; Citterio, L.; De Grandi, A.; Dominiczak, A.; Duan, J.; Elliott, P.; Elosua, R.; Eriksson, J. G.; Freimer, N. B.; Geus, E. J.; Glorioso, N.; Haiqing, S.; Hartikainen, A. L.; Havulinna, A. S.; Hicks, A. A.; Hui, J.; Igl, W.; Illig, T.; Jula, A.; Kajantie, E.; Kilpelainen, T. O.; Koiranen, M.; Kolcic, I.; Koskinen, S.; Kovacs, P.; Laitinen, J.; Liu, J.; Lokki, M. L.; Marusic, A.; Maschio, A.; Meitinger, T.; Mulas, A.; Pare, G.; Parker, A. N.; Peden, J. F.; Petersmann, A.; Pichler, I.; Pietilainen, K. H.; Pouta, A.; Ridderstrale, M.; Rotter, J. I.; Sambrook, J. G.; Sanders, A. R.; Oliver Schmidt, C.; Sinisalo, J.; Smit, J. H.; Stringham, H. M.; Bragi Walters, G.; Widen, E.; Wild, S. H.; Willemsen, G.; Zagato, L.; Zgaga, L.; Zitting, P.; Alavere, H.; Farrall, M.; McArdle, W. L.; Nelis, M.; Peters, M. J.; Ripatti, S.; van Meurs, J. B.; Aben, K. K.; Ardlie, K. G.; Beckmann, J. S.; Beilby, J. P.; Bergman, R. N.; Bergmann, S.; Collins, F. S.; Cusi, D.; den Heijer, M.; Eiriksdottir, G.; Gejman, P. V.; Hall, A. S.; Hamsten, A.; Huikuri, H. V.; Iribarren, C.; Kahonen, M.; Kaprio, J.; Kathiresan, S.; Kiemeney, L.; Kocher, T.; Launer, L. J.; Lehtimaki, T.; Melander, O.; Mosley Jr, T. H.; Musk, A. W.; Nieminen, M. S.; O'Donnell, C. J.; Ohlsson, C.; Oostra, B.; Palmer, L. J.; Raitakari, O.; Ridker, P. M.; Rioux, J. D.; Rissanen, A.; Rivolta, C.; Schunkert, H.; Shuldiner, A. R.; Siscovick, D. S.; Stumvoll, M.; Tonjes, A.; Tuomilehto, J.; van Ommen, G. J.; Viikari, J.; Heath, A. C.; Martin, N. G.; Montgomery, G. W.; Province, M. A.; Kayser, M.; Arnold, A. M.; Atwood, L. D.; Boerwinkle, E.; Chanock, S. J.; Deloukas, P.; Gieger, C.; Gronberg, H.; Hall, P.; Hattersley, A. T.; Hengstenberg, C.; Hoffman, W.; Mark Lathrop, G.; Salomaa, V.; Schreiber, S.; Uda, M.; Waterworth, D.; Wright, A. F.; Assimes, T. L.; Barroso, I.; Hofman, A.; Mohlke, K. L.; Boomsma, D. I.; Caulfield, M. J.; Adrienne Cupples, L.; Erdmann, J.; Fox, C. S.; Gudnason, V.; Gyllensten, U.; Harris, T. B.; Hayes, R. B.; Jarvelin, M. R.; Mooser, V.; Munroe, P. B.; Ouwehand, W. H.; Penninx, B. W.; Pramstaller, P. P.; Quertermous, T.; Rudan, I.; Samani, N. J.; Spector, T. D.; Volzke, H.; Watkins, H.; Wilson, J. F.; Groop, L. C.; Haritunians, T.; Hu, F. B.; Kaplan, R. C.; Metspalu, A.; North, K. E.; Schlessinger, D.; Wareham, N. J.; Hunter, D. J.; O'Connell, J. R.; Strachan, D. P.; Wichmann, H. E.; Borecki, I. B.; van Duijn, C. M.; Schadt, E. E.; Thorsteinsdottir, U.; Peltonen, L.; Uitterlinden, A. G.; Visscher, P. M.; Chatterjee, N.; Loos, R. J.; Boehnke, M.; McCarthy, M. I.; Ingelsson, E.; Lindgren, C. M.; Abecasis, G. R.; Stefansson, K.; Frayling, T. M.; Hirschhorn, J. N. (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height Nature, 467 ,832-838 [Journal Article] Online
Abstract: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
PubMed Accession Number :: 20881960.

Hallal, P.; Ekelund, U. (2010) CRF, MVPA, NEAT, PAEE, and Now Sedentary Time: Will the Pendulum Swing Back Again? J Phys Act Health, 7 (5),569-70 [Journal Article] Online
Abstract: Scientific knowledge is constantly progressing- today faster than ever before-and physical activity epidemiology research is no exception. Over the last 30 years this research area has expanded its focus beyond vigorous-intensity structured exercise to also incorporate moderate-to-vigorous intensity physical activity (MVPA). As a consequence, the public health goal slowly shifted from improving cardio-respiratory fitness (CRF) to include physical activity promotion.
PubMed Accession Number :: 20864750.

Waterworth, D. M.; Ricketts, S. L.; Song, K.; Chen, L.; Zhao, J. H.; Ripatti, S.; Aulchenko, Y. S.; Zhang, W.; Yuan, X.; Lim, N.; Luan, J.; Ashford, S.; Wheeler, E.; Young, E. H.; Hadley, D.; Thompson, J. R.; Braund, P. S.; Johnson, T.; Struchalin, M.; Surakka, I.; Luben, R.; Khaw, K. T.; Rodwell, S. A.; Loos, R. J.; Boekholdt, S. M.; Inouye, M.; Deloukas, P.; Elliott, P.; Schlessinger, D.; Sanna, S.; Scuteri, A.; Jackson, A.; Mohlke, K. L.; Tuomilehto, J.; Roberts, R.; Stewart, A.; Kesaniemi, Y. A.; Mahley, R. W.; Grundy, S. M.; McArdle, W.; Cardon, L.; Waeber, G.; Vollenweider, P.; Chambers, J. C.; Boehnke, M.; Abecasis, G. R.; Salomaa, V.; Jarvelin, M. R.; Ruokonen, A.; Barroso, I.; Epstein, S. E.; Hakonarson, H. H.; Rader, D. J.; Reilly, M. P.; Witteman, J. C.; Hall, A. S.; Samani, N. J.; Strachan, D. P.; Barter, P.; van Duijn, C. M.; Kooner, J. S.; Peltonen, L.; Wareham, N. J.; McPherson, R.; Mooser, V.; Sandhu, M. S. (2010) Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease Arterioscler Thromb Vasc Biol, 30 ,2264-2276 [Journal Article] Online
Abstract: OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6x10(-8) to 3.1x10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1x10(-3) to 1.2x10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
PubMed Accession Number :: 20864672.

van den Borst, B.; Souren, N. Y.; Gielen, M.; Loos, R. J.; Paulussen, A. D.; Derom, C.; Schols, A. M.; Zeegers, M. P. (2010) Association between the IL6 -174G/C SNP and maximally attained lung function Thorax, , [Journal Article] Online
PubMed Accession Number :: 20864574.

Patel, P. S.; Sharp, S. J.; Jansen, E.; Luben, R. N.; Khaw, K. T.; Wareham, N. J.; Forouhi, N. G. (2010) Fatty acids measured in plasma and erythrocyte-membrane phospholipids and derived by food-frequency questionnaire and the risk of new-onset type 2 diabetes: a pilot study in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort Am J Clin Nutr, 92 ,1214-1222 [Journal Article] Online
Abstract: BACKGROUND: Epidemiologic evidence for the association between types of fatty acid and risk of type 2 diabetes is inconsistent. This may in part be due to the limitations of fatty acid measurement methods. OBJECTIVE: The objective was to use 3 different measures of fatty acid to estimate the prospective association between fatty acid composition and development of incident diabetes. DESIGN: We analyzed 199 cases of clinically incident diabetes and 184 noncases aged 40-79 y at baseline in the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study. Fatty acids were derived from a food-frequency questionnaire (FFQ) and measured in plasma phospholipid (P-FA) and erythrocyte-membrane phospholipid (Ery-FA) fractions by gas chromatography. RESULTS: There were stronger associations with diabetes risk with the use of objectively measured fatty acids (P-FA and Ery-FA) than with the FFQ in analyses adjusted for age, sex, and potential confounders. Positive associations with diabetes were greater in magnitude with the use of P-FA than with Ery-FA (highest:lowest tertiles): for example, the palmitic acid odds ratios (ORs) were 2.47 (95% CI: 1.37, 4.46) and 1.96 (95% CI: 1.10,3.49), respectively. Inverse associations with diabetes were also stronger with the use of P-FA than with Ery-FA: for example, the OR for linoleic acid was 0.50 (95% CI: 0.28, 0.91) compared with 0.77 (95% CI: 0.43, 1.37), respectively. CONCLUSIONS: The objective measurement of fatty acids with the use of either P-FA or Ery-FA identifies important associations with diabetes incidence that may be missed when assessed by FFQ. Fatty acids measured in P-FA appear to be more strongly associated with diabetes incidence. These findings endorse the use of objective measurement of fatty acids for nutritional-epidemiologic studies, and the apparently stronger findings for the plasma fraction should be confirmed in larger studies and in different populations.
PubMed Accession Number :: 20861175.

Welch, A. A.; Shakya-Shrestha, S.; Lentjes, M. A.; Wareham, N. J.; Khaw, K. T. (2010) Dietary intake and status of n-3 polyunsaturated fatty acids in a population of fish-eating and non-fish-eating meat-eaters, vegetarians, and vegans and the precursor-product ratio of {alpha}-linolenic acid to long-chain n-3 polyunsaturated fatty acids: results from the EPIC-Norfolk cohort Am J Clin Nutr, 92 ,1040-1051 [Journal Article] Online
Abstract: BACKGROUND: Intakes of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) are important for health. Because fish is the major source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), non-fish-eaters may have suboptimal n-3 PUFA status, although the importance of the conversion of plant-derived alpha-linolenic acid (ALA) to EPA and DHA is debated. OBJECTIVE: The objective was to determine intakes, food sources, and status of n-3 PUFAs according to dietary habit (fish-eaters and non-fish-eating meat-eaters, vegetarians, or vegans) and estimated conversion between dietary ALA and circulating long-chain n-3 PUFAs. DESIGN: This study included 14,422 men and women aged 39-78 y from the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk cohort with 7-d diary data and a substudy in 4902 individuals with plasma phospholipid fatty acid measures. Intakes and status of n-3 PUFAs were measured, and the precursor-product ratio of ALA to circulating n-3 PUFAs was calculated. RESULTS: Most of the dietary intake of EPA and DHA was supplied by fish; however, meat was the major source in meat-eaters, and spreading fats, soups, and sauces were the major sources in vegetarians. Total n-3 PUFA intakes were 57-80% lower in non-fish-eaters than in fish-eaters, but status differences were considerably smaller. The estimated precursor-product ratio was greater in women than in men and greater in non-fish-eaters than in fish-eaters. CONCLUSIONS: Substantial differences in intakes and in sources of n-3 PUFAs existed between the dietary-habit groups, but the differences in status were smaller than expected, possibly because the precursor-product ratio was greater in non-fish-eaters than in fish-eaters, potentially indicating increased estimated conversion of ALA. If intervention studies were to confirm these findings, it could have implications for fish requirements.
PubMed Accession Number :: 20861171.

Chamnan, P.; Simmons, R. K.; Jackson, R.; Khaw, K. T.; Wareham, N. J.; Griffin, S. J. (2010) Non-diabetic hyperglycaemia and cardiovascular risk: moving beyond categorisation to individual interpretation of absolute risk Diabetologia, , [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Non-diabetic hyperglycaemia is usually not considered at all or is viewed as a binary risk category in isolation from other factors when quantifying cardiovascular risk. We argue that hyperglycaemia should be considered as a continuous risk factor and only in the context of other vascular risk factors. To examine the potential impact of hyperglycaemia on cardiovascular disease (CVD) risk, we calculated the absolute CVD risk in groups defined by different levels of HbA(1c) and other CVD risk factors. METHODS: We used data on 10,144 men and women from the European Prospective Investigation of Cancer-Norfolk cohort to calculate CVD rates across levels of HbA(1c) in groups characterised by different levels of traditional risk factors. RESULTS: We found significant differences in CVD rates across levels of HbA(1c) in groups defined by different levels of the other risk factors. CVD rates for non-diabetic individuals with an HbA(1c) of <5.5% increased from 0.6 (95% CI 0.3-1.2) to 29.6 (95% CI 14.8-59.1) per 1,000 person-years when traditional CVD risk factors were added sequentially to the lowest risk reference group. In most cases, non-diabetic individuals with an HbA(1c) of <5.5% and high values for all other CVD risk factors had substantially higher absolute CVD rates than those with an HbA(1c) of 6.0% to 6.4% but with no other raised CVD risk factors (29.6 [95% CI 14.8-59.1] and 2.5 [95% CI 0.4-18.1], respectively). A history of diabetes significantly increased CVD risk over the non-diabetic hyperglycaemia range. Comparisons of CVD rates across tertiles of total cholesterol:HDL-cholesterol ratio or mean systolic blood pressure in groups characterised by different levels of other risk factors showed similar findings. CONCLUSIONS/INTERPRETATION: In people with non-diabetic hyperglycaemia, cardiovascular risk is highly dependent on the presence of other CVD risk factors. Attention should be given not to whether an individual has 'pre-diabetes', 'hypertension' or 'hypercholesterolaemia', but to an integrated assessment of CVD risk, based on the combination of risk factors present and potential benefits of treatment.
PubMed Accession Number :: 20859613.

Soranzo, N.; Sanna, S.; Wheeler, E.; Gieger, C.; Radke, D.; Dupuis, J.; Bouatia-Naji, N.; Langenberg, C.; Prokopenko, I.; Stolerman, E.; Sandhu, M. S.; Heeney, M. M.; Devaney, J. M.; Reilly, M. P.; Ricketts, S. L.; Stewart, A. F.; Voight, B. F.; Willenborg, C.; Wright, B.; Altshuler, D.; Arking, D.; Balkau, B.; Barnes, D.; Boerwinkle, E.; Bohm, B.; Bonnefond, A.; Bonnycastle, L. L.; Boomsma, D. I.; Bornstein, S. R.; Bottcher, Y.; Bumpstead, S.; Burnett-Miller, M. S.; Campbell, H.; Cao, A.; Chambers, J.; Clark, R.; Collins, F. S.; Coresh, J.; de Geus, E. J.; Dei, M.; Deloukas, P.; Doring, A.; Egan, J. M.; Elosua, R.; Ferrucci, L.; Forouhi, N.; Fox, C. S.; Franklin, C.; Franzosi, M. G.; Gallina, S.; Goel, A.; Graessler, J.; Grallert, H.; Greinacher, A.; Hadley, D.; Hall, A.; Hamsten, A.; Hayward, C.; Heath, S.; Herder, C.; Homuth, G.; Hottenga, J. J.; Hunter-Merrill, R.; Illig, T.; Jackson, A. U.; Jula, A.; Kleber, M.; Knouff, C. W.; Kong, A.; Kooner, J.; Kottgen, A.; Kovacs, P.; Krohn, K.; Kuhnel, B.; Kuusisto, J.; Laakso, M.; Lathrop, M.; Lecoeur, C.; Li, M.; Li, M.; Loos, R. J.; Luan, J.; Lyssenko, V.; Magi, R.; Magnusson, P. K.; Malarstig, A.; Mangino, M.; Martinez-Larrad, M. T.; Marz, W.; McArdle, W. L.; McPherson, R.; Meisinger, C.; Meitinger, T.; Melander, O.; Mohlke, K. L.; Mooser, V. E.; Morken, M. A.; Narisu, N.; Nathan, D. M.; Nauck, M.; O'Donnell, C.; Oexle, K.; Olla, N.; Pankow, J. S.; Payne, F.; Peden, J. F.; Pedersen, N. L.; Peltonen, L.; Perola, M.; Polasek, O.; Porcu, E.; Rader, D. J.; Rathmann, W.; Ripatti, S.; Rocheleau, G.; Roden, M.; Rudan, I.; Salomaa, V.; Saxena, R.; Schlessinger, D.; Schunkert, H.; Schwarz, P.; Seedorf, U.; Selvin, E.; Serrano-Rios, M.; Shrader, P.; Silveira, A.; Siscovick, D.; Song, K.; Spector, T. D.; Stefansson, K.; Steinthorsdottir, V.; Strachan, D. P.; Strawbridge, R.; Stumvoll, M.; Surakka, I.; Swift, A. J.; Tanaka, T.; Teumer, A.; Thorleifsson, G.; Thorsteinsdottir, U.; Tonjes, A.; Usala, G.; Vitart, V.; Volzke, H.; Wallaschofski, H.; Waterworth, D. M.; Watkins, H.; Wichmann, H. E.; Wild, S. H.; Willemsen, G.; Williams, G. H.; Wilson, J. F.; Winkelmann, J.; Wright, A. F.; Zabena, C.; Zhao, J. H.; Epstein, S. E.; Erdmann, J.; Hakonarson, H. H.; Kathiresan, S.; Khaw, K. T.; Roberts, R.; Samani, N. J.; Fleming, M. D.; Sladek, R.; Abecasis, G.; Boehnke, M.; Froguel, P.; Groop, L.; McCarthy, M. I.; Kao, W. H.; Florez, J. C.; Uda, M.; Wareham, N. J.; Barroso, I.; Meigs, J. B. (2010) Common variants at ten genomic loci influence hemoglobin A1C levels via glycemic and non-glycemic pathways Diabetes, , [Journal Article] Online
Abstract: AbstractObjective - Glycated hemoglobin (HbA(1C)), used to monitor and diagnose diabetes, is influenced by average glycemia over 2-3 months. Genetic factors affecting expression, turnover and abnormal glycation of hemoglobin could also be associated with increased levels of HbA(1C). It is uncertain to what extent such genetic variation influences diabetes classification based on HbA(1C) levels. Research Design and Methods - We studied associations with HbA(1C) in up to 46,368 non-diabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA(1C) loci using a multi-locus risk score, and used net reclassification to estimate genetic effects on diabetes screening. Results - Ten loci reached genome-wide significant association with HbA(1C), including six new loci near FN3K (lead SNP/P-value, rs1046896/P=1.6x10(-26)), HFE (rs1800562/P=2.6x10(-20)), TMPRSS6 (rs855791/P=2.7x10(-14)), ANK1 (rs4737009/P=6.1x10(-12)), SPTA1 (rs2779116/P=2.8x10(-9)) and ATP11A/TUBGCP3 (rs7998202/P=5.2x10(-9)), and four known HbA(1C) loci: HK1 (rs16926246/P=3.1x10(-54)), MTNR1B (rs1387153/P=4.0x10(-11)), GCK (rs1799884/P=1.5x10(-20)) and G6PC2/ABCB11 (rs552976/P=8.2x10(-18)). We show that associations with HbA(1C) are partly a function of hyperglycemia associated with three of the ten loci (GCK, G6PC2 and MTNR1B). The seven non-glycemic loci accounted for a 0.19 (% HbA(1C)) difference between the extreme 10% tails of the risk score, and would reclassify approximately 2% of a general white population screened for diabetes with HbA(1C). Conclusions - GWAS identified ten genetic loci reproducibly associated with HbA(1C). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA(1C) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA(1C).
PubMed Accession Number :: 20858683.

Watkinson, C.; van Sluijs, E. M.; Sutton, S.; Hardeman, W.; Corder, K.; Griffin, S. J. (2010) Overestimation of physical activity level is associated with lower BMI: a cross-sectional analysis Int J Behav Nutr Phys Act, 7 (1),68 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Poor recognition of physical inactivity may be an important barrier to healthy behaviour change, but little is known about this phenomenon. We aimed to characterize a high-risk population according to the discrepancies between objective and self-rated physical activity (PA), defined as awareness. METHODS: An exploratory cross-sectional analysis of PA awareness using baseline data collected from 365 ProActive participants between 2001 and 2003 in East Anglia, England. Self-rated PA was defined as 'active' or 'inactive' (assessed via questionnaire). Objective PA was defined according to achievement of guideline activity levels (>30 minutes or <30 minutes spent at least moderate intensity PA, assessed by heart rate monitoring). Four awareness groups were created: 'Realistic Actives', 'Realistic Inactives', 'Overestimators' and 'Underestimators'. Logistic regression was used to assess associations between awareness group and 17 personal, social and biological correlates. RESULTS: 63.3% of participants (N=231) were inactive according to objective measurement. Of these, 45.9% rated themselves as active ('Overestimators'). In a multiple logistic regression model adjusted for age and smoking, males (OR=2.11, 95% CI=0.84, 0.95), those with lower BMI (OR=0.89, 95% CI=0.84, 0.95), younger age at completion of full-time education (OR=0.83, 95% CI=0.74, 0.93) and higher general health perception (OR=1.02 CI=1.00, 1.04) were more likely to overestimate their PA. CONCLUSIONS: Overestimation of PA is associated with favourable indicators of relative slimness and general health. Feedback about PA levels could help reverse misperceptions.
PubMed Accession Number :: 20854659.

Lee, C. C.; Stolk, R. P.; Adler, A. I.; Patel, A.; Chalmers, J.; Neal, B.; Poulter, N.; Harrap, S.; Woodward, M.; Marre, M.; Grobbee, D. E.; Beulens, J. W. (2010) Association between alcohol consumption and diabetic retinopathy and visual acuity-the AdRem Study Diabet Med, 27 (10),1130-1137 [Journal Article] Online
Abstract: Diabet. Med. 27, 1130-1137 (2010) ABSTRACT: Aims We investigated the association between alcohol consumption and diabetic retinopathy and deterioration of visual acuity in individuals with Type 2 diabetes. Methods We conducted a cohort analysis of 1239 participants with Type 2 diabetes aged 55-81 years enrolled in the AdRem study, a sub-study of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Current and past consumption of wine, spirits and beer was measured by self-report. Moderate and heavy alcohol consumption was defined as 1-14 and > 14 drinks/week, respectively. Diabetic retinopathy, measured by mydriatic stereoscopic seven-field retinal photography, was defined by a 2-step progression in the Early Treatment of Diabetic Retinopathy Study (ETDRS) score or the presence of any retinal vascular lesions. Deterioration of visual acuity was defined by a decrease of two lines in best vision in either eye, measured corrected, or through a pinhole using a Snellen chart. Results In a mean follow-up of 5.5 years, we identified 182 participants with a 2-step progression in the ETDRS score, 640 participants with the presence of any retinal vascular lesions and 693 participants with a deterioration of visual acuity. Current moderate consumption of alcohol, compared with no current consumption, was not associated with presence or progression of diabetic retinopathy; however, it was associated with higher risk of deterioration of visual acuity (multivariable-adjusted OR 1.83; 95% CI 1.34-2.48; P < 0.001). Conclusions Alcohol consumption is associated with increased risk of deterioration of visual acuity, but not with retinopathy in individuals with Type 2 diabetes.
PubMed Accession Number :: 20854380.

van Sluijs, E. M.; Jones, N. R.; Jones, A. P.; Sharp, S. J.; Harrison, F.; Griffin, S. J. (2010) School-level correlates of physical activity intensity in 10-year-old children Int J Pediatr Obes, , [Journal Article] Online
Abstract: Abstract Purpose. Little is known about school environmental factors that promote or inhibit activity, especially from studies using objective measures in large representative samples. We therefore aimed to study associations between activity intensities and physical and social school environmental factors. Methods. A population-based sample of 1 908 British children (SPEEDY study), mean age 10.3 years (Standard deviation [SD]: 0.3), recruited from 92 schools across Norfolk, UK, with valid activity data (assessed with Actigraph accelerometers). Outcome measures were school-based (8 am-4 pm on weekdays) time (in minutes) spent in sedentary (<100 counts/min), moderate (2 000-3 999 counts/min) and vigorous (>/=4 000 counts/min) activity. A total of 40 school physical and social environmental factors were assessed. Multivariable multilevel linear regression analyses adjusted for children's sex and body mass index were conducted; interactions with sex were investigated. Results. Availability of a 'Park and Stride' scheme was negatively associated with sedentary minutes (-7.74; 95% CI: -14.8; -0.70). Minutes of moderate activity were associated with the availability of a lollypop person (1.33, 95% CI: 0.35; 2.62) and objectively-assessed walking provision (1.70, 95% CI: 0.85; 2.56). The number of sports facilities of at least medium quality (0.47, 95% CI: 0.16; 0.79), not having a policy on physical activity (-2.28, 95% CI: -3.62; -0.95), and, in boys only, provision of pedestrian training (1.89; 95% CI: 0.77; 3.01) were associated with minutes of vigorous activity. Conclusions. Only a small number of school-level factors were associated with children's objectively-measured physical activity intensity, giving few pointers for potential future intervention efforts. Further research should focus on using objective measures to elucidate what factors may explain the school-level variance in activity levels.
PubMed Accession Number :: 20854106.

Liu, C.; Li, H.; Qi, Q.; Lu, L.; Gan, W.; Loos, R. J.; Lin, X. (2010) Common variants in or near FGF5, CYP17A1 and MTHFR genes are associated with blood pressure and hypertension in Chinese Hans J Hypertens, , [Journal Article] Online
Abstract: OBJECTIVES: Recent genome-wide association studies have identified a number of variants influencing blood pressure. We aimed to examine whether these associations can be replicated in Chinese. METHODS: We genotyped eight of these variants (in or near FGF5, CYP17A1, MTHFR, ZNF652, PLCD3, ATP2B1, c10orf107) in a population-based cohort of Chinese Hans (N = 3210). Logistics regression and generalized linear analyses were applied to test for association of each variant with hypertension risk and blood pressure (BP), BMI, waistline and high-sensitivity C-reactive protein (hsCRP), respectively. RESULTS: Six variants showed directionally consistent association with blood pressure and risk of hypertension, of which four (FGF5, two in CYP17A1, MTHFR) reached significance. The associations were most pronounced for FGF5-rs16998073 [SBP: beta = 1.97 mmHg/allele, P = 0.0006; DBP: beta = 0.95 mmHg/allele, P = 0.0008, hypertension: odds ratio (OR) 1.36/allele, P = 0.0001]. Effect size of FGF5-rs16998073 on SBP and hypertension were significantly more pronounced in Han Chinese compared to white Europeans. None of these variants was associated with BMI, waistline or hsCRP that are the well established risk factors for hypertension. The genetic risk score, calculated as the sum of BP-increasing alleles of FGF5-rs16998073, CYP17A1-rs11191548, CYP17A1-rs1004467 and MTHFR-rs17367504, was significantly associated with increased SBP (1.16 mmHg/allele, P = 9.01E-5), DBP (0.51 mmHg/allele, P = 4.40E-4) and hypertension risk (OR = 1.22/allele, P = 2.74E-7). CONCLUSION: Variants in or near FGF5, CYP17A1 and MTHFR contributed to variation in BP and hypertension risk. Effect sizes of these three loci tended to be larger in Chinese than in white Europeans, but more studies with larger sample size are required for a definitive conclusion.
PubMed Accession Number :: 20852445.

Michaud, D. S.; Gallo, V.; Schlehofer, B.; Tjonneland, A.; Olsen, A.; Overvad, K.; Dahm, C. C.; Teucher, B.; Lukanova, A.; Boeing, H.; Schutze, M.; Trichopoulou, A.; Lagiou, P.; Kyrozis, A.; Sacerdote, C.; Krogh, V.; Masala, G.; Tumino, R.; Mattiello, A.; Bueno-de-Mesquita, H. B.; Ros, M. M.; Peeters, P. H.; van Gils, C. H.; Skeie, G.; Engeset, D.; Parr, C. L.; Ardanaz, E.; Chirlaque, M. D.; Dorronsoro, M.; Sanchez, M. J.; Arguelles, M.; Jakszyn, P.; Nilsson, L. M.; Melin, B. S.; Manjer, J.; Wirfalt, E.; Khaw, K. T.; Wareham, N.; Allen, N. E.; Key, T. J.; Romieu, I.; Vineis, P.; Riboli, E. (2010) Coffee and tea intake and risk of brain tumors in the European Prospective Investigation into Cancer and Nutrition cohort study Am J Clin Nutr, 92 ,1145-1150 [Journal Article] Online
Abstract: BACKGROUND: In a recent US cohort study, total coffee and tea consumption was inversely associated with risk of glioma, and experimental studies showed that caffeine can slow the invasive growth of glioblastoma. OBJECTIVE: The objective was to examine the relation between coffee and tea intake and the risk of glioma and meningioma in a large European cohort study, the European Prospective Investigation into Cancer and Nutrition (EPIC). DESIGN: Data on coffee and tea intake were collected from men and women recruited into the EPIC cohort study. Over an average of 8.5 y of follow-up, 343 cases of glioma and 245 cases of meningioma were newly diagnosed in 9 countries. We used Cox proportional hazards models to examine the relation between coffee and tea and brain tumors. RESULTS: We observed no associations between coffee, tea, or combined coffee and tea consumption and risk of either type of brain tumor when using quantiles based on country-specific distributions of intake. However, a significant inverse association was observed for glioma risk among those consuming >/=100 mL coffee and tea per day compared with those consuming <100 mL/d (hazard ratio: 0.66; 95% CI: 0.44, 0.97; P = 0.03). The association was slightly stronger in men (hazard ratio: 0.59; 95% CI: 0.34, 1.01) than in women (hazard ratio: 0.74; 95% CI: 0.42, 1.31), although neither was statistically significant. CONCLUSIONS: In this large cohort study, we observed an inverse association between total coffee and tea consumption and risk of glioma that was consistent with the findings of a recent study. These findings, if further replicated in other studies, may provide new avenues of research on gliomas.
PubMed Accession Number :: 20844074.

Dossus, L.; Rinaldi, S.; Becker, S.; Lukanova, A.; Tjonneland, A.; Olsen, A.; Stegger, J.; Overvad, K.; Chabbert-Buffet, N.; Jimenez-Corona, A.; Clavel-Chapelon, F.; Rohrmann, S.; Teucher, B.; Boeing, H.; Schutze, M.; Trichopoulou, A.; Benetou, V.; Lagiou, P.; Palli, D.; Berrino, F.; Panico, S.; Tumino, R.; Sacerdote, C.; Redondo, M. L.; Travier, N.; Sanchez, M. J.; Altzibar, J. M.; Chirlaque, M. D.; Ardanaz, E.; Bueno-de-Mesquita, H. B.; van Duijnhoven, F. J.; Onland-Moret, N. C.; Peeters, P. H.; Hallmans, G.; Lundin, E.; Khaw, K. T.; Wareham, N.; Allen, N.; Key, T.; Slimani, N.; Hainaut, P.; Romaguera, D.; Norat, T.; Riboli, E.; Kaaks, R. (2010) Obesity, inflammatory markers and endometrial cancer risk: a prospective case-control study Endocr Relat Cancer, , [Journal Article] Online
Abstract: Obesity, a major risk factor for endometrial cancer, is a low grade inflammatory state characterized by elevated concentrations of cytokines and acute phase reactants. The current study had two aims: first, to investigate the associations of C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1Ra) with endometrial cancer risk and second to examine to which extent these markers can influence the association between obesity and endometrial cancer. We conducted a case-control study, nested within the European Prospective Investigation into Cancer and Nutrition, that comprised 305 incident cases of endometrial cancer and 574 matched controls. CRP, IL-6 and IL-1Ra were measured in prospectively collected blood specimens by immunoassays. Data were analyzed using conditional logistic regression. All statistical tests were two-sided and P-values <0.05 were considered statistically significant. We observed a significant increase in risk of endometrial cancer with elevated levels of CRP (odds ratio [OR] for top versus bottom quartile: 1.58, 95%CI: 1.03-2.41, Ptrend=0.02), IL-6 (OR for top versus bottom quartile: 1.66, 95%CI: 1.08-2.54, Ptrend=0.008) and IL-1Ra (OR for top versus bottom category: 1.82, 95%CI: 1.22-2.73, Ptrend=0.004). After adjustment for BMI, the estimates were strongly reduced and became non-significant. The association between BMI and endometrial cancer was also substantially attenuated (~10-20%) after adjustment for inflammatory markers, even when the effects of C-peptide or estrone had already been taken into account. We provide epidemiologic evidence that chronic inflammation might mediate the association between obesity and endometrial cancer and that endometrial carcinogenesis could be promoted by an inflammatory milieu.
PubMed Accession Number :: 20843938.

Corder, K.; van Sluijs, E. M.; Ekelund, U.; Jones, A. P.; Griffin, S. J. (2010) Changes in Children's Physical Activity Over 12 Months: Longitudinal Results From the SPEEDY Study Pediatrics, 126 ,e926-935 [Journal Article] Online
Abstract: Objective: We measured physical activity changes among 10-year-old British children over 12 months and assessed biological and demographic determinants. Methods: Physical activity was measured with accelerometers (counts per minute) over >/=3 days at baseline and 1 year later in a prospective study of 844 children (41.6% male; mean +/- SD baseline age: 10.2 +/- 0.3 years) from 92 schools. Meeting physical activity recommendations was defined as >/=60 minutes/day at >/=2000 counts per minute. Biological (height, weight, and fat percentage) and demographic factors (gender, rural/urban home location, and socioeconomic status) were assessed at baseline. Associations between physical activity changes and multiple factors were studied. Results: Physical activity decreased over 1 year (baseline: 665.7 +/- 209.8 counts per minute; follow-up: 623.2 +/- 179.2 counts per minute; P < .001), with 70.4% of children meeting physical activity recommendations at the baseline evaluation and 65.8% at the follow-up evaluation (P < .001). The decrease occurred mainly on weekends (-47.2 +/- 395.8 counts per minute; P = .002), with no significant change on weekdays (8.0 +/- 201.6 counts per minute; P = .20). Girls (P < .001), participants with greater body fat percentage (P = .001), and participants of higher socioeconomic status (P = .008) were more likely to exhibit physical activity decreases. Conclusions: Physical activity decreased over 1 year among children in primary school, predominantly during the weekend. Because these children were relatively active at baseline, prevention of physical activity decreases in childhood, particularly among girls and on weekends, may be a suitable health promotion target.
PubMed Accession Number :: 20837590.

Smart-Halajko, M. C.; Robciuc, M. R.; Cooper, J. A.; Jauhiainen, M.; Kumari, M.; Kivimaki, M.; Khaw, K. T.; Boekholdt, S. M.; Wareham, N. J.; Gaunt, T. R.; Day, I. N.; Braund, P. S.; Nelson, C. P.; Hall, A. S.; Samani, N. J.; Humphries, S. E.; Ehnholm, C.; Talmud, P. J. (2010) The Relationship Between Plasma Angiopoietinlike Protein 4 Levels, Angiopoietinlike Protein 4 Genotype, and Coronary Heart Disease Risk Arterioscler Thromb Vasc Biol, , [Journal Article] Online
Abstract: OBJECTIVE: To investigate the relationship between angiopoietinlike protein 4 (Angptl4) levels, coronary heart disease (CHD) biomarkers, and ANGPTL4 variants. METHODS AND RESULTS: Plasma Angptl4 was quantified in 666 subjects of the Northwick Park Heart Study II using a validated ELISA. Seven ANGPTL4 single-nucleotide polymorphisms were genotyped, and CHD biomarkers were assessed in the whole cohort (N=2775). Weighted mean+/-SD plasma Angptl4 levels were 10.0+/-11.0 ng/mL. Plasma Angptl4 concentration correlated positively with age (r=0.15, P<0.001) and body fat mass (r=0.19, P=0.003) but negatively with plasma high-density lipoprotein cholesterol (r=-0.13, P=0.01). No correlation with triglycerides (TGs) was observed. T266 mol/L was independently associated with plasma Angptl4 levels (P<0.001) but was not associated with TGs or CHD risk in the meta-analysis of 5 studies (4061 cases/15 395 controls). E40K showed no independent association with plasma Angptl4 levels. In human embryonic kidney 293 and human hepatoma 7 cells compared with wild type, E40K and T266 mol/L showed significantly altered synthesis and secretion, respectively. CONCLUSIONS: Circulating Angptl4 levels may not influence TG levels or CHD risk for the following reasons: (1) Angptl4 levels were not correlated with TGs; (2) T266 mol/L, although associated with Angptl4 levels, showed no association with plasma TGs; and (3) TG-lowering E40K did not influence Angptl4 levels. These results provide new insights into the role of Angptl4 in TG metabolism.
PubMed Accession Number :: 20829508.

Levy-Marchal, C.; Arslanian, S.; Cutfield, W.; Sinaiko, A.; Druet, C.; Marcovecchio, M. L.; Chiarelli, F. (2010) Insulin Resistance in Children: Consensus, Perspective, and Future Directions J Clin Endocrinol Metab, , [Journal Article] Online
Abstract: Objective: Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points. Participants: The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants. Evidence: An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children. Consensus Process: The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement. Conclusions: Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases.
PubMed Accession Number :: 20829185.

Tsimikas, S.; Mallat, Z.; Talmud, P. J.; Kastelein, J. J.; Wareham, N. J.; Sandhu, M. S.; Miller, E. R.; Benessiano, J.; Tedgui, A.; Witztum, J. L.; Khaw, K. T.; Boekholdt, S. M. (2010) Oxidation-Specific Biomarkers, Lipoprotein(a), and Risk of Fatal and Nonfatal Coronary Events J Am Coll Cardiol, 56 (12),946-55 [Journal Article] Online
Abstract: OBJECTIVES: This study sought to assess whether oxidation-specific biomarkers are associated with an increased risk of coronary artery disease (CAD) events. BACKGROUND: The relationship of a panel of oxidative biomarkers and lipoprotein(a) [Lp(a)] to CAD risk is not fully determined. METHODS: A prospective case-control study nested in the EPIC (European Prospective Investigation of Cancer)-Norfolk cohort of 45- to 79-year-old apparently healthy men and women followed for approximately 6 years was designed. Cases consisted of participants in whom fatal or nonfatal CAD developed, matched by sex, age, and enrollment time with controls without CAD. Baseline levels of oxidized phospholipids on apolipoprotein B-100 particles and Lp(a) were measured in 763 cases and 1,397 controls. Their relationship to secretory phospholipase A(2) type IIA mass and activity, myeloperoxidase mass, and lipoprotein-associated phospholipase A(2) activity and association with CAD events were determined. RESULTS: After adjusting for age, smoking, diabetes, low- and high-density lipoprotein cholesterol, and systolic blood pressure, the highest tertiles of oxidized phospholipids on apolipoprotein B-100 particles and Lp(a) were associated with a significantly higher risk of CAD events (odds ratios: 1.67 and 1.64, respectively; p < 0.001) compared with the lowest tertiles. The odds ratio of CAD events associated with the highest tertiles of oxidized phospholipids on apolipoprotein B-100 particles or Lp(a) was significantly potentiated (approximately doubled) by the highest tertiles of secretory phospholipase A(2) activity and mass but less so for myeloperoxidase and lipoprotein-associated phospholipase A(2) activity. The odds ratios for fatal CAD were higher than for the combined end point. After taking into account the Framingham Risk Score, c-index values progressively increased when oxidative biomarkers were added to the model. CONCLUSIONS: This EPIC-Norfolk study links pathophysiologically related oxidation-specific biomarkers and Lp(a) with CAD events. Oxidation-specific biomarkers provide cumulative predictive value when added to traditional cardiovascular risk factors.
PubMed Accession Number :: 20828647.

Li, S.; Zhao, J. H.; Luan, J.; Ekelund, U.; Luben, R. N.; Khaw, K. T.; Wareham, N. J.; Loos, R. J. (2010) Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study PLoS Med, 7 (8), [Journal Article] Online
Abstract: BACKGROUND: We have previously shown that multiple genetic loci identified by genome-wide association studies (GWAS) increase the susceptibility to obesity in a cumulative manner. It is, however, not known whether and to what extent this genetic susceptibility may be attenuated by a physically active lifestyle. We aimed to assess the influence of a physically active lifestyle on the genetic predisposition to obesity in a large population-based study. METHODS AND FINDINGS: We genotyped 12 SNPs in obesity-susceptibility loci in a population-based sample of 20,430 individuals (aged 39-79 y) from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with an average follow-up period of 3.6 y. A genetic predisposition score was calculated for each individual by adding the body mass index (BMI)-increasing alleles across the 12 SNPs. Physical activity was assessed using a self-administered questionnaire. Linear and logistic regression models were used to examine main effects of the genetic predisposition score and its interaction with physical activity on BMI/obesity risk and BMI change over time, assuming an additive effect for each additional BMI-increasing allele carried. Each additional BMI-increasing allele was associated with 0.154 (standard error [SE] 0.012) kg/m(2) (p = 6.73x10(-37)) increase in BMI (equivalent to 445 g in body weight for a person 1.70 m tall). This association was significantly (p(interaction) = 0.005) more pronounced in inactive people (0.205 [SE 0.024] kg/m(2) [p = 3.62x10(-18); 592 g in weight]) than in active people (0.131 [SE 0.014] kg/m(2) [p = 7.97x10(-21); 379 g in weight]). Similarly, each additional BMI-increasing allele increased the risk of obesity 1.116-fold (95% confidence interval [CI] 1.093-1.139, p = 3.37x10(-26)) in the whole population, but significantly (p(interaction) = 0.015) more in inactive individuals (odds ratio [OR] = 1.158 [95% CI 1.118-1.199; p = 1.93x10(-16)]) than in active individuals (OR = 1.095 (95% CI 1.068-1.123; p = 1.15x10(-12)]). Consistent with the cross-sectional observations, physical activity modified the association between the genetic predisposition score and change in BMI during follow-up (p(interaction) = 0.028). CONCLUSIONS: Our study shows that living a physically active lifestyle is associated with a 40% reduction in the genetic predisposition to common obesity, as estimated by the number of risk alleles carried for any of the 12 recently GWAS-identified loci. Please see later in the article for the Editors' Summary.
PubMed Accession Number :: 20824172.

Chamnan, P.; Simmons, R. K.; Hori, H.; Sharp, S.; Khaw, K. T.; Wareham, N. J.; Griffin, S. J. (2010) A simple risk score using routine data for predicting cardiovascular disease in primary care Br J Gen Pract, 60 (577),590-596 [Journal Article] Online
Abstract: BACKGROUND: Population-based screening for cardiovascular disease (CVD) risk, incorporating blood tests, is proposed in several countries. AIM: The aim of this study was to evaluate whether a simple approach to identifying individuals at high risk of CVD using routine data might be effective. DESIGN OF STUDY: Prospective cohort study (EPIC-Norfolk). SETTING: Norfolk area, UK. METHOD: A total of 21 867 men and women aged 40-74 years, who were free from CVD and diabetes at baseline, participated in the study. The discrimination (the area under the receiver operating characteristic curve [aROC]), calibration, sensitivity/specificity, and positive/negative predictive value were evaluated for different risk thresholds of the Framingham risk equations and the Cambridge diabetes risk score (as an example of a simple risk score using routine data from electronic general practice records). RESULTS: During 203 664 person-years of follow-up, 2213 participants developed a first CVD event (10.9 per 1000 person-years). The Cambridge diabetes risk score predicted CVD events reasonably well (aROC 0.72; 95% confidence interval [CI] = 0.71 to 0.73), while the Framingham risk score had the best predictive ability (aROC 0.77; 95% CI = 0.76 to 0.78). The Framingham risk score overestimated risk of developing CVD in this representative British population by 60%. CONCLUSION: A risk score incorporating routinely available data from GP records performed reasonably well at predicting CVD events. This suggests that it might be more efficient to use routine data as the first stage in a stepwise population screening programme to identify people at high risk of developing CVD before more time- and resource-consuming tests are used.
PubMed Accession Number :: 20822683.

Romaguera, D.; Norat, T.; Vergnaud, A. C.; Mouw, T.; May, A. M.; Agudo, A.; Buckland, G.; Slimani, N.; Rinaldi, S.; Couto, E.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Cottet, V.; Rohrmann, S.; Teucher, B.; Bergmann, M.; Boeing, H.; Tjonneland, A.; Halkjaer, J.; Jakobsen, M. U.; Dahm, C. C.; Travier, N.; Rodriguez, L.; Sanchez, M. J.; Amiano, P.; Barricarte, A.; Huerta, J. M.; Luan, J.; Wareham, N.; Key, T. J.; Spencer, E. A.; Orfanos, P.; Naska, A.; Trichopoulou, A.; Palli, D.; Agnoli, C.; Mattiello, A.; Tumino, R.; Vineis, P.; Bueno-de-Mesquita, H. B.; Buchner, F. L.; Manjer, J.; Wirfalt, E.; Johansson, I.; Hellstrom, V.; Lund, E.; Braaten, T.; Engeset, D.; Odysseos, A.; Riboli, E.; Peeters, P. H. (2010) Mediterranean dietary patterns and prospective weight change in participants of the EPIC-PANACEA project Am J Clin Nutr, 92 ,912-921 [Journal Article] Online
Abstract: BACKGROUND: There is an association between a greater adherence to a Mediterranean diet and a reduced risk of developing chronic diseases. However, it is not clear whether this dietary pattern may be also protective against the development of obesity. OBJECTIVE: We assessed the association between the adherence to the Mediterranean dietary pattern (MDP), prospective weight change, and the incidence of overweight or obesity. DESIGN: We conducted a prospective cohort study [the European Prospective Investigation into Cancer and Nutrition-Physical Activity, Nutrition, Alcohol Consumption, Cessation of Smoking, Eating Out of Home, and Obesity (EPIC-PANACEA) project] in 373,803 individuals (103,455 men and 270,348 women; age range: 25-70 y) from 10 European countries. Anthropometric measurements were obtained at recruitment and after a median follow-up time of 5 y. The relative Mediterranean Diet Score (rMED; score range: 0-18) was used to assess adherence to the MDP according to the consumption of 9 dietary components that are characteristic of the Mediterranean diet. The association between the rMED and 5-y weight change was modeled through multiadjusted mixed-effects linear regression. RESULTS: Individuals with a high adherence to the MDP according to the rMED (11-18 points) showed a 5-y weight change of -0.16 kg (95% CI: -0.24, -0.07 kg) and were 10% (95% CI: 4%, 18%) less likely to develop overweight or obesity than were individuals with a low adherence to the MDP (0-6 points). The low meat content of the Mediterranean diet seemed to account for most of its positive effect against weight gain. CONCLUSION: This study shows that promoting the MDP as a model of healthy eating may help to prevent weight gain and the development of obesity.
PubMed Accession Number :: 20810975.

Buchner, F. L.; Bueno-de-Mesquita, H. B.; Ros, M. M.; Overvad, K.; Dahm, C. C.; Hansen, L.; Tjonneland, A.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Touillaud, M.; Kaaks, R.; Rohrmann, S.; Boeing, H.; Nothlings, U.; Trichopoulou, A.; Zylis, D.; Dilis, V.; Palli, D.; Sieri, S.; Vineis, P.; Tumino, R.; Panico, S.; Peeters, P. H.; van Gils, C. H.; Lund, E.; Gram, I. T.; Braaten, T.; Sanchez, M. J.; Agudo, A.; Larranaga, N.; Ardanaz, E.; Navarro, C.; Arguelles, M. V.; Manjer, J.; Wirfalt, E.; Hallmans, G.; Rasmuson, T.; Key, T. J.; Khaw, K. T.; Wareham, N.; Slimani, N.; Vergnaud, A. C.; Xun, W. W.; Kiemeney, L. A.; Riboli, E. (2010) Variety in Fruit and Vegetable Consumption and the Risk of Lung Cancer in the European Prospective Investigation into Cancer and Nutrition Cancer Epidemiol Biomarkers Prev, , [Journal Article] Online
Abstract: BACKGROUND: We investigated whether a varied consumption of vegetables and fruits is associated with lower lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study. METHODS: After a mean follow-up of 8.7 years, 1,613 of 452,187 participants with complete information were diagnosed with lung cancer. Diet diversity scores (DDS) were used to quantify the variety in fruit and vegetable consumption. Multivariable proportional hazards models were used to assess the associations between DDS and lung cancer risk. All models were adjusted for smoking behavior and the total consumption of fruit and vegetables. RESULTS: With increasing variety in vegetable subgroups, risk of lung cancer decreases [hazard ratios (HR), 0.77; 95% confidence interval (CI), 0.64-0.94 highest versus lowest quartile; P trend = 0.02]. This inverse association is restricted to current smokers (HR, 0.73; 95% CI, 0.57-0.93 highest versus lowest quartile; P trend = 0.03). In continuous analyses, in current smokers, lower risks were observed for squamous cell carcinomas with more variety in fruit and vegetable products combined (HR/two products, 0.88; 95% CI, 0.82-0.95), vegetable subgroups (HR/subgroup, 0.88; 95% CI, 0.79-0.97), vegetable products (HR/two products, 0.87; 95% CI, 0.79-0.96), and fruit products (HR/two products, 0.84; 95% CI, 0.72-0.97). CONCLUSION: Variety in vegetable consumption was inversely associated with lung cancer risk among current smokers. Risk of squamous cell carcinomas was reduced with increasing variety in fruit and/or vegetable consumption, which was mainly driven by the effect in current smokers. Impact: Independent from quantity of consumption, variety in fruit and vegetable consumption may decrease lung cancer risk. Cancer Epidemiol Biomarkers Prev; 19(9); 2278-86. (c)2010 AACR.
PubMed Accession Number :: 20807832.

Corder, K.; van Sluijs, E. M.; Steele, R. M.; Stephen, A. M.; Dunn, V.; Bamber, D.; Goodyer, I.; Griffin, S. J.; Ekelund, U. (2010) Breakfast consumption and physical activity in British adolescents Br J Nutr, ,1-6 [Journal Article] Online
Abstract: Studies show an inverse relationship between breakfast frequency and weight gain. This may reflect poor eating habits generally and associated low physical activity (PA) or direct impacts of breakfast on mechanisms leading to lethargy and reduced PA. The relationship between breakfast frequency and PA is inconclusive. We aimed to determine whether breakfast frequency is associated with PA levels in British adolescents independent of body composition and socio-economic status (SES). Habitual breakfast frequency (self-report questionnaire) was assessed in 877 adolescents (43 % male, age 14.5 (sd 0.5) years old). PA was measured over 5 d (accelerometry, average counts/min; cpm). Associations between daily PA and breakfast frequency were assessed using linear regression adjusted for body fat percentage and SES. Effect modification by sex and associations with PA during the morning (06.00-12.00 hours) were explored. For boys, there were no significant associations between breakfast frequency and PA. For girls, less frequent breakfast consumption was significantly associated with lower PA (cpm) during the morning (occasional v. frequent beta - 6.1 (95 % CI - 11.1, - 1.1), P = 0.017) when adjusted for body fat percentage and SES. There were no associations between PA and breakfast consumption over the whole day; however, for girls, less frequent breakfast consumption may be associated with lower PA levels during the morning, suggesting that breakfast consumption should perhaps be taken into consideration when aiming to promote PA in adolescent girls.
PubMed Accession Number :: 20807464.

Michaud, D. S.; Gallo, V.; Schlehofer, B.; Tjonneland, A. M.; Olsen, A.; Overvad, K.; Dahm, C. C.; Kaaks, R.; Lukanova, A.; Boeing, H.; Schutze, M.; Trichopoulou, A.; Bamia, C.; Kyrozis, A.; Sacerdote, C.; Agnoli, C.; Palli, D.; Tumino, R.; Mattiello, A.; Bueno-de-Mesquita, B.; Ros, M.; Peeters, P. H.; van Gils, C.; Lund, E.; Bakken, K.; Gram, I.; Barricarte, A.; Navarro, C.; Dorronsoro, M.; Sanchez Perez, M.; Rodriguez, L.; Duell, E.; Hallmans, G.; Melin, B.; Manjer, J.; Borgquist, S.; Khaw, K. T.; Wareham, N. J.; Allen, N. E.; Tsilidis, K.; Romieu, I.; Rinaldi, S.; Vineis, P.; Riboli, E. (2010) Reproductive factors and exogenous hormone use in relation to risk of glioma and meningioma in a large European cohort study Cancer Epidemiol Biomarkers Prev, 19 ,2562-2569 [Journal Article] Online
Abstract: BACKGROUND: The aetiologies of glioma and meningioma tumors are largely unknown. Although reproductive hormones are thought to influence the risk of these tumors, epidemiologic data are not supportive of this hypothesis; however, few cohort studies have published on this topic. We examined the relation between reproductive factors and risk of glioma and meningioma among women in the European Prospective Investigation into Cancer and Nutrition (EPIC).METHODS: After a mean of 8.4 years of follow-up, 193 glioma and 194 meningioma were identified among 276,212 women. Information on reproductive factors and hormone use was collected at baseline. Cox proportional hazard regression was used to determine hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: No associations were observed between glioma or meningioma risk and reproductive factors, including age at menarche, parity, age at first birth, menopausal status, and age at menopause. A higher risk of meningioma was observed among postmenopausal women who were current users of hormone replacement therapy (HR = 1.62, 95% CI = 1.04-2.54) compared with never users. Similarly, current users of oral contraceptives were at higher risk of meningioma than never users (HR = 3.61, 95% CI = 1.75-7.46). CONCLUSION: Our results do not support a role for estrogens and glioma risk. Use of exogenous hormones, especially current use, appears to increase meningioma risk. However, these findings could be due to diagnostic bias and require confirmation.Impact: Elucidating the role of hormones in brain tumor development has important implications and needs to be further examined using biological measurements.
PubMed Accession Number :: 20802020.

den Hoed, M.; Ekelund, U.; Brage, S.; Grontved, A.; Zhao, J. H.; Sharp, S. J.; Ong, K. K.; Wareham, N. J.; Loos, R. J. (2010) Genetic susceptibility to obesity and related traits in childhood and adolescence; influence of loci identified by genome-wide association studies Diabetes, 59 ,2980-2988 [Journal Article] Online
Abstract: AbstractObjective: Large-scale genome-wide association (GWA) studies have so far identified 16 loci incontrovertibly associated with obesity-related traits in adults. We examined associations of variants in these loci with anthropometric traits in children/adolescents. Research design and methods: Seventeen variants representing 16 obesity-susceptibility loci were genotyped in 1,252 children (mean+/-SD age: 9.7+/-0.4yrs) and 790 adolescents (15.5+/-0.5yrs) from the European Youth Heart Study (EYHS). We tested for association of individual variants and a genetic predisposition score (GPS-17), calculated by summing the number of effect-alleles, with anthropometric traits. For 13 variants, summary statistics for associations with BMI were meta-analysed with previously reported data (N(total)=13,071 children/adolescents). Results: In EYHS, 15 variants showed associations or trends with anthropometric traits that were directionally consistent with earlier reports in adults. The meta-analysis showed directionally consistent associations with BMI for all 13 variants of which 9 were significant (0.033-0.098SD/allele, P<0.05). The near-TMEM18 variant had the strongest effect (0.098SD/allele, P=8.5.10(-11)). Effect sizes for BMI tended to be more pronounced in children/adolescents than reported earlier in adults for variants in/near SEC16B, TMEM18 and KCTD15, (0.028-0.035SD/allele higher), and less pronounced for rs925946 in BDNF (0.028SD/allele lower). Each additional effect-allele in the GPS-17 was associated with an increase of 0.034SD in BMI (P=3.6.10(-5)), 0.039SD in sum of skinfolds (P=1.7.10(-7)) and 0.022SD in waist circumference (P=1.7.10(-4)), comparable with reported results in adults (0.039SD/allele for BMI, 0.033SD/allele for waist circumference). Conclusions: Most obesity-susceptibility loci identified by GWA studies in adults are already associated with anthropometric traits in children/adolescents. While the association of some variants may differ with age, the cumulative effect size is similar.
PubMed Accession Number :: 20724581.

Sargeant, L. A.; Simmons, R. K.; Barling, R. S.; Butler, R.; Williams, K. M.; Prevost, A. T.; Kinmonth, A. L.; Wareham, N. J.; Griffin, S. J. (2010) Who attends a UK diabetes screening programme? Findings from the ADDITION-Cambridge study Diabet Med, 27 (9),995-1003 [Journal Article] Online
Abstract: Diabet. Med. 27, 995-1003 (2010) Abstract Aims One of the factors influencing the cost-effectiveness of population screening for Type 2 diabetes may be uptake. We examined attendance and practice- and individual-level factors influencing uptake at each stage of a diabetes screening programme in general practice. Methods A stepwise screening programme was undertaken among 135 825 people aged 40-69 years without known diabetes in 49 general practices in East England. The programme included a score based on routinely available data (age, sex, body mass index and prescribed medication) to identify those at high risk, who were offered random capillary blood glucose (RBG) and glycosylated haemoglobin tests. Those screening positive were offered fasting capillary blood glucose (FBG) and confirmatory oral glucose tolerance tests (OGTT). Results There were 33 539 high-risk individuals invited for a RBG screening test; 24 654 (74%) attended. Ninety-four per cent attended the follow-up FBG test and 82% the diagnostic OGTT. Seventy per cent of individuals completed the screening programme. Practices with higher general practitioner staff complements and those located in more deprived areas had lower uptake for RBG and FBG tests. Male sex and a higher body mass index were associated with lower attendance for RBG testing. Older age, prescription of antihypertensive medication and a higher risk score were associated with higher attendance for FBG and RBG tests. Conclusions High attendance rates can be achieved by targeted stepwise screening of individuals assessed as high risk by data routinely available in general practice. Different strategies may be required to increase initial attendance, ensure completion of the screening programme, and reduce the risk that screening increases health inequalities.
PubMed Accession Number :: 20722672.

Ros, M. M.; Bas Bueno-de-Mesquita, H.; Buchner, F. L.; Aben, K. K.; Kampman, E.; Egevad, L.; Overvad, K.; Tjonneland, A.; Roswall, N.; Clavel-Chapelon, F.; Kaaks, R.; Cheng-Claude, J.; Boeing, H.; Weikert, S.; Trichopoulou, A.; Orfanos, P.; Stasinopulou, G.; Saieva, C.; Krogh, V.; Vineis, P.; Tumino, R.; Mattiello, A.; Peeters, P. H.; An Duijnhoven, F. J.; Lund, E.; Gram, I. T.; Chirlaque, M. D.; Barricarte, A.; Rodriguez, L.; Molina, E.; Gonzalez, C.; Dorronsoro, M.; Manjer, J.; Ehrnstrom, R.; Ljungberg, B.; Allen, N. E.; Roddam, A. W.; Khaw, K. T.; Wareham, N.; Boffetta, P.; Slimani, N.; Michaud, D. S.; Kiemeney, L. A.; Riboli, E. (2010) Fluid intake and the risk of urothelial cell carcinomas in the European Prospective Investigation into Cancer and Nutrition (EPIC) Int J Cancer, , [Journal Article] Online
Abstract: Results from previous studies investigating the association between fluid intake and urothelial cell carcinomas (UCC) are inconsistent. We evaluated this association among 233,236 subjects in the European Prospective Investigation into Cancer and Nutrition (EPIC), who had adequate baseline information on water and total fluid intake. During a mean follow-up of 9.3 years, 513 first primary UCC occurred. At recruitment, habitual fluid intake was assessed by a food frequency questionnaire. Multivariable hazard ratios were estimated using Cox regression stratified by age, sex and center and adjusted for energy intake, smoking status, duration of smoking and lifetime intensity of smoking.Using the lowest tertile of intake as reference, total fluid intake was not associated with risk of all UCC (HR 1.12; 95%CI 0.86-1.45, p-trend=0.42), nor with risk of prognostically high risk UCC (HR 1.28; 95%CI 0.85-1.93, p-trend=0.27) or prognostically low risk UCC (HR 0.93; 95%CI 0.65-1.33, p-trend=0.74). No associations were observed between risk of UCC and intake of water, coffee, tea and herbal tea, and milk and other dairy beverages. For prognostically low risk UCC suggestions of an inverse association with alcoholic beverages and of a positive association with soft drinks were seen. Increased risks were found for all UCC and prognostically low risk UCC with higher intake of fruit and vegetable juices.In conclusion, total usual fluid intake is not associated with UCC risk in EPIC. The relationships observed for some fluids may be due to chance but further investigation of the role of all types of fluid is warranted.
PubMed Accession Number :: 20715171.

Ward, H.; Luben, R. N.; Wareham, N. J.; Khaw, K. T. (2010) CHD risk in relation to alcohol intake from categorical and open-ended dietary instruments Public Health Nutr, ,1-8 [Journal Article] Online
Abstract: OBJECTIVE: To examine the risk of CHD in relation to alcohol intake from three different instruments. DESIGN: In the European Prospective Investigation into Cancer in Norfolk study, weekly alcohol intake was estimated from a single question in a mail-in health and lifestyle questionnaire (HLQ), a semi-quantitative FFQ, and a 7 d diet diary (7DD). Information on smoking status, physical activity, disease history, social class and medication use was reported in the HLQ. Height, weight, blood pressure and blood lipids were measured at a health check-up. The average length of follow-up was 11 years. The association between alcohol intake and incident fatal and non-fatal CHD in a nested case-control sample was calculated using logistic regression. SETTING: Norfolk, England. SUBJECTS: A total of 2151 cases of incident fatal and non-fatal CHD and 5354 controls. RESULTS: The Spearman correlation values between the 7DD, FFQ and HLQ alcohol estimates ranged from r = 0.70 to 0.82 (P < 0.0001 for all r values). Alcohol intake from all instruments was inversely associated with the risk of CHD in age- and multivariate-adjusted models. The relationships between the risk of CHD and alcohol intake from the 7DD, HLQ or FFQ were not significantly different from each other (P >0.10). A marginal difference between men and women was detected for the risk of CHD in relation to HLQ alcohol intake (P = 0.065). CONCLUSIONS: In conclusion, while the instruments were not uniform in their assessment of alcohol intake levels, the 7DD, HLQ and FFQ yielded similar inverse associations between alcohol intake and risk of CHD.
PubMed Accession Number :: 20707945.

Arsenault, B. J.; Despres, J. P.; Stroes, E. S.; Wareham, N. J.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2010) Lipid assessment, metabolic syndrome and coronary heart disease risk Eur J Clin Invest, , [Journal Article] Online
Abstract: Background Although the total to high-density lipoprotein cholesterol ratio (TC/HDL-C) has been used for decades to identify individuals at risk for coronary heart disease (CHD), apolipoprotein-based (apolipoprotein B/apolipoprotein A-I [apoB/apoA-I]) and nuclear magnetic resonance spectroscopy (NMR)-based lipoprotein concentrations (low-density lipoprotein(NMR)/high-density lipoprotein(NMR) [LDL(NMR)/HDL(NMR)]) may also be useful for CHD risk stratification. Materials and methods In a case-control study conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study population, 870 individuals who developed CHD during a 6-year follow-up were matched to 1659 controls on the basis of gender, age and enrolment time. LDL(NMR) and HDL(NMR) were measured by proton NMR spectroscopy. Results After adjusting for traditional CHD risk factors, men in the top quintile of the various lipoprotein ratios proved to be at increased CHD risk (OR = 2.59 [95% IC, 1.76-3.83] for TC/HDL-C ratio, 2.59 [1.75-3.83] for apoB/apoA-I ratio and 2.78 [1.86-4.17] for LDL(NMR)/HDL(NMR) ratio) compared with men in the bottom quintile. Similar associations were observed in women (OR = 2.86 [1.71-4.80] for TC/HDL-C ratio, 2.94 [1.74-4.97] for apoB/apoA-I ratio and 2.03 [1.21-3.43] for LDL(NMR)/HDL(NMR) ratio). Compared with participants with only one component of the metabolic syndrome, those who had five had an increased TC/HDL-C ratio (73.0% and 80.4% in men and women respectively), apoB/apoA-I ratio (58.0% and 62.9% in men and women respectively) and for LDL(NMR)/HDL(NMR) ratio (52.6% and 54.1% in men and women respectively). Conclusion In this European study population, the TC/HDL-C, apoB/apoA-I and LDL(NMR)/HDL(NMR) ratios were similarly associated with components of the metabolic syndrome and CHD risk.
PubMed Accession Number :: 20701625.

Maisonet, M.; Christensen, K. Y.; Rubin, C.; Holmes, A.; Flanders, W. D.; Heron, J.; Ong, K. K.; Golding, J.; McGeehin, M. A.; Marcus, M. (2010) Role of Prenatal Characteristics and Early Growth on Pubertal Attainment of British Girls Pediatrics, 126 ,e591-600 [Journal Article] Online
Abstract: Objectives: The objective of this study was to explore the influence of maternal prenatal characteristics and behaviors and of weight and BMI gain during early childhood on the timing of various puberty outcomes in girls who were enrolled in the Avon Longitudinal Study of Parents and Children. Methods: Repeated self-assessments of pubertal development were obtained from approximately 4000 girls between the ages of 8 and 14. Data on prenatal characteristics and weight at birth and 2, 9, and 20 months of age were obtained from questionnaires, birth records, and clinic visits. Infants' weights were converted to weight-for-age and BMI SD scores (SDSs; z scores), and change values were obtained for the 0- to 20-month and other intervals within that age range. We used parametric survival models to estimate associations with age of entry into Tanner stages of breast and pubic hair and menarche. Results: Maternal initiation of menarche at age <12, smoking during pregnancy, and primiparity were associated with earlier puberty. A 1-unit increase in the weight SDS change values for the 0- to 20-month age interval was associated with earlier ages of entry into pubertal outcomes (0.19-0.31 years). Increases in the BMI SDS change values were also associated with earlier entry into pubertal outcomes (0.07-0.11 years). Conclusions: Many of the maternal prenatal characteristics and weight and BMI gain during infancy seemed to have similar influences across different puberty outcomes. Either such early factors have comparable influences on each of the hormonal processes involved in puberty, or processes are linked and awakening of 1 aspect triggers the others.
PubMed Accession Number :: 20696722.

Nettleton, J. A.; McKeown, N. M.; Kanoni, S.; Lemaitre, R. N.; Hivert, M. F.; Ngwa, J.; van Rooij, F. J.; Sonestedt, E.; Wojczynski, M. K.; Ye, Z.; Tanaka, T. (2010) Interactions of dietary whole grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies Diabetes Care, , [Journal Article] Online
Abstract: AbstractObjective: Whole grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. Research Design & Methods: Via meta-analysis of data from 14 cohorts comprising approximately 48,000 participants of European descent, we studied interactions of whole grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a p-value <0.0028 (0.05/18 tests) as statistically significant. Results: Greater whole grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (beta [95% CI] per 1-serving greater whole grain intake: -0.009 mmol/L glucose [-0.013, -0.005], p <0.0001 and -0.011 pmol/L (ln) insulin [-0.015, -0.007], p =0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole grain intake was rs780094 (GCKR) for fasting insulin (p = 0.006), where greater whole grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. Conclusions: Our results support the favorable association of whole grain intake with fasting glucose and insulin and suggest potential interaction between variation in GCKR and whole grain intake in influencing fasting insulin concentrations.
PubMed Accession Number :: 20693352.

Teslovich, T. M.; Musunuru, K.; Smith, A. V.; Edmondson, A. C.; Stylianou, I. M.; Koseki, M.; Pirruccello, J. P.; Ripatti, S.; Chasman, D. I.; Willer, C. J.; Johansen, C. T.; Fouchier, S. W.; Isaacs, A.; Peloso, G. M.; Barbalic, M.; Ricketts, S. L.; Bis, J. C.; Aulchenko, Y. S.; Thorleifsson, G.; Feitosa, M. F.; Chambers, J.; Orho-Melander, M.; Melander, O.; Johnson, T.; Li, X.; Guo, X.; Li, M.; Shin Cho, Y.; Jin Go, M.; Jin Kim, Y.; Lee, J. Y.; Park, T.; Kim, K.; Sim, X.; Twee-Hee Ong, R.; Croteau-Chonka, D. C.; Lange, L. A.; Smith, J. D.; Song, K.; Hua Zhao, J.; Yuan, X.; Luan, J.; Lamina, C.; Ziegler, A.; Zhang, W.; Zee, R. Y.; Wright, A. F.; Witteman, J. C.; Wilson, J. F.; Willemsen, G.; Wichmann, H. E.; Whitfield, J. B.; Waterworth, D. M.; Wareham, N. J.; Waeber, G.; Vollenweider, P.; Voight, B. F.; Vitart, V.; Uitterlinden, A. G.; Uda, M.; Tuomilehto, J.; Thompson, J. R.; Tanaka, T.; Surakka, I.; Stringham, H. M.; Spector, T. D.; Soranzo, N.; Smit, J. H.; Sinisalo, J.; Silander, K.; Sijbrands, E. J.; Scuteri, A.; Scott, J.; Schlessinger, D.; Sanna, S.; Salomaa, V.; Saharinen, J.; Sabatti, C.; Ruokonen, A.; Rudan, I.; Rose, L. M.; Roberts, R.; Rieder, M.; Psaty, B. M.; Pramstaller, P. P.; Pichler, I.; Perola, M.; Penninx, B. W.; Pedersen, N. L.; Pattaro, C.; Parker, A. N.; Pare, G.; Oostra, B. A.; O'Donnell, C. J.; Nieminen, M. S.; Nickerson, D. A.; Montgomery, G. W.; Meitinger, T.; McPherson, R.; McCarthy, M. I.; McArdle, W.; Masson, D.; Martin, N. G.; Marroni, F.; Mangino, M.; Magnusson, P. K.; Lucas, G.; Luben, R.; Loos, R. J.; Lokki, M. L.; Lettre, G.; Langenberg, C.; Launer, L. J.; Lakatta, E. G.; Laaksonen, R.; Kyvik, K. O.; Kronenberg, F.; Konig, I. R.; Khaw, K. T.; Kaprio, J.; Kaplan, L. M.; Johansson, A.; Jarvelin, M. R.; Cecile, J. W. Janssens A.; Ingelsson, E.; Igl, W.; Kees Hovingh, G.; Hottenga, J. J.; Hofman, A.; Hicks, A. A.; Hengstenberg, C.; Heid, I. M.; Hayward, C.; Havulinna, A. S.; Hastie, N. D.; Harris, T. B.; Haritunians, T.; Hall, A. S.; Gyllensten, U.; Guiducci, C.; Groop, L. C.; Gonzalez, E.; Gieger, C.; Freimer, N. B.; Ferrucci, L.; Erdmann, J.; Elliott, P.; Ejebe, K. G.; Doring, A.; Dominiczak, A. F.; Demissie, S.; Deloukas, P.; de Geus, E. J.; de Faire, U.; Crawford, G.; Collins, F. S.; Chen, Y. D.; Caulfield, M. J.; Campbell, H.; Burtt, N. P.; Bonnycastle, L. L.; Boomsma, D. I.; Boekholdt, S. M.; Bergman, R. N.; Barroso, I.; Bandinelli, S.; Ballantyne, C. M.; Assimes, T. L.; Quertermous, T.; Altshuler, D.; Seielstad, M.; Wong, T. Y.; Tai, E. S.; Feranil, A. B.; Kuzawa, C. W.; Adair, L. S.; Taylor, H. A., Jr.; Borecki, I. B.; Gabriel, S. B.; Wilson, J. G.; Holm, H.; Thorsteinsdottir, U.; Gudnason, V.; Krauss, R. M.; Mohlke, K. L.; Ordovas, J. M.; Munroe, P. B.; Kooner, J. S.; Tall, A. R.; Hegele, R. A.; Kastelein, J. J.; Schadt, E. E.; Rotter, J. I.; Boerwinkle, E.; Strachan, D. P.; Mooser, V.; Stefansson, K.; Reilly, M. P.; Samani, N. J.; Schunkert, H.; Cupples, L. A.; Sandhu, M. S.; Ridker, P. M.; Rader, D. J.; van Duijn, C. M.; Peltonen, L.; Abecasis, G. R.; Boehnke, M.; Kathiresan, S. (2010) Biological, clinical and population relevance of 95 loci for blood lipids Nature, 466 (7307),707-13 [Journal Article] Online
Abstract: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
PubMed Accession Number :: 20686565.

Simmons, R. K.; Ko, G. T.; Chan, J. C.; Cockram, C. S.; Nan, J. H.; Griffin, S. J. (2010) Glucose intolerance and cardiovascular risk factors in Hong Kong: Data from two occupation-based cross-sectional surveys Diabetes Res Clin Pract, , [Journal Article] Online
Abstract: AIMS: To examine the distribution of plasma glucose and related cardiovascular risk factors in two occupation-based cross-sectional surveys in a Chinese ethnic population. METHODS: Two cross-sectional surveys in a Hong Kong working population. In 1990, 1496 participants aged 18-66 years underwent an OGTT, anthropometric, and other biochemical measures. Identical measures were collected from 534 participants aged 20-72 years in 2001-2003. Data were direct age-standardised to compare CVD risk factor prevalence. Linear regression modelling was used to examine the distribution of continuous CVD risk factors. RESULTS: Mean (SD) 2-h plasma glucose values were 5.6mmol/l (2.1) in 1990 and 6.5mmol/l (2.5) in 2001-2003, an apparent increase of 0.5mmol/l (95% CI 0.3 to 0.7, p<0.001) after age and sex adjustment. However, there was no significant difference in the age-standardised prevalence of glucose intolerance, overweight or obesity. There were significantly smaller proportions of women with hypertension and hyperlipidaemia and male smokers in the second compared to the first survey. CONCLUSIONS: We observed a relatively adverse glycaemia profile, which may have worsened over time, in two healthy populations of survey respondents, with comparatively low rates of most CVD risk factors. This has implications for the future burden of disease associated with hyperglycaemia in this population.
PubMed Accession Number :: 20675005.

Naska, A.; Orfanos, P.; Trichopoulou, A.; May, A. M.; Overvad, K.; Jakobsen, M. U.; Tjonneland, A.; Halkjaer, J.; Fagherazzi, G.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Rohrmann, S.; Hermann, S.; Steffen, A.; Haubrock, J.; Oikonomou, E.; Dilis, V.; Katsoulis, M.; Sacerdote, C.; Sieri, S.; Masala, G.; Tumino, R.; Mattiello, A.; Bueno-de-Mesquita, H. B.; Skeie, G.; Engeset, D.; Barricarte, A.; Rodriguez, L.; Dorronsoro, M.; Sanchez, M. J.; Chirlaque, M. D.; Agudo, A.; Manjer, J.; Wirfalt, E.; Hellstrom, V.; Shungin, D.; Khaw, K. T.; Wareham, N. J.; Spencer, E. A.; Freisling, H.; Slimani, N.; Vergnaud, A. C.; Mouw, T.; Romaguera, D.; Odysseos, A.; Peeters, P. H. (2010) Eating out, weight and weight gain. A cross-sectional and prospective analysis in the context of the EPIC-PANACEA study Int J Obes (Lond), , [Journal Article] Online
Abstract: Objective:The aim of this study was to examine the association of body mass index (BMI) and weight gain with eating at restaurants and similar establishments or eating at work among 10 European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Subjects:This study included a representative sample of 24 310 randomly selected EPIC participants.Methods:Single 24-h dietary recalls with information on the place of consumption were collected using standardized procedures between 1995 and 2000. Eating at restaurants was defined to include all eating and drinking occasions at restaurants, cafeterias, bars and fast food outlets. Eating at work included all eating and drinking occasions at the workplace. Associations between eating at restaurants or eating at work and BMI or annual weight changes were assessed using sex-specific linear mixed-effects models, controlling for potential confounders.Results:In southern Europe energy intake at restaurants was higher than intake at work, whereas in northern Europe eating at work appeared to contribute more to the mean daily intake than eating at restaurants. Cross-sectionally, eating at restaurants was found to be positively associated with BMI only among men (beta=+0.24, P=0.003). Essentially no association was found between BMI and eating at work among both genders. In a prospective analysis among men, eating at restaurants was found to be positively, albeit nonsignificantly, associated with weight gain (beta=+0.05, P=0.368). No association was detected between energy intake at restaurants and weight changes, controlling for total energy intake.Conclusion:Among men, eating at restaurants and similar establishments was associated with higher BMI and possibly weight gain.International Journal of Obesity advance online publication, 27 July 2010; doi:10.1038/ijo.2010.142.
PubMed Accession Number :: 20661252.

Surtees, P. G.; Wainwright, N. W.; Luben, R.; Wareham, N. J.; Bingham, S. A.; Khaw, K. T. (2010) Mastery is associated with cardiovascular disease mortality in men and women at apparently low risk Health Psychol, 29 (4),412-20 [Journal Article] Online
Abstract: Objective: We examine the prospective relationship between mastery, where limited mastery is defined as the inability to control negative emotions (and perceiving stressful experiences as beyond personal control), and cardiovascular disease (CVD) mortality particularly among individuals at apparently low CVD risk. Design: Prospective population-based study of 19,067 men and women, aged 41-80 years with no previous heart disease or stroke at baseline assessment. Main Outcome Measures: Primary outcome measure CVD mortality. Results: A total of 791 CVD deaths were recorded up to June 2009 during a median 11.3 person-years of follow-up. Limited perceived mastery over life circumstances was associated with an increased risk of CVD mortality, independently of biological, lifestyle, and socioeconomic risk factors (hazard ratio 1.11 per SD decrease in mastery score, 95% confidence interval 1.01-1.21). This association was more pronounced among those participants apparently at low CVD risk (p = .01 for test of interaction according to the number of CVD risk factors at baseline). Conclusions: Limited perceived control over life circumstances is associated with an increased risk of CVD mortality, independently of classical cardiovascular risk factors, and particularly among those at apparently low risk. Future attention should be given to this potentially modifiable personal characteristic, through the design of preliminary intervention studies, to reduce cardiovascular risk. (PsycINFO Database Record (c) 2010 APA, all rights reserved).
PubMed Accession Number :: 20658829.

King, A. C.; Parkinson, K. N.; Adamson, A. J.; Murray, L.; Besson, H.; Reilly, J. J.; Basterfield, L. (2010) Correlates of objectively measured physical activity and sedentary behaviour in English children Eur J Public Health, , [Journal Article] Online
Abstract: BACKGROUND: Evidence on the correlates of objectively measured physical activity and sedentary behaviour in childhood is limited. This study aimed to identify correlates of physical activity and sedentary behaviour among 7-year-old children in England. METHODS: Physical activity was measured using Actigraph accelerometry in 480 participants as part of the Gateshead Millennium Study during 2006-07. Twenty-two potential correlates across five domains (demographic and biological; psychological, cognitive and emotional; behavioural; social and cultural; physical environmental) were tested for associations with total volume of habitual physical activity, moderate-vigorous intensity physical activity (MVPA) and sedentary behaviour. Multiple linear regression analysis was used. RESULTS: Seven correlates, including four that are potentially modifiable, were significantly associated with total physical activity, MVPA and sedentary behaviour in final models: gender, child weight status, maternal age, child interest in active play, active commuting to school, parenting practice and season. Four of these variables were significantly associated with all three constructs in final models. The final models explained 18, 18 and 24% of variance in total volume of physical activity, MVPA and sedentary behaviour, respectively. CONCLUSION: A number of potentially modifiable factors are associated with increased physical activity and/or reduced sedentary behaviour in English children. These could be valuable targets of future interventions.
PubMed Accession Number :: 20650946.

Romaguera, D.; Angquist, L.; Du, H.; Jakobsen, M. U.; Forouhi, N. G.; Halkjaer, J.; Feskens, E. J.; van der, A. Dl; Masala, G.; Steffen, A.; Palli, D.; Wareham, N. J.; Overvad, K.; Tjonneland, A.; Boeing, H.; Riboli, E.; Sorensen, T. I. (2010) Dietary determinants of changes in waist circumference adjusted for body mass index - a proxy measure of visceral adiposity PLoS One, 5 (7),e11588 [Journal Article] Online
Abstract: BACKGROUND: Given the recognized health effects of visceral fat, the understanding of how diet can modulate changes in the phenotype "waist circumference for a given body mass index (WC(BMI))", a proxy measure of visceral adiposity, is deemed necessary. Hence, the objective of the present study was to assess the association between dietary factors and prospective changes in visceral adiposity as measured by changes in the phenotype WC(BMI). METHODS AND FINDINGS: We analyzed data from 48,631 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Anthropometric measurements were obtained at baseline and after a median follow-up time of 5.5 years. WC(BMI) was defined as the residuals of waist circumference regressed on body mass index, and annual change in WC(BMI) (DeltaWC(BMI), cm/y) was defined as the difference between residuals at follow-up and baseline, divided by follow-up time. The association between energy, energy density (ED), macronutrients, alcohol, glycemic index (GI), glycemic load (GL), fibre and DeltaWC(BMI) was modelled using centre-specific adjusted linear regression, and random-effects meta-analyses to obtain pooled estimates. Men and women with higher ED and GI diets showed significant increases in their WC(BMI), compared to those with lower ED and GI [1 kcal/g greater ED predicted a DeltaWC(BMI) of 0.09 cm (95% CI 0.05 to 0.13) in men and 0.15 cm (95% CI 0.09 to 0.21) in women; 10 units greater GI predicted a DeltaWC(BMI) of 0.07 cm (95% CI 0.03 to 0.12) in men and 0.06 cm (95% CI 0.03 to 0.10) in women]. Among women, lower fibre intake, higher GL, and higher alcohol consumption also predicted a higher DeltaWC(BMI). CONCLUSIONS: Results of this study suggest that a diet with low GI and ED may prevent visceral adiposity, defined as the prospective changes in WC(BMI). Additional effects may be obtained among women of low alcohol, low GL, and high fibre intake.
PubMed Accession Number :: 20644647.

Vergeer, M.; Boekholdt, S. M.; Sandhu, M. S.; Ricketts, S. L.; Wareham, N. J.; Brown, M. J.; de Faire, U.; Leander, K.; Gigante, B.; Kavousi, M.; Hofman, A.; Uitterlinden, A. G.; van Duijn, C. M.; Witteman, J. C.; Jukema, J. W.; Schadt, E. E.; van der Schoot, E.; Kastelein, J. J.; Khaw, K. T.; Dullaart, R. P.; van Tol, A.; Trip, M. D.; Dallinga-Thie, G. M. (2010) Genetic Variation at the Phospholipid Transfer Protein Locus Affects Its Activity and High-Density Lipoprotein Size and Is a Novel Marker of Cardiovascular Disease Susceptibility Circulation, 122 ,470-477 [Journal Article] Online
Abstract: BACKGROUND: -In contrast to clear associations between variants in genes participating in low-density lipoprotein metabolism and cardiovascular disease risk, such associations for high-density lipoprotein (HDL)-related genes are not well supported by recent large studies. We aimed to determine whether genetic variants at the locus encoding phospholipid transfer protein (PLTP), a protein involved in HDL remodeling, underlie altered PLTP activity, HDL particle concentration and size, and cardiovascular disease risk. Methods and Results-We assessed associations between 6 PLTP tagging single nucleotide polymorphisms and PLTP activity in 2 studies (combined n=384) and identified 2 variants that show reproducible associations with altered plasma PLTP activity. A gene score based on these variants is associated with lower hepatic PLTP transcription (P=3.2x10(-18)) in a third study (n=957) and with an increased number of HDL particles of smaller size (P=3.4x10(-17)) in a fourth study (n=3375). In a combination of 5 cardiovascular disease case-control studies (n=4658 cases and 11 459 controls), a higher gene score was associated with a lower cardiovascular disease risk (per-allele odds ratio, 0.94; 95% confidence interval, 0.90 to 0.98; P=1.2x10(-3); odds ratio for highest versus lowest gene score, 0.69; 95% confidence interval, 0.55 to 0.86; P=1.0x10(-3)). Conclusions-A gene score based on 2 PLTP single nucleotide polymorphisms is associated with lower PLTP transcription and activity, an increased number of HDL particles, smaller HDL size, and decreased risk of cardiovascular disease. These findings indicate that PLTP is a proatherogenic entity and suggest that modulation of specific elements of HDL metabolism may offer cardiovascular benefit.
PubMed Accession Number :: 20644014.

Arsenault, B. J.; Lemieux, I.; Despres, J. P.; Wareham, N. J.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2010) The hypertriglyceridemic-waist phenotype and the risk of coronary artery disease: results from the EPIC-Norfolk Prospective Population Study Cmaj, 182 ,1427-1432 [Journal Article] Online
Abstract: BACKGROUND: Screening for increased waist circumference and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) has been proposed as an inexpensive approach to identify patients with excess intra-abdominal adiposity and associated metabolic abnormalities. We examined the relationship between the hypertriglyceridemic-waist phenotype to the risk of coronary artery disease in apparently healthy individuals. METHODS: A total of 21 787 participants aged 45-79 years were followed for a mean of 9.8 (standard deviation 1.7) years. Coronary artery disease developed in 2109 of them during follow-up. The hypertriglyceridemic-waist phenotype was defined as a waist circumference of 90 cm or more and a triglyceride level of 2.0 mmol/L or more in men, and a waist circumference of 85 cm or more and a triglyceride level of 1.5 mmol/L or more in women. RESULTS: Compared with participants who had a waist circumference and triglyceride level below the threshold, those with the hypertriglyceridemic-waist phenotype had higher blood pressure indices, higher levels of apolipoprotein B and C-reactive protein, lower levels of high-density lipoprotein cholesterol and apolipoprotein A-I, and smaller low-density lipoprotein particles. Among men, those with the hypertriglyceridemic-waist phenotype had an unadjusted hazard ratio for future coronary artery disease of 2.40 (95% confidence interval [CI] 2.02-2.87) compared with men who did not have the phenotype. Women with the phenotype had an unadjusted hazard ratio of 3.84 (95% CI 3.20-4.62) compared with women who did not have the phenotype. INTERPRETATION: Among participants from a European cohort representative of a contemporary Western population, the hypertriglyceridemic-waist phenotype was associated with a deteriorated cardiometabolic risk profile and an increased risk for coronary artery disease.
PubMed Accession Number :: 20643837.

Owen, C. G.; Nightingale, C. M.; Rudnicka, A. R.; Ekelund, U.; McMinn, A. M.; van Sluijs, E. M.; Griffin, S. J.; Cook, D. G.; Whincup, P. H. (2010) Family dog ownership and levels of physical activity in childhood: findings from the child heart and health study in England Am J Public Health, 100 (9),1669-71 [Journal Article] Online
Abstract: Dog ownership is associated with higher physical activity levels in adults; whether this association occurs in children is unknown. We used accelerometry to examine physical activity levels in 2065 children aged 9 to 10 years. Children from dog-owning families spent more time in light or moderate to vigorous physical activity and recorded higher levels of activity counts per minute (25; 95% confidence interval [CI] = 6, 44) and steps per day (357; 95% CI = 14, 701) than did children without dogs.
PubMed Accession Number :: 20634441.

Aleksandrova, K.; Jenab, M.; Boeing, H.; Jansen, E.; Bueno-de-Mesquita, H. B.; Rinaldi, S.; Riboli, E.; Overvad, K.; Dahm, C. C.; Olsen, A.; Tjonneland, A.; Boutron-Ruault, M. C.; Clavel-Chapelon, F.; Morois, S.; Palli, D.; Krogh, V.; Tumino, R.; Vineis, P.; Panico, S.; Kaaks, R.; Rohrmann, S.; Trichopoulou, A.; Lagiou, P.; Trichopoulos, D.; van Duijnhoven, F. J.; Leufkens, A. M.; Peeters, P. H.; Rodriguez, L.; Bonet, C.; Sanchez, M. J.; Dorronsoro, M.; Navarro, C.; Barricarte, A.; Palmqvist, R.; Hallmans, G.; Khaw, K. T.; Wareham, N.; Allen, N. E.; Spencer, E.; Romaguera, D.; Norat, T.; Pischon, T. (2010) Circulating C-Reactive Protein Concentrations and Risks of Colon and Rectal Cancer: A Nested Case-Control Study Within the European Prospective Investigation into Cancer and Nutrition Am J Epidemiol, 172 ,407-418 [Journal Article] Online
Abstract: The authors investigated associations between serum C-reactive protein (CRP) concentrations and colon and rectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (1992-2003) among 1,096 incident cases and 1,096 controls selected using risk-set sampling and matched on study center, age, sex, time of blood collection, fasting status, menopausal status, menstrual cycle phase, and hormone replacement therapy. In conditional logistic regression with adjustment for education, smoking, nutritional factors, body mass index, and waist circumference, CRP showed a significant nonlinear association with colon cancer risk but not rectal cancer risk. Multivariable-adjusted relative risks for CRP concentrations of >/=3.0 mg/L versus <1.0 mg/L were 1.36 (95% confidence interval (CI): 1.00, 1.85; P-trend = 0.01) for colon cancer and 1.02 (95% CI: 0.67, 1.57; P-trend = 0.65) for rectal cancer. Colon cancer risk was significantly increased in men (relative risk = 1.74, 95% CI: 1.11, 2.73; P-trend = 0.01) but not in women (relative risk = 1.06, 95% CI: 0.67, 1.68; P-trend = 0.13). Additional adjustment for C-peptide, glycated hemoglobin, and high density lipoprotein cholesterol did not attenuate these results. These data provide evidence that elevated CRP concentrations are related to a higher risk of colon cancer but not rectal cancer, predominantly among men and independently of obesity, insulin resistance, and dyslipidemia.
PubMed Accession Number :: 20634278.

Chamnan, P.; Simmons, R. K.; Forouhi, N. G.; Luben, R. R.; Khaw, K. T.; Wareham, N. J.; Griffin, S. J. (2010) Incidence of type 2 diabetes using proposed HbA1c diagnostic criteria in the EPIC-Norfolk cohort: implications for preventive strategies Diabetes Care, , [Journal Article] Online
Abstract: AbstractObjectives: To evaluate the incidence and relative risk of type 2 diabetes defined by the newly proposed HbA(1c) diagnostic criteria in groups categorised by different baseline HbA(1c) levels. Research Design and Methods: Using data from the EPIC-Norfolk cohort with repeat HbA(1c) measurements, we estimated the prevalence of known and previously-undiagnosed diabetes at baseline (baseline HbA(1c) >/=6.5%) and the incidence of diabetes over 3 years. We also examined the incidence and corresponding odds ratios (OR) by different levels of baseline HbA(1c). Incident diabetes was defined clinically (self-report at follow-up, prescribed diabetes medication or inclusion on a diabetes register) and/or biochemically (HbA(1c) >/=6.5% at the second health assessment). Results: Overall prevalence of diabetes was 4.7%; 41% of prevalent cases were previously undiagnosed. Among 5,735 participants without diabetes at baseline (identified clinically and/or using HbA(1c) criteria), 72 developed diabetes over 3 years (1.3%; 95%CI 1.0-1.5), of which half (49%) were identified using the HbA(1c) criteria. Six percent of the total population had a baseline HbA(1c) in the range 6.0-6.4%; one-third of incident cases arose in this group. Incidence of diabetes in this group was 15 times higher than in those with a baseline HbA(1c) of <5.0% (OR 15.5; 95%CI 7.2-33.3). Conclusions: The cumulative incidence of diabetes defined using a newly proposed HbA(1c) threshold in this middle-aged British cohort was 1.3% over 3 years. Targeting interventions to individuals with an HbA(1c) of 6.0-6.4% might represent a feasible preventive strategy, although complementary population-based preventive strategies are also needed to reduce the growing burden of diabetes.
PubMed Accession Number :: 20622160.

Mbanya, J. C.; Motala, A. A.; Sobngwi, E.; Assah, F. K.; Enoru, S. T. (2010) Diabetes in sub-Saharan Africa Lancet, 375 (9733),2254-66 [Journal Article] Online
Abstract: In Sub-Saharan Africa, prevalence and burden of type 2 diabetes are rising quickly. Rapid uncontrolled urbanisation and major changes in lifestyle could be driving this epidemic. The increase presents a substantial public health and socioeconomic burden in the face of scarce resources. Some types of diabetes arise at younger ages in African than in European populations. Ketosis-prone atypical diabetes is mostly recorded in people of African origin, but its epidemiology is not understood fully because data for pathogenesis and subtypes of diabetes in sub-Saharan African communities are scarce. The rate of undiagnosed diabetes is high in most countries of sub-Saharan Africa, and individuals who are unaware they have the disorder are at very high risk of chronic complications. Therefore, the rate of diabetes-related morbidity and mortality in this region could grow substantially. A multisectoral approach to diabetes control and care is vital for expansion of socioculturally appropriate diabetes programmes in sub-Saharan African countries.
PubMed Accession Number :: 20609971.

Foster, P. J.; Broadway, D. C.; Hayat, S.; Luben, R.; Dalzell, N.; Bingham, S.; Wareham, N. J.; Khaw, K. T. (2010) Refractive error, axial length and anterior chamber depth of the eye in British adults: the EPIC-Norfolk Eye Study Br J Ophthalmol, 94 (7),827-30 [Journal Article] Online
Abstract: PURPOSE: To describe the distribution, and demographic and socioeconomic correlates of refractive error and related ocular biometry in an older British population. METHODS: Refractive error was measured using an auto-refractor without cycloplegia. Pseudophakic individuals and those who had undergone refractive surgery were excluded from analysis. Axial length and anterior chamber depth were measured using partial coherence laser interferometry. Occupation category and highest educational achievement were recorded. RESULTS: Biometric data were available for 2519 people (1090 men, 1429 women; 93.2% of all participants) aged 48 to 88 years. Refractive data were available for both eyes in 2210 bilaterally phakic participants. Among phakic individuals, axial length of the eye was strongly inversely correlated with refractive error in both men and women (p<0.001). Axial length of the eye was strongly, independently related to height, weight and social class, but most strongly related to educational achievement. In contrast, anterior chamber depth varied with age and sex, but not with socioeconomic status. There was a significant inverse association between anterior chamber depth and refraction in women (p<0.001) but not in men (p=0.495). CONCLUSION: Refractive error in this predominantly white older UK population was associated with axial biometry and sociodemographic characteristics. Educational status was the strongest determinant of axial length.
PubMed Accession Number :: 20606021.

Wilks, D. C.; Besson, H.; Lindroos, A. K.; Ekelund, U. (2010) Objectively measured physical activity and obesity prevention in children, adolescents and adults: a systematic review of prospective studies Obes Rev, , [Journal Article] Online
Abstract: Summary This study aimed at synthesizing the prospective associations between measured physical activity (PA) and change in adiposity in children, adolescents and adults following from two previous reviews. Search terms were adapted and a systematic literature search was conducted (January 2000-September 2008) and later updated (up to October 2009), considering observational and intervention studies of weight gain that measured both PA and body composition. Sixteen observational studies (six comprising adults) and five trials (one comprising adults) were eligible. For consistency, whenever possible either baseline PA energy expenditure or accelerometer output (counts min(-1)) and change in per cent body fat were the extracted exposure and outcome measures. Results of observational studies suggest that PA is not strongly prospectively related with adiposity: five studies on children and three on adults reported no association between baseline PA and change in adiposity, one study found a weak positive association and the other studies observed a weak negative association. Negative associations were more frequently observed in studies that analysed the association between change in the exposure and outcome. Intervention studies show generally no effect on either PA or adiposity. In conclusion, despite the well-established health benefits of PA, it may not be a key determinant of excessive gain in adiposity.
PubMed Accession Number :: 20604868.

Moayyeri, A.; Besson, H.; Luben, R. N.; Wareham, N. J.; Khaw, K. T. (2010) The association between physical activity in different domains of life and risk of osteoporotic fractures Bone, 47 (3),693-700 [Journal Article] Online
Abstract: A large body of epidemiological evidence suggests an inverse relationship between physical activity and risk of fractures. However, it is unclear how this association varies according to the domain of life in which the activity is undertaken. In this analysis of the European Prospective Investigation of Cancer- Norfolk study, we assessed total and domain-specific physical activity using a validated questionnaire (EPAQ2) in 14,903 participants (6,514 men, mean age 62yr) who also underwent quantitative ultrasound of the heel. After a median follow-up of 7.5years, there were 504 fractures of which 164 were hip fractures. In multivariable linear regression analysis, broadband ultrasound attenuation (BUA) was positively associated with total and leisure time activities while showing no association with transportation and work activities. Home activities were associated with a lower BUA among younger participants. In multivariable Cox proportional-hazards models, moderate activities at home and in leisure time were associated with lower hip fracture risk among women (hazard ratios [HR] 0.51 and 0.55, p value 0.02 and 0.03, respectively). Among men, leisure time activities were associated with lower risk of hip fracture (HR=0.58; p for trend<0.001) whereas activities at home were associated with higher risk of any fracture (HR=1.25; p for trend=0.008). Walking for leisure or transport was associated with lower risk of fracture in both men and women. Multivariable fractional polynomial modelling showed a U-shaped association between home activities and fracture risk especially among women. This study suggests that different domains of physical activity may relate differently to fracture risk and these relationships may vary by sex.
PubMed Accession Number :: 20601303.

Vergnaud, A. C.; Norat, T.; Romaguera, D.; Mouw, T.; May, A. M.; Travier, N.; Luan, J.; Wareham, N.; Slimani, N.; Rinaldi, S.; Couto, E.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Cottet, V.; Palli, D.; Agnoli, C.; Panico, S.; Tumino, R.; Vineis, P.; Agudo, A.; Rodriguez, L.; Sanchez, M. J.; Amiano, P.; Barricarte, A.; Huerta, J. M.; Key, T. J.; Spencer, E. A.; Bueno-de-Mesquita, B.; Buchner, F. L.; Orfanos, P.; Naska, A.; Trichopoulou, A.; Rohrmann, S.; Hermann, S.; Boeing, H.; Buijsse, B.; Johansson, I.; Hellstrom, V.; Manjer, J.; Wirfalt, E.; Jakobsen, M. U.; Overvad, K.; Tjonneland, A.; Halkjaer, J.; Lund, E.; Braaten, T.; Engeset, D.; Odysseos, A.; Riboli, E.; Peeters, P. H. (2010) Meat consumption and prospective weight change in participants of the EPIC-PANACEA study Am J Clin Nutr, 92 ,398-407 [Journal Article] Online
Abstract: BACKGROUND: Meat intake may be related to weight gain because of its high energy and fat content. Some observational studies have shown that meat consumption is positively associated with weight gain, but intervention studies have shown mixed results. OBJECTIVE: Our objective was to assess the association between consumption of total meat, red meat, poultry, and processed meat and weight gain after 5 y of follow-up, on average, in the large European population who participated in the European Prospective Investigation into Cancer and Nutrition-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating Out of Home and Obesity (EPIC-PANACEA) project. DESIGN: A total of 103,455 men and 270,348 women aged 25-70 y were recruited between 1992 and 2000 in 10 European countries. Diet was assessed at baseline with the use of country-specific validated questionnaires. A dietary calibration study was conducted in a representative subsample of the cohort. Weight and height were measured at baseline and self-reported at follow-up in most centers. Associations between energy from meat (kcal/d) and annual weight change (g/y) were assessed with the use of linear mixed models, controlled for age, sex, total energy intake, physical activity, dietary patterns, and other potential confounders. RESULTS: Total meat consumption was positively associated with weight gain in men and women, in normal-weight and overweight subjects, and in smokers and nonsmokers. With adjustment for estimated energy intake, an increase in meat intake of 250 g/d (eg, one steak at approximately 450 kcal) would lead to a 2-kg higher weight gain after 5 y (95% CI: 1.5, 2.7 kg). Positive associations were observed for red meat, poultry, and processed meat. CONCLUSION: Our results suggest that a decrease in meat consumption may improve weight management.
PubMed Accession Number :: 20592131.

Voight, B. F.; Scott, L. J.; Steinthorsdottir, V.; Morris, A. P.; Dina, C.; Welch, R. P.; Zeggini, E.; Huth, C.; Aulchenko, Y. S.; Thorleifsson, G.; McCulloch, L. J.; Ferreira, T.; Grallert, H.; Amin, N.; Wu, G.; Willer, C. J.; Raychaudhuri, S.; McCarroll, S. A.; Langenberg, C.; Hofmann, O. M.; Dupuis, J.; Qi, L.; Segre, A. V.; van Hoek, M.; Navarro, P.; Ardlie, K.; Balkau, B.; Benediktsson, R.; Bennett, A. J.; Blagieva, R.; Boerwinkle, E.; Bonnycastle, L. L.; Bostrom, K. B.; Bravenboer, B.; Bumpstead, S.; Burtt, N. P.; Charpentier, G.; Chines, P. S.; Cornelis, M.; Couper, D. J.; Crawford, G.; Doney, A. S.; Elliott, K. S.; Elliott, A. L.; Erdos, M. R.; Fox, C. S.; Franklin, C. S.; Ganser, M.; Gieger, C.; Grarup, N.; Green, T.; Griffin, S.; Groves, C. J.; Guiducci, C.; Hadjadj, S.; Hassanali, N.; Herder, C.; Isomaa, B.; Jackson, A. U.; Johnson, P. R.; Jorgensen, T.; Kao, W. H.; Klopp, N.; Kong, A.; Kraft, P.; Kuusisto, J.; Lauritzen, T.; Li, M.; Lieverse, A.; Lindgren, C. M.; Lyssenko, V.; Marre, M.; Meitinger, T.; Midthjell, K.; Morken, M. A.; Narisu, N.; Nilsson, P.; Owen, K. R.; Payne, F.; Perry, J. R.; Petersen, A. K.; Platou, C.; Proenca, C.; Prokopenko, I.; Rathmann, W.; Rayner, N. W.; Robertson, N. R.; Rocheleau, G.; Roden, M.; Sampson, M. J.; Saxena, R.; Shields, B. M.; Shrader, P.; Sigurdsson, G.; Sparso, T.; Strassburger, K.; Stringham, H. M.; Sun, Q.; Swift, A. J.; Thorand, B.; Tichet, J.; Tuomi, T.; van Dam, R. M.; van Haeften, T. W.; van Herpt, T.; van Vliet-Ostaptchouk, J. V.; Walters, G. B.; Weedon, M. N.; Wijmenga, C.; Witteman, J.; Bergman, R. N.; Cauchi, S.; Collins, F. S.; Gloyn, A. L.; Gyllensten, U.; Hansen, T.; Hide, W. A.; Hitman, G. A.; Hofman, A.; Hunter, D. J.; Hveem, K.; Laakso, M.; Mohlke, K. L.; Morris, A. D.; Palmer, C. N.; Pramstaller, P. P.; Rudan, I.; Sijbrands, E.; Stein, L. D.; Tuomilehto, J.; Uitterlinden, A.; Walker, M.; Wareham, N. J.; Watanabe, R. M.; Abecasis, G. R.; Boehm, B. O.; Campbell, H.; Daly, M. J.; Hattersley, A. T.; Hu, F. B.; Meigs, J. B.; Pankow, J. S.; Pedersen, O.; Wichmann, H. E.; Barroso, I.; Florez, J. C.; Frayling, T. M.; Groop, L.; Sladek, R.; Thorsteinsdottir, U.; Wilson, J. F.; Illig, T.; Froguel, P.; van Duijn, C. M.; Stefansson, K.; Altshuler, D.; Boehnke, M.; McCarthy, M. I. (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis Nat Genet, 42 ,579-589 [Journal Article] Online
Abstract: By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
PubMed Accession Number :: 20581827.

Wareham, N. J.; Pfister, R. (2010) Diabetes: Glycated hemoglobin is a marker of diabetes and CVD risk Nat Rev Cardiol, 7 (7),367-8 [Journal Article] Online
PubMed Accession Number :: 20577298.

Wijndaele, K.; Brage, S.; Besson, H.; Khaw, K. T.; Sharp, S. J.; Luben, R.; Wareham, N. J.; Ekelund, U. (2010) Television viewing time independently predicts all-cause and cardiovascular mortality: the EPIC Norfolk Study Int J Epidemiol, , [Journal Article] Online
Abstract: BACKGROUND: Television viewing (TV), a highly prevalent behaviour, is associated with higher cardiovascular risk independently of physical activity. The relationship with mortality, however, is relatively unknown. METHODS: We examined the prospective relationship between TV time and all-cause, cardiovascular and cancer mortality in a population-based cohort [The European Prospective Investigation into Cancer and Nutrition (EPIC), Norfolk] of 13 197 men and women {age [SD (standard deviation)]: 61.5 +/- 9.0 years}. Participants were free from stroke, myocardial infarction and cancer at baseline in 1998-2000 and were followed up for death ascertainment until 2009 (9.5 +/- 1.6 years). TV time, total physical activity energy expenditure (PAEE), education level, smoking status, alcohol consumption, anti-hypertensive and lipid-lowering medication use, participant and family history of disease and total energy intake were self-reported; height and weight were measured by standardized procedures. Hazard ratios (HRs) [95% confidence interval (CI)] for mortality were estimated per 1-h/day increase in TV. RESULTS: Each 1-h/day increase in TV time was associated with increased hazard of all-cause (HR = 1.04, 95% CI = 1.01-1.09; 1270 deaths) and cardiovascular (HR = 1.07, 95% CI = 1.01-1.15; 373 deaths), but not cancer mortality (HR = 1.04, 95% CI = 0.98-1.10; 570 deaths). This was independent of gender, age, education, smoking, alcohol, medication, diabetes history, family history of cardiovascular disease and cancer, body mass index (BMI) and PAEE. They were similar when stratified by gender, age, education, BMI and PAEE. The population-attributable fraction for all-cause mortality comparing the highest TV tertile (>3.6 h/day) with the lowest (<2.5 h/day) was 5.4%. CONCLUSIONS: These findings suggest that public health recommendations should consider advising a reduction in TV time, a predominant leisure activity in modern society, in addition to advocating physical activity.
PubMed Accession Number :: 20576628.

Besson, H.; Harwood, C. A.; Ekelund, U.; Finucane, F. M.; McDermott, C. J.; Shaw, P. J.; Wareham, N. J. (2010) Validation of the historical adulthood physical activity questionnaire (HAPAQ) against objective measurements of physical activity Int J Behav Nutr Phys Act, 7 (1),54 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Lifetime physical activity energy expenditure (PAEE) is an important determinant of risk for many chronic diseases but remains challenging to measure. Previously reported historical physical activity (PA) questionnaires appear to be reliable, but their validity is less well established. METHODS: We sought to design and validate an historical adulthood PA questionnaire (HAPAQ) against objective PA measurements from the same individuals. We recruited from a population-based cohort in Cambridgeshire, UK, (Medical Research Council Ely Study) in whom PA measurements, using individually calibrated heart rate monitoring, had been obtained in the past, once between 1994 and 1996 and once between 2000 and 2002. 100 individuals from this cohort attended for interview. Historical PA within the domains of home, work, transport, sport and exercise was recalled using the questionnaire by asking closed questions repeated for several discrete time periods from the age of 20 years old to their current age. The average PAEE from the 2 periods of objective measurements was compared to the self-reported data from the corresponding time periods in the questionnaire. RESULTS: Significant correlations were observed between HAPAQ-derived and objectively measured total PAEE for both time periods (Spearman r = 0.44; P < 0.001). Similarly, self-reported time spent in vigorous PA was significantly correlated with objective measurements of vigorous PA (Spearman r = 0.40; P < 0.001). CONCLUSIONS: HAPAQ demonstrates convergent validity for total PAEE and vigorous PA. This instrument will be useful for ranking individuals according to their past PA in studies of chronic disease aetiology, where activity may be an important underlying factor contributing to disease pathogenesis.
PubMed Accession Number :: 20576086.

Beardsall, K.; Vanhaesebrouck, S.; Ogilvy-Stuart, A. L.; Vanhole, C.; Palmer, C. R.; Ong, K.; Vanweissenbruch, M.; Midgley, P.; Thompson, M.; Thio, M.; Cornette, L.; Ossuetta, I.; Iglesias, I.; Theyskens, C.; de Jong, M.; Gill, B.; Ahluwalia, J. S.; de Zegher, F.; Dunger, D. B. (2010) Prevalence and Determinants of Hyperglycemia in Very Low Birth Weight Infants: Cohort Analyses of the NIRTURE Study J Pediatr, 157 ,715-719.e3 [Journal Article] Online
Abstract: OBJECTIVES: To investigate the prevalence and determinants of hyperglycemia in the preterm population, as part of the Neonatal Insulin Therapy in Europe (NIRTURE) Trial. STUDY DESIGN: We conducted prospective cohort analyses of continuous glucose monitoring data from control infants participating in an international randomized controlled trial. Data were collected from 188 very low birth weight infants (<1500 g). RESULTS: In the first week of life, 80% of infants had evidence of glucose levels >8 mmol/L, and 32% had glucose levels >10 mmol/L >10% of the time. Independent risk factors for hyperglycemia included increasing prematurity, small size at birth, use of inotropes, lipid infusions, and sepsis. There was a lack of association between rate of dextrose infused and risk of hyperglycemia. CONCLUSION: The prevalence of hyperglycemia in the very low birth weight infant is high, with marked variability in prevalence between infants, not simply related to rates of glucose infused, but to other potentially modifiable risk factors.
PubMed Accession Number :: 20570286.

Qi, Q.; Li, H.; Wu, Y.; Liu, C.; Wu, H.; Yu, Z.; Qi, L.; Hu, F. B.; Loos, R. J.; Lin, X. (2010) Combined effects of 17 common genetic variants on type 2 diabetes risk in a Han Chinese population Diabetologia, 53 ,2163-2166 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The recent advent of genome-wide association studies has considerably accelerated the identification of type 2 diabetes loci. We aimed to investigate the combined effects of multiple genetic variants, alone or in combination with conventional risk factors, on type 2 diabetes and diabetes-related traits in Han Chinese. METHODS: We genotyped 17 variants in 17 loci in a population-based Han Chinese cohort including 3,210 unrelated individuals. A genetic risk score (GRS) was calculated on the basis of these variants. The discriminatory ability was assessed by the area under the receiver operating characteristics curve. RESULTS: The odds ratio for type 2 diabetes and hyperglycaemia with each GRS point (per risk allele) was 1.18 (95% CI 1.12-1.23, p = 1.3 x 10(-12)) and 1.12 (95% CI 1.09-1.16, p = 7.5 x 10(-14)), respectively. Compared with participants with GRS </=11.0 (7.63%), those with GRS >/=19.0 (8.87%) had a 4.58-fold higher risk (95% CI 2.49-8.42) of type 2 diabetes. The GRS also showed a significant association with lower beta cell function estimated by HOMA of beta cell function (p = 8.4 x 10(-10)). In addition, we observed significant interactive effects between GRS and BMI on fasting glucose and HbA(1c) levels (p = 0.04 and p = 0.03 for interaction, respectively). Discrimination of diabetes risk was improved (p < 0.001) when the GRS was added to a model including clinical risk factors. The AUCs were 0.62 and 0.77, respectively, for the GRS and conventional clinic risk factors alone, and 0.79 when the GRS was added. CONCLUSIONS/INTERPRETATION: In this Han Chinese population, the GRS of 17 combined variants modestly but significantly improved discrimination of the conventional risk factors for type 2 diabetes.
PubMed Accession Number :: 20556352.

Ong, K. K. (2010) Early Determinants of Obesity Endocr Dev, 19 ,53-61 [Journal Article] Online
Abstract: High rates of overweight and obesity even in very young children argue the case for strategies to prevent overweight from very young ages. Historical studies, prospective birth cohorts, and more recently genetic studies all indicate that the rapid weight gain trajectory to later obesity starts in the first months of life, even from birth. Early puberty and age at menarche are consequences of rapid infant weight gain and childhood overweight, and in turn these adolescent traits are predictive for obesity, diabetes, hypertension and cardiovascular disease events in later life. Understanding of the nutritional, parental and wider determinants of rapid infant weight gain are informing the development of obesity prevention strategies starting in early life. Such strategies could be further refined by future studies that address the specific regulation of infant adiposity, and also by studies that explore whether these life-course trajectories are modifiable during adolescence.
PubMed Accession Number :: 20551668.

Johansson, M.; Relton, C.; Ueland, P. M.; Vollset, S. E.; Midttun, O.; Nygard, O.; Slimani, N.; Boffetta, P.; Jenab, M.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Fagherazzi, G.; Kaaks, R.; Rohrmann, S.; Boeing, H.; Weikert, C.; Bueno-de-Mesquita, H. B.; Ros, M. M.; van Gils, C. H.; Peeters, P. H.; Agudo, A.; Barricarte, A.; Navarro, C.; Rodriguez, L.; Sanchez, M. J.; Larranaga, N.; Khaw, K. T.; Wareham, N.; Allen, N. E.; Crowe, F.; Gallo, V.; Norat, T.; Krogh, V.; Masala, G.; Panico, S.; Sacerdote, C.; Tumino, R.; Trichopoulou, A.; Lagiou, P.; Trichopoulos, D.; Rasmuson, T.; Hallmans, G.; Riboli, E.; Vineis, P.; Brennan, P. (2010) Serum B vitamin levels and risk of lung cancer Jama, 303 (23),2377-85 [Journal Article] Online
Abstract: CONTEXT: B vitamins and factors related to 1-carbon metabolism help to maintain DNA integrity and regulate gene expression and may affect cancer risk. OBJECTIVE: To investigate if 1-carbon metabolism factors are associated with onset of lung cancer. DESIGN, SETTING, AND PARTICIPANTS: The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 519,978 participants from 10 countries between 1992 and 2000, of whom 385,747 donated blood. By 2006, 899 lung cancer cases were identified and 1770 control participants were individually matched by country, sex, date of birth, and date of blood collection. Serum levels were measured for 6 factors of 1-carbon metabolism and cotinine. MAIN OUTCOME MEASURE: Odds ratios (ORs) of lung cancer by serum levels of 4 B vitamins (B(2), B(6), folate [B(9)], and B(12)), methionine, and homocysteine. RESULTS: Within the entire EPIC cohort, the age-standardized incidence rates of lung cancer (standardized to the world population, aged 35-79 years) were 6.6, 44.9, and 156.1 per 100,000 person-years among never, former, and current smokers for men, respectively. The corresponding incidence rates for women were 7.1, 23.9, and 100.9 per 100,000 person-years, respectively. After accounting for smoking, a lower risk for lung cancer was seen for elevated serum levels of B(6) (fourth vs first quartile OR, 0.44; 95% confidence interval [CI], 0.33-0.60; P for trend <.000001), as well as for serum methionine (fourth vs first quartile OR, 0.52; 95% CI, 0.39-0.69; P for trend <.000001). Similar and consistent decreases in risk were observed in never, former, and current smokers, indicating that results were not due to confounding by smoking. The magnitude of risk was also constant with increasing length of follow-up, indicating that the associations were not explained by preclinical disease. A lower risk was also seen for serum folate (fourth vs first quartile OR, 0.68; 95% CI, 0.51-0.90; P for trend = .001), although this was apparent only for former and current smokers. When participants were classified by median levels of serum methionine and B(6), having above-median levels of both was associated with a lower lung cancer risk overall (OR, 0.41; 95% CI, 0.31-0.54), as well as separately among never (OR, 0.36; 95% CI, 0.18-0.72), former (OR, 0.51; 95% CI, 0.34-0.76), and current smokers (OR, 0.42; 95% CI, 0.27-0.65). CONCLUSION: Serum levels of vitamin B(6) and methionine were inversely associated with risk of lung cancer.
Keywords: Adult Aged Cohort Studies Europe/epidemiology Female Humans Incidence Lung Neoplasms/*blood/*epidemiology/prevention & control Male Methionine/*blood Middle Aged Odds Ratio Risk Vitamin B 6/*blood Vitamin B Complex/blood
PubMed Accession Number :: 20551408.

Miles, H. L.; Gidlof, S.; Nordenstrom, A.; Ong, K. K.; Hughes, I. A. (2010) The role of androgens in fetal growth: observational study in two genetic models of disordered androgen signalling Arch Dis Child Fetal Neonatal Ed, 95 ,F435-F438 [Journal Article] Online
Abstract: Objective To examine the role of androgens on birth weight in genetic models of altered androgen signalling. Setting Cambridge Disorders of Sex Development (DSD) database and the Swedish national screening programme for congenital adrenal hyperplasia (CAH). Patients (1) 29 girls with XY karyotype and mutation positive complete androgen insensitivity syndrome (CAIS); (2) 43 girls and 30 boys with genotype confirmed CAH. Main outcome measures Birth weight, birth weight-for-gestational-age (birth weight standard deviation score (SDS)) calculated by comparison with national references. Results Mean birth weight SDS in CAIS XY infants was higher than the reference for girls (mean, 95% CI: 0.4, 0.1 to 0.7; p=0.02) and was similar to the national reference for boys (0.1, -0.2 to 0.4). Birth weight SDS in CAH girls was similar to the national reference for girls (0.0, -0.2 to 0.2) and did not vary by severity of gene mutation. Birth weight SDS in CAH boys was also similar to the national reference for boys (0.2, -0.2 to 0.6). Conclusion CAIS XY infants have a birth weight distribution similar to normal male infants and birth weight is not increased in infants with CAH. Alterations in androgen signalling have little impact on birth weight. Sex dimorphism in birth size is unrelated to prenatal androgen exposure.
PubMed Accession Number :: 20547585.

Wang, T. J.; Zhang, F.; Richards, J. B.; Kestenbaum, B.; van Meurs, J. B.; Berry, D.; Kiel, D. P.; Streeten, E. A.; Ohlsson, C.; Koller, D. L.; Peltonen, L.; Cooper, J. D.; O'Reilly, P. F.; Houston, D. K.; Glazer, N. L.; Vandenput, L.; Peacock, M.; Shi, J.; Rivadeneira, F.; McCarthy, M. I.; Anneli, P.; de Boer, I. H.; Mangino, M.; Kato, B.; Smyth, D. J.; Booth, S. L.; Jacques, P. F.; Burke, G. L.; Goodarzi, M.; Cheung, C. L.; Wolf, M.; Rice, K.; Goltzman, D.; Hidiroglou, N.; Ladouceur, M.; Wareham, N. J.; Hocking, L. J.; Hart, D.; Arden, N. K.; Cooper, C.; Malik, S.; Fraser, W. D.; Hartikainen, A. L.; Zhai, G.; Macdonald, H. M.; Forouhi, N. G.; Loos, R. J.; Reid, D. M.; Hakim, A.; Dennison, E.; Liu, Y.; Power, C.; Stevens, H. E.; Jaana, L.; Vasan, R. S.; Soranzo, N.; Bojunga, J.; Psaty, B. M.; Lorentzon, M.; Foroud, T.; Harris, T. B.; Hofman, A.; Jansson, J. O.; Cauley, J. A.; Uitterlinden, A. G.; Gibson, Q.; Jarvelin, M. R.; Karasik, D.; Siscovick, D. S.; Econs, M. J.; Kritchevsky, S. B.; Florez, J. C.; Todd, J. A.; Dupuis, J.; Hypponen, E.; Spector, T. D. (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study Lancet, 376 (9736),180-188 [Journal Article] Online
Abstract: BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
PubMed Accession Number :: 20541252.

Freitas, R. N.; Khaw, K. T.; Wu, K.; Bowman, R.; Jeffery, H.; Luben, R.; Wareham, N. J.; Bingham, S. A. (2010) A single nucleotide polymorphism in the 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene ( HMGCR) influences the serum triacylglycerol relationship with dietary fat and fibre in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk) study Br J Nutr, 104 ,765-772 [Journal Article] Online
Abstract: The objective of the present study was to investigate the influence of the single nucleotide polymorphism (rs17238540) at the 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene (HMGCR) on the relationship between serum lipids and dietary fat and fibre (NSP). FFQ and pyrosequencing were used to assess cross-sectional dietary intake and HMGCR genotype in a population study with data for serum lipids available. Genotype frequencies and allele distributions for 23 011 participants were: TT 95.65 %, TG 4.29 % and GG 0.06 %; T 97.8 % and G 2.2 %. In regression analyses, the TG+GG group showed a significant positive relationship between TAG and SFA intake (+0.11 (95 % CI 0.02, 0.20) mmol TAG/l; P = 0.017; per 3 % SFA energy increase) while the TT individuals showed no change in the TAG levels related to SFA intake ( - 0.0007 (95 % CI - 0.02, 0.02) mmol TAG/l; P = 0.99). TG+GG individuals showed an inverse relationship between TAG and fibre intake higher ( - 0.14 (95 % CI - 0.22, - 0.05) mmol TAG/l than the TT group ( - 0.04 (95 % CI - 0.06, - 0.02) mmol TAG/l). In both cases the respective coefficient regressions of TAG were different between the genotype groups (Z = 2.27, P = 0.023 for SFA intake; Z = 2.19, P = 0.029 for fibre intake). Individuals carrying the G allele may show a greater response in lower TAG levels with reduced SFA intake and increased fibre intake compared with those homozygous for the T allele. The effectiveness of different dietary interventions to control serum lipids may vary according to HMGCR genotype.
PubMed Accession Number :: 20540816.

Assah, F. K.; Ekelund, U.; Brage, S.; Wright, A.; Mbanya, J. C.; Wareham, N. J. (2010) Accuracy and validity of a combined heart rate and motion sensor for the measurement of free-living physical activity energy expenditure in adults in Cameroon Int J Epidemiol, , [Journal Article] Online
Abstract: BACKGROUND: The increasing burden of non-communicable diseases in sub-Saharan Africa (SSA) warrants rigorous studies of contributing lifestyle factors. Combined heart rate (HR) and movement monitoring make it possible to objectively measure physical activity in free-living individuals. We examined the validity of a combined HR and motion sensor in estimating physical activity energy expenditure (PAEE) in free-living adults in rural and urban Cameroon compared with doubly-labelled water (DLW) as criterion. METHODS: PAEE was measured in 33 free-living rural and urban dwellers by DLW over 7 consecutive days. Simultaneously, the combined sensor recorded HR and uni-axial acceleration. Individual HR vs PAEE calibration was done by a step test. Branched equation modelling was used to estimate PAEE from HR and acceleration. Validity and accuracy of prediction were expressed as mean bias and root mean square error (RMSE). Agreement was analysed using Bland and Altman limits of agreement (LOA). RESULTS: There was no significant mean bias between PAEE estimated from the combined sensor or measured by DLW [mean bias (standard error): -5.4 (5.1) kJ/kg/day; P = 0.3; RMSE = 29.3 kJ/kg/day]. The bias doubled for group compared with individual calibration of HR [-9.1 (5.0) kJ/kg/day, P = 0.08]. PAEE prediction was more accurate in urban compared with rural volunteers. The 95% LOAs between predicted and measured PAEE were approximately 50-60 kJ/kg/day above or below perfect agreement. CONCLUSIONS: Combined HR and movement sensing is a valid method for estimating free-living PAEE on group level in adults in SSA.
PubMed Accession Number :: 20529884.

Elks, C. E.; Loos, R. J.; Sharp, S. J.; Langenberg, C.; Ring, S. M.; Timpson, N. J.; Ness, A. R.; Davey Smith, G.; Dunger, D. B.; Wareham, N. J.; Ong, K. K. (2010) Genetic markers of adult obesity risk are associated with greater early infancy weight gain and growth PLoS Med, 7 (5),e1000284 [Journal Article] Online
Abstract: BACKGROUND: Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity. METHODS AND FINDINGS: Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an "obesity-risk-allele score" comprising the total number of risk alleles (range: 2-15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00-0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023-0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004-0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032-0.284) and with reduced risk of early infancy failure to thrive (odds ratio = 0.92 per allele; 0.86-0.98; p = 0.009). CONCLUSIONS: The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort. Please see later in the article for the Editors' Summary.
PubMed Accession Number :: 20520848.

Sarwar, N.; Aspelund, T.; Eiriksdottir, G.; Gobin, R.; Seshasai, S. R.; Forouhi, N. G.; Sigurdsson, G.; Danesh, J.; Gudnason, V. (2010) Markers of Dysglycaemia and Risk of Coronary Heart Disease in People without Diabetes: Reykjavik Prospective Study and Systematic Review PLoS Med, 7 (5),e1000278 [Journal Article] Online
Abstract: BACKGROUND: Associations between circulating markers of dysglycaemia and coronary heart disease (CHD) risk in people without diabetes have not been reliably characterised. We report new data from a prospective study and a systematic review to help quantify these associations. METHODS AND FINDINGS: Fasting and post-load glucose levels were measured in 18,569 participants in the population-based Reykjavik study, yielding 4,664 incident CHD outcomes during 23.5 y of mean follow-up. In people with no known history of diabetes at the baseline survey, the hazard ratio (HR) for CHD, adjusted for several conventional risk factors, was 2.37 (95% CI 1.79-3.14) in individuals with fasting glucose >/=7.0 mmol/l compared to those <7 mmol/l. At fasting glucose values below 7 mmol/l, adjusted HRs were 0.95 (0.89-1.01) per 1 mmol/l higher fasting glucose and 1.03 (1.01-1.05) per 1 mmol/l higher post-load glucose. HRs for CHD risk were generally modest and nonsignificant across tenths of glucose values below 7 mmol/l. We did a meta-analysis of 26 additional relevant prospective studies identified in a systematic review of Western cohort studies that recorded fasting glucose, post-load glucose, or glycated haemoglobin (HbA(1c)) levels. In this combined analysis, in which participants with a self-reported history of diabetes and/or fasting blood glucose >/=7 mmol/l at baseline were excluded, relative risks for CHD, adjusted for several conventional risk factors, were: 1.06 (1.00-1.12) per 1 mmol/l higher fasting glucose (23 cohorts, 10,808 cases, 255,171 participants); 1.05 (1.03-1.07) per 1 mmol/l higher post-load glucose (15 cohorts, 12,652 cases, 102,382 participants); and 1.20 (1.10-1.31) per 1% higher HbA(1c) (9 cohorts, 1639 cases, 49,099 participants). CONCLUSIONS: In the Reykjavik Study and a meta-analysis of other Western prospective studies, fasting and post-load glucose levels were modestly associated with CHD risk in people without diabetes. The meta-analysis suggested a somewhat stronger association between HbA(1c) levels and CHD risk. Please see later in the article for the Editors' Summary.
PubMed Accession Number :: 20520805.

De Lucia Rolfe, E.; Loos, R. J.; Druet, C.; Stolk, R. P.; Ekelund, U.; Griffin, S. J.; Forouhi, N. G.; Wareham, N. J.; Ong, K. K. (2010) Association between birth weight and visceral fat in adults Am J Clin Nutr, 92 (2),347-352 [Journal Article] Online
Abstract: BACKGROUND: Several studies reported inverse associations between birth weight and central adiposity in adults. However, few studied investigated the contributions of different abdominal fat compartments. OBJECTIVE: We examined associations between birth weight and adult visceral and subcutaneous abdominal fat in the population-based Fenland study. DESIGN: A total of 1092 adults (437 men and 655 women) aged 30-55 y had available data on reported birth weight, standard anthropometric measures, and visceral and subcutaneous abdominal fat estimated by ultrasound. In a subgroup (n = 766), dual-energy X-ray absorptiometry (DXA) assessment of total abdominal fat was performed. Linear regression models were used to analyze relations between birth weight and the various fat variables adjusted for sex, age, education, smoking, and body mass index (BMI). RESULTS: After adjustment for adult BMI, there was an inverse association between birth weight and total abdominal fat [B (partial regression coefficient expressed as SD/1-kg change in birth weight) = -0.09, P = 0.002] and visceral fat (B = -0.07, P = 0.01) but not between birth weight and subcutaneous abdominal fat (B = -0.01, P = 0.3). Tests for interaction showed that adult BMI modified the association between birth weight and visceral fat (P for interaction = 0.01). In stratified analysis, the association between birth weight and visceral fat was apparent only in individuals with the highest BMI tertile (B = -0.08, P = 0.04). CONCLUSIONS: The inverse association between birth weight and adult abdominal fat appeared to be specific to visceral fat. However, associations with birth weight were apparent only after adjustment for adult BMI. Therefore, we suggest that rapid postnatal weight gain, rather than birth weight alone, leads to increased visceral fat.
PubMed Accession Number :: 20519560.

Timpson, N. J.; Forouhi, N. G.; Brion, M. J.; Harbord, R. M.; Cook, D. G.; Johnson, P.; McConnachie, A.; Morris, R. W.; Rodriguez, S.; Luan, J.; Ebrahim, S.; Padmanabhan, S.; Watt, G.; Bruckdorfer, K. R.; Wareham, N. J.; Whincup, P. H.; Chanock, S.; Sattar, N.; Lawlor, D. A.; Smith, G. D. (2010) Genetic variation at the SLC23A1 locus is associated with circulating concentrations of L-ascorbic acid (vitamin C): evidence from 5 independent studies with >15,000 participants Am J Clin Nutr, 92 (2),375-382 [Journal Article] Online
Abstract: BACKGROUND: l-Ascorbic acid is an essential part of the human diet and has been associated with a wide range of chronic complex diseases, including cardiovascular outcomes. To date, there are no confirmed genetic correlates of circulating concentrations of l-ascorbic acid. OBJECTIVE: We aimed to confirm the existence of an association between common variation at the SLC23A1 gene locus and circulating concentrations of l-ascorbic acid. DESIGN: We used a 2-stage design, which included a discovery cohort (the British Women's Heart and Health Study), a series of follow-up cohorts, and meta-analysis (totaling 15,087 participants) to assess the relation between variation at SLC23A1 and circulating concentrations of l-ascorbic acid. RESULTS: In the discovery cohort, variation at rs33972313 was associated with a reduction in circulating concentrations of l-ascorbic acid (-4.15 mumol/L; 95% CI: -0.49, -7.81; P = 0.03 reduction per minor allele). Pooled analysis of the relation between rs33972313 and circulating l-ascorbic acid across all studies confirmed this and showed that each additional rare allele was associated with a reduction in circulating concentrations of l-ascorbic acid of -5.98 mumol/L (95% CI: -8.23, -3.73; P = 2.0 x 10(-7) per minor allele). CONCLUSIONS: A genetic variant (rs33972313) in the SLC23A1 vitamin C active transporter locus was identified that is reliably associated with circulating concentrations of l-ascorbic acid in the general population. This finding has implications more generally for the epidemiologic investigation of relations between circulating l-ascorbic acid and health outcomes.
PubMed Accession Number :: 20519558.

Tan, Q.; Zhao, J. H.; Li, S.; Kruse, T. A.; Christensen, K. (2010) Power assessment for genetic association study of human longevity using offspring of long-lived subjects Eur J Epidemiol, 25 ,501-506 [Journal Article] Online
Abstract: Recently, an indirect genetic association approach that compares genotype frequencies in offspring of long-lived subjects and offspring from random families has been introduced to study gene-longevity associations. Although the indirect genetic association has certain advantages over the direct association approach that compares genotype frequency between centenarians and young controls, the power has been of concern. This paper reports a power study performed on the indirect approach using computer simulation. We perform our simulation study by introducing the current Danish population life table and the proportional hazard model for generating individual lifespan. Family genotype data is generated using a genetic linkage program for given SNP allele frequency. Power is estimated by setting the type I error rate at 0.05 and by calculating the Armitage's chi-squared test statistic for 200 replicate samples for each setting of the specified allele risk and frequency parameters under different modes of inheritance and for different sample sizes. The indirect genetic association analysis is a valid approach for studying gene-longevity association, but the sample size requirement is about 3-4 time larger than the direct approach. It also has low power in detecting non-additive effect genes. Indirect genetic association using offspring from families with both parents as nonagenarians is nearly as powerful as using offspring from families with one centenarian parent. In conclusion, the indirect design can be a good choice for studying longevity in comparison with other alternatives, when relatively large sample size is available.
PubMed Accession Number :: 20512403.

Qi, Q.; Li, H.; Loos, R. J.; Liu, C.; Hu, F. B.; Wu, H.; Yu, Z.; Lin, X. (2010) Association of PCSK1 rs6234 with obesity and related traits in a Chinese Han population PLoS One, 5 (5),e10590 [Journal Article] Online
Abstract: BACKGROUND: Common variants in PCSK1 have been reported to be associated with obesity in populations of European origin. We aimed to replicate this association in Chinese. METHODOLOGY/PRINCIPAL FINDINGS: Two PCSK1 variants rs6234 and rs6235 (in strong LD with each other, r(2) = 0.98) were genotyped in a population-based cohort of 3,210 Chinese Hans. The rs6234 was used for further association analyses with obesity and related traits. We found no significant association of rs6234 with obesity, overweight, BMI, waist circumference, or body fat percentage (P > 0.05) in all participants. However, the rs6234 G-allele showed a significant association with increased risk of combined phenotype of obesity and overweight (OR 1.21[1.03-1.43], P = 0.0193) and a trend toward association with obesity (OR 1.25[0.98-1.61], P = 0.08) in men, but not in women (P > or = 0.29). Consistently, the rs6234 G-allele showed significant association with increased BMI (P = 0.0043), waist circumference (P = 0.008) and body fat percentage (P = 0.0131) only in men, not in women (P > or = 0.24). Interestingly, the rs6234 G-allele was significantly associated with increased HOMA-B (P = 0.0059) and decreased HOMA-S (P = 0.0349) in all participants. CONCLUSION/SIGNIFICANCE: In this study, we found modest evidence for association of the PCSK1 rs6234 with BMI and overweight in men only but not in women, which suggested that PCSK1 rs6234 might not be an important contributor to obesity in Chinese Hans. However, further studies with larger sample sizes are needed to draw a firm conclusion.
PubMed Accession Number :: 20498726.

Peters, T. M.; Moore, S. C.; Xiang, Y. B.; Yang, G.; Shu, X. O.; Ekelund, U.; Ji, B. T.; Tan, Y. T.; Liu da, K.; Schatzkin, A.; Zheng, W.; Chow, W. H.; Matthews, C. E.; Leitzmann, M. F. (2010) Accelerometer-measured physical activity in Chinese adults Am J Prev Med, 38 (6),583-91 [Journal Article] Online
Abstract: BACKGROUND: Following adoption of a Western lifestyle, China is experiencing a decline in physical activity levels, which is projected to contribute to future increases in the burden of chronic diseases. PURPOSE: This study aims to target public health interventions and identify personal characteristics associated with physical activity and sedentary behavior in urban Chinese adults. METHODS: In a sample of 576 men and women aged 40-74 years from Shanghai, multiple logistic regression was used to examine demographic, anthropometric, and lifestyle factors in relation to levels of physical activity and sedentary behavior assessed by Actigraph accelerometers. RESULTS: Participants spent 317 minutes/day in physical activity and 509 minutes/day sedentary. In multivariate models, people aged > or =60 years were significantly less likely than those aged <50 years to engage in physical activity (OR=0.29, 95% CI=0.17, 0.49) and more likely to spend time sedentary (OR=2.77, 95% CI=1.53, 5.05). Similarly, obese individuals were less likely to be physically active (OR=0.34, 95% CI=0.17, 0.66) and they were suggestively more likely to be sedentary (OR=1.87, 95% CI=0.94, 3.71) than normal-weight individuals. Furthermore, current cigarette smokers were less physically active than those who formerly or never smoked (OR=0.47, 95% CI=0.28, 0.78). CONCLUSIONS: Physical activity promotion programs in urban China should target older people, obese individuals, and cigarette smokers, as these population subgroups exhibited low levels of physical activity.
PubMed Accession Number :: 20494234.

Lek, N.; Prentice, P.; Williams, R. M.; Ong, K. K.; Amos Burke, G. A.; Acerini, C. L. (2010) Risk factors for obesity in childhood survivors of suprasellar brain tumours: retrospective study Acta Paediatr, 99 ,1522-1526 [Journal Article] Online
Abstract: Abstract Aim: To characterise post-diagnosis changes in body mass index (BMI) among childhood survivors of suprasellar brain tumours, and to determine the risk factors associated with obesity. Methods: We conducted a retrospective analysis of 46 children (16 boys and 30 girls) with median (IQR) age of 7.49 (3.47-11.59) years at tumour diagnosis, and followed up for 3.93 (1.68-7.27) years. Survival analyses were used to identify risks of developing obesity. Results: There were no sex differences in age at tumour diagnosis, duration of follow-up, tumour types, endocrinopathies, treatment modalities, or baseline BMI SDS. In the first year after tumour diagnosis, DeltaBMI SDS (median; IQR) was greater in girls (1.32; 0.07-2.08) than in boys (0.48; -0.40-0.89) (p = 0.01). At diagnosis, 3/46 children (6%) were obese; this increased to 20/46 (43%) by last follow-up (p < 0.001), and was more common in girls (17/30; 57%) than in boys (3/16; 19%). Female gender (hazard ratio 5.0, 95%-CI 1.2-21.7; p = 0.04) and greater than average baseline BMI (hazard ratio 4.7, 95%-CI 1.1-20.8; p = 0.02) were risk factors for subsequent obesity. Conclusion: Accurate prediction of obesity risk is important and would allow early targeted intervention in high-risk patients.
PubMed Accession Number :: 20491696.

Rohrmann, S.; Linseisen, J.; Jakobsen, M. U.; Overvad, K.; Raaschou-Nielsen, O.; Tjonneland, A.; Boutron-Ruault, M. C.; Kaaks, R.; Becker, N.; Bergmann, M.; Boeing, H.; Khaw, K. T.; Wareham, N. J.; Key, T. J.; Travis, R.; Benetou, V.; Naska, A.; Trichopoulou, A.; Pala, V.; Tumino, R.; Masala, G.; Mattiello, A.; Brustad, M.; Lund, E.; Skeie, G.; Bueno-de-Mesquita, H. B.; Peeters, P. H.; Vermeulen, R. C.; Jakszyn, P.; Dorronsoro, M.; Barricarte, A.; Tormo, M. J.; Molina, E.; Arguelles, M.; Melin, B.; Ericson, U.; Manjer, J.; Rinaldi, S.; Slimani, N.; Boffetta, P.; Vergnaud, A. C.; Khan, A.; Norat, T.; Vineis, P. (2010) Consumption of meat and dairy and lymphoma risk in the european prospective investigation into cancer and nutrition Int J Cancer, , [Journal Article] Online
Abstract: The consumption of meat and other foods of animal origin is a risk factor for several types of cancer, but the results for lymphomas are inconclusive. Therefore, we examined these associations among 411,097 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). During a median follow-up of 8.5 years, 1334 lymphomas (1,267 non-Hodgkin lymphoma, 67 Hodgkin lyphomas) were identified. Consumption of red and processed meat, poultry, milk, and dairy products was assessed by dietary questionnaires. Cox proportional hazard regression was used to evaluate the association of the consumption of these food groups with lymphoma risk. Overall, consumption of foods of animal origin were not associated with an increased risk of NHL or HL, but associations with specific subgroups of NHL entities were noted. A high intake of processed meat was associated with an increased risk of B-cell chronic lymphocytic leukaemia (BCLL) (relative risk (RR) per 50 g intake = 1.31, 95% confidence interval (CI) 1.06-1.63), but a decreased risk of follicular lymphomas (FL) (RR=0.58; 0.38-0.89). A high intake of poultry was related to an increased risk of B-cell lymphomas (RR=1.22, 1.05-1.42 per 10 g intake), FL (RR=1.65; 1.18-2.32), and BCLL (RR=1.54; 1.18-2.01) in the continuous models. In conclusion, no consistent associations between red and processed meat consumption and lymphoma risk were observed, but we found that the consumption of poultry was related to an increased risk of B-cell lymphomas. Chance is a plausible explanation of the observed associations, which need to be confirmed in further studies.
PubMed Accession Number :: 20473877.

Marteau, T. M.; Mann, E.; Prevost, A. T.; Vasconcelos, J. C.; Kellar, I.; Sanderson, S.; Parker, M.; Griffin, S.; Sutton, S.; Kinmonth, A. L. (2010) Impact of an informed choice invitation on uptake of screening for diabetes in primary care (DICISION): randomised trial Bmj, 340 ,c2138 [Journal Article] Online
Abstract: OBJECTIVE: To compare the effect of an invitation promoting informed choice for screening with a standard invitation on attendance and motivation to engage in preventive action. DESIGN: Randomised controlled trial. SETTING: Four English general practices. PARTICIPANTS: 1272 people aged 40-69 years, at risk for diabetes, identified from practice registers using a validated risk score and invited to attend for screening. INTERVENTION: Intervention was a previously validated invitation to inform the decision to attend screening, presenting diabetes as a serious potential problem, and providing details of possible costs and benefits of screening and treatment in text and pie charts. This was compared with a brief, standard invitation simply describing diabetes as a serious potential problem. MAIN OUTCOME MEASURES: The primary end point was attendance for screening. The secondary outcome measures were intention to make changes to lifestyle and satisfaction with decisions made among attenders. RESULTS: The primary end point was analysed for all 1272 participants. 55.8% (353/633) of those in the informed choice group attended for screening, compared with 57.6% (368/639) in the standard invitation group (mean difference -1.8%, 95% confidence interval -7.3% to 3.6%; P=0.51). Attendance was lower among the more deprived group (most deprived third 47.5% v least deprived third 64.3%; P<0.001). Interaction between deprivation and effect of invitation type on attendance was not significant. Among attenders, intention to change behaviour was strong and unaffected by invitation type. CONCLUSIONS: Providing information to support choice did not adversely affect attendance for screening for diabetes. Those from more socially deprived groups were, however, less likely to attend, regardless of the type of invitation received. Further attention to invitation content alone is unlikely to achieve equity in uptake of preventive services. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 73125647.
PubMed Accession Number :: 20466791.

Vergeer, M.; Cohn, D. M.; Boekholdt, S. M.; Sandhu, M. S.; Prins, H. M.; Ricketts, S. L.; Wareham, N. J.; Kastelein, J. J.; Khaw, K. T.; Kamphuisen, P. W.; Dallinga-Thie, G. M. (2010) Lack of association between common genetic variation in endothelial lipase (LIPG) and the risk for CAD and DVT Atherosclerosis, 211 ,551-557 [Journal Article] Online
Abstract: Objectives: Low levels of high-density lipoprotein cholesterol (HDL-C) are a risk factor for coronary artery disease (CAD) and possibly for deep venous thrombosis (DVT). Endothelial lipase is involved in HDL-C metabolism. Common variants in the endothelial lipase gene (LIPG) have been reported to be associated with HDL-C levels and atherothrombosis, but these findings were not consistent. We determined whether five tagging single nucleotide polymorphisms (SNP) in LIPG were associated with lipid parameters, the risk of CAD and the risk of DVT. Methods: We used the prospective case-control study nested in the EPIC-Norfolk cohort (1138 CAD cases, 2237 matched controls) for the initial association study and, subsequently, the ACT study (185 patients with documented DVT, 586 patients in which DVT was ruled out) to replicate our findings regarding DVT risk. Results: In EPIC-Norfolk, we found that the minor allele of one SNP, rs2000813 (p.T111I), was associated with moderately higher HDL-C and apolipoprotein A-I levels, higher HDL particle number and larger HDL size. No variants were associated with CAD risk, but three variants were associated with DVT risk (odds ratios 0.60 [95%CI 0.43-0.84], 2.04 [95%CI 1.40-2.98] and 1.67 [95%CI 1.18-2.38] per minor allele for rs2000813, rs6507931 and rs2097055 respectively, p<0.005 for each). However, the association between LIPG SNPs and DVT risk could not be replicated in the ACT study. Conclusions: Our data support a modest association between the LIPG rs2000813 variant and parameters of HDL metabolism, but no association between common genetic variants in LIPG and CAD or DVT risk.
PubMed Accession Number :: 20466371.

Ogilvie, D.; Mitchell, R.; Mutrie, N.; Petticrew, M.; Platt, S. (2010) Shoe leather epidemiology: active travel and transport infrastructure in the urban landscape Int J Behav Nutr Phys Act, 7 (1),43 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Building new transport infrastructure could help to promote changes in patterns of mobility, physical activity, and other determinants of population health such as economic development. However, local residents may not share planners' goals or assumptions about the benefits of such interventions. A particularly contentious example is the construction of major roads close to deprived residential areas. We report the qualitative findings of the baseline phase of a longitudinal mixed-method study of a new urban section of the M74 motorway in Glasgow, Scotland, that aims to combine quantitative epidemiological and spatial data with qualitative interview data from local residents. METHODS: We interviewed 12 residents purposively sampled from a larger study cohort of 1322 to include men and women, different age groups, and people with and without cars, all living within 400 metres of the proposed route of the new motorway. We elicited their views and experiences of the local urban environment and the likely impact of the new motorway using a topic guide based on seven key environmental constructs (aesthetics, green space, convenience of routes, access to amenities, traffic, road danger and personal danger) reflecting an overall ecological model of walking and cycling. RESULTS: Traffic was widely perceived to be heavy despite a low local level of car ownership. Few people cycled, and cycling on the roads was widely perceived to be dangerous for both adults and children. Views about the likely impacts of the new motorway on traffic congestion, pollution and the pleasantness of the local environment were polarised. A new motorway has potential to cause inequitable psychological or physical severance of routes to local amenities, and people may not necessarily use local walking routes or destinations such as parks and shops if these are considered undesirable, unsafe or 'not for us'. Public transport may have the potential to promote or discourage active travel in different socioeconomic contexts. CONCLUSIONS: Altering the urban landscape may influence walking and cycling in ways that vary between individuals, may be inequitable, and may not be predictable from quantitative data alone. A more applied ecological behavioural model may be required to capture these effects.
PubMed Accession Number :: 20459803.

Owen, C. G.; Nightingale, C. M.; Rudnicka, A. R.; Sattar, N.; Cook, D. G.; Ekelund, U.; Whincup, P. H. (2010) Physical activity, obesity and cardiometabolic risk factors in 9- to 10-year-old UK children of white European, South Asian and black African-Caribbean origin: the Child Heart And health Study in England (CHASE) Diabetologia, 53 ,1620-1630 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Physical inactivity is implicated in unfavourable patterns of obesity and cardiometabolic risk in childhood. However, few studies have quantified these associations using objective physical activity measurements in children from different ethnic groups. We examined these associations in UK children of South Asian, black African-Caribbean and white European origin. METHODS: This was a cross-sectional study of 2,049 primary school children in three UK cities, who had standardised anthropometric measurements, provided fasting blood samples and wore activity monitors for up to 7 days. Data were analysed using multilevel linear regression and allowing for measurement error. RESULTS: Overall physical activity levels showed strong inverse graded associations with adiposity markers (particularly sum of skinfold thicknesses), fasting insulin, HOMA insulin resistance, triacylglycerol and C-reactive protein; for an increase of 100 counts of physical activity per min of registered time, levels of these factors were 12.2% (95% CI 10.2-14.1%), 10.2% (95% CI 7.5-12.8%), 10.2% (95% CI 7.5-12.8%), 5.8% (95% CI 4.0-7.5%) and 19.2% (95% CI 13.9-24.2%) lower, respectively. Similar increments in physical activity levels were associated with lower diastolic blood pressure (1.0 mmHg, 95% CI 0.6-1.5 mmHg) and LDL-cholesterol (0.04 mmol/l, 95% CI 0.01-0.07 mmol/l), and higher HDL-cholesterol (0.02 mmol/l, 95% CI 0.01-0.04 mmol/l). Moreover, associations were broadly similar in strength in all ethnic groups. All associations between physical activity and cardiometabolic risk factors were reduced (albeit variably) after adjustment for adiposity. CONCLUSIONS/INTERPRETATION: Objectively measured physical activity correlates at least as well with obesity and cardiometabolic risk factors in South Asian and African-Caribbean children as in white European children, suggesting that efforts to increase activity levels in such groups would have equally beneficial effects.
PubMed Accession Number :: 20454952.

Sarwar, N.; Sandhu, M. S.; Ricketts, S. L.; Butterworth, A. S.; Di Angelantonio, E.; Boekholdt, S. M.; Ouwehand, W.; Watkins, H.; Samani, N. J.; Saleheen, D.; Lawlor, D.; Reilly, M. P.; Hingorani, A. D.; Talmud, P. J.; Danesh, J. (2010) Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies Lancet, 375 (9726),1634-9 [Journal Article] Online
Abstract: BACKGROUND: Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. METHODS: We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. FINDINGS: The minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride. INTERPRETATION: These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. FUNDING: British Heart Foundation, UK Medical Research Council, Novartis.
PubMed Accession Number :: 20452521.

Szopa, M.; Meirhaeghe, A.; Luan, J.; Moreno, L. A.; Gonzalez-Gross, M.; Vidal-Puig, A.; Cooper, C.; Hagen, R.; Amouyel, P.; Wareham, N. J.; Loos, R. J. (2010) No association between polymorphisms in the INSIG1 gene and the risk of type 2 diabetes and related traits Am J Clin Nutr, 92 ,252-257 [Journal Article] Online
Abstract: BACKGROUND: The insulin-induced gene 1 (INSIG1) encodes a protein that blocks proteolytic activation of sterol regulatory element binding proteins, which are transcription factors that activate genes that regulate cholesterol, fatty acid, and glucose metabolism. OBJECTIVE: We tested for associations between 6 INSIG1 tag single nucleotide polymorphisms (SNPs) (and captured all common variations in INSIG1) and the risk of type 2 diabetes (T2D), obesity, and related traits in 10,567 adults and 1155 adolescents from 5 population-based studies, a T2D case-control study, and a T2D case-series. DESIGN: We genotyped tag SNPs and tested them for associations with the risk of T2D or obesity and with body mass index, waist circumference, systolic and diastolic blood pressure, and concentrations of fasting glucose, 2-h oral-glucose-tolerance test glucose, cholesterol, and triglyceride, assuming an additive effect of the minor allele. Dominant effects were tested for the less-frequent SNPs (minor allele frequency <5%). Summary statistics of each study underwent meta-analysis. RESULTS: Meta-analyses, which included 1655 T2D cases and 2911 control subjects, showed no association between any of the INSIG1 SNPs and T2D (P > 0.08). Furthermore, none of the SNPs showed an association with obesity in 1666 obese and 5737 nonobese individuals (P > 0.17). In agreement, none of the associations between the SNPs and any of the metabolic traits showed convincing associations in the 7562 adults from 4 population-based studies. Although a few nominally significant associations emerged, none of the associations survived multiple-testing correction. We observed no convincing associations with any of the studied traits in 1155 adolescents. CONCLUSION: Although our study was sufficiently powered to identify small effects, the results suggest that common variation in INSIG1 is unlikely to have a major effect on T2D and obesity risk and related traits in white Europeans.
PubMed Accession Number :: 20444954.

Jones, N. R.; Jones, A.; van Sluijs, E. M.; Panter, J.; Harrison, F.; Griffin, S. J. (2010) School environments and physical activity: The development and testing of an audit tool Health Place, 16 ,776-783 [Journal Article] Online
Abstract: The aim of this study was to develop, test, and employ an audit tool to objectively assess the opportunities for physical activity within school environments. A 44 item tool was developed and tested at 92 primary schools in the county of Norfolk, England, during summer term of 2007. Scores from the tool covering 6 domains of facility provision were examined against objectively measured hourly moderate to vigorous physical activity levels in 1868 9-10 year old pupils attending the schools. The tool was found to have acceptable reliability and good construct validity, differentiating the physical activity levels of children attending the highest and lowest scoring schools. The characteristics of school grounds may influence pupil's physical activity levels.
PubMed Accession Number :: 20435506.

Simmons, R. K.; van Sluijs, E. M.; Hardeman, W.; Sutton, S.; Griffin, S. J.; Project Team, T. P. (2010) Who will increase their physical activity? Predictors of change in objectively measured physical activity over 12 months in the ProActive cohort BMC Public Health, 10 (1),226 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: The aim was to identify predictors of change in objectively measured physical activity over 12 months in the ProActive cohort to improve understanding of factors influencing change in physical activity. METHODS: ProActive is a physical activity promotion trial that took place in Eastern England (1999-2004). 365 offspring of people with type 2 diabetes underwent measurement of physical activity energy expenditure (PAEE) using heart rate monitoring, fitness, and anthropometric and biochemical status at baseline and 1 year (n=321). Linear regression was used to quantify the associations between baseline demographic, clinical, psychosocial and behavioural variables and change in PAEE over 12 months. This study is registered as ISRCTN61323766. RESULTS: ProActive participants significantly increased their PAEE by 0.6kj/min (SD 4.2, p=0.006) over one year, the equivalent of around 20 minutes brisk walking/day. Male sex and higher fitness at baseline predicted increase in PAEE. No significant associations were found for any other variables. Very few baseline demographic, clinical, psychosocial and behavioural predictors were associated with change in objectively measured physical activity. CONCLUSIONS: Traditional baseline determinants of self-reported physical activity targeted by behavioural interventions may be relatively weak predictors of change in objectively measured physical activity. Further research is needed to improve our understanding of factors influencing change in physical activity to inform the development and targeting of interventions. Trial Registration Number: ISRCTN61323766.
PubMed Accession Number :: 20433700.

van Wijk, D. F.; van Leuven, S. I.; Sandhu, M. S.; Tanck, M. W.; Hutten, B. A.; Wareham, N. J.; Kastelein, J. J.; Stroes, E. S.; Khaw, K. T.; Boekholdt, S. M. (2010) Chemokine Ligand 2 Genetic Variants, Serum Monocyte Chemoattractant Protein-1 Levels, and the Risk of Coronary Artery Disease Arterioscler Thromb Vasc Biol, 30 ,1460-1466 [Journal Article] Online
Abstract: OBJECTIVE: In humans, evidence about the association between levels of monocyte chemoattractant protein-1 (MCP-1), its coding gene chemokine (C-C motif) ligand 2 (CCL2), and risk of coronary artery disease (CAD) is contradictory. METHODS AND RESULTS: We performed a nested case-control study in the prospective EPIC-Norfolk cohort investigating the relationship between CCL2 single-nucleotide polymorphisms (SNPs), MCP-1 concentrations, and the risk of future CAD. Cases (n=1138) were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n=2237) were matched by age, sex, and enrollment time. Using linear regression analysis no association between CCL2 SNPs and MCP-1 serum concentrations became apparent, nor did we find a significant association between MCP-1 serum levels and risk of future CAD. Finally, Cox regression analysis showed no significant association between CCL2 SNPs and the future CAD risk. In addition, we did not find any robust associations between the CCL2 haplotypes and MCP-1 serum concentration or future CAD risk. CONCLUSIONS: Our data do not support previous publications indicating that MCP-1 is involved in the pathogenesis of CAD.
PubMed Accession Number :: 20431065.

Myint, P. K.; Luben, R. N.; Surtees, P. G.; Wainwright, N. W.; Wareham, N. J.; Khaw, K. T. (2010) Physical functional health predicts the incidence of coronary heart disease in the European Prospective Investigation into Cancer-Norfolk prospective population-based study Int J Epidemiol, 39 , [Journal Article]

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Abstract: BACKGROUND: Little is known about the relationship between physical functional health and long-term risk of coronary heart disease (CHD) independently of known risk factors in a general population. METHODS: Men and women aged 40-79 years at baseline who completed a health and lifestyle questionnaire and attended a health examination during 1993-97 participating in the European Prospective Investigation into Cancer-Norfolk who were free of myocardial infarction (MI), stroke and cancer were included. Eighteen months later, physical functional health was assessed using physical component summary (PCS) scores of Short-Form 36-item questionnaire (SF-36). The incidence of CHD was ascertained by death certification and hospital record linkage up to March 2008. RESULTS: A total of 14 222 men and women were included in the study. There were 389 incident CHD (total person-years = 126 896 years). People who reported better physical functional health had significantly lower risk of CHD. Using Cox proportional hazard models adjusting for age, sex, body mass index, cholesterol, systolic blood pressure, smoking, alcohol consumption, physical activity, diabetes, family history of MI, social class and aspirin usage, it was found that men and women who were in the top quartile of SF-36 PCS had half the risk of CHD [relative risk (RR) = 0.46; 95% confidence interval (CI) = 0.32-0.65] compared with the people in the bottom quartile. The relationships remained essentially unchanged after excluding incident CHD within the first 2 years of follow-up (RR = 0.48; 95% CI = 0.33-0.70). CONCLUSIONS: Physical functional health predicts subsequent CHD risk independently of known risk factors in a general population. People with poor physical functional health may benefit from targeted preventive interventions.
PubMed Accession Number :: 20421200.

Liu, J. Z.; Tozzi, F.; Waterworth, D. M.; Pillai, S. G.; Muglia, P.; Middleton, L.; Berrettini, W.; Knouff, C. W.; Yuan, X.; Waeber, G.; Vollenweider, P.; Preisig, M.; Wareham, N. J.; Zhao, J. H.; Loos, R. J.; Barroso, I.; Khaw, K. T.; Grundy, S.; Barter, P.; Mahley, R.; Kesaniemi, A.; McPherson, R.; Vincent, J. B.; Strauss, J.; Kennedy, J. L.; Farmer, A.; McGuffin, P.; Day, R.; Matthews, K.; Bakke, P.; Gulsvik, A.; Lucae, S.; Ising, M.; Brueckl, T.; Horstmann, S.; Wichmann, H. E.; Rawal, R.; Dahmen, N.; Lamina, C.; Polasek, O.; Zgaga, L.; Huffman, J.; Campbell, S.; Kooner, J.; Chambers, J. C.; Burnett, M. S.; Devaney, J. M.; Pichard, A. D.; Kent, K. M.; Satler, L.; Lindsay, J. M.; Waksman, R.; Epstein, S.; Wilson, J. F.; Wild, S. H.; Campbell, H.; Vitart, V.; Reilly, M. P.; Li, M.; Qu, L.; Wilensky, R.; Matthai, W.; Hakonarson, H. H.; Rader, D. J.; Franke, A.; Wittig, M.; Schafer, A.; Uda, M.; Terracciano, A.; Xiao, X.; Busonero, F.; Scheet, P.; Schlessinger, D.; Clair, D. S.; Rujescu, D.; Abecasis, G. R.; Grabe, H. J.; Teumer, A.; Volzke, H.; Petersmann, A.; John, U.; Rudan, I.; Hayward, C.; Wright, A. F.; Kolcic, I.; Wright, B. J.; Thompson, J. R.; Balmforth, A. J.; Hall, A. S.; Samani, N. J.; Anderson, C. A.; Ahmad, T.; Mathew, C. G.; Parkes, M.; Satsangi, J.; Caulfield, M.; Munroe, P. B.; Farrall, M.; Dominiczak, A.; Worthington, J.; Thomson, W.; Eyre, S.; Barton, A.; Mooser, V.; Francks, C.; Marchini, J. (2010) Meta-analysis and imputation refines the association of 15q25 with smoking quantity Nat Genet, 42 ,441-447 [Journal Article] Online
Abstract: Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.
PubMed Accession Number :: 20418889.

Chamnan, P.; Simmons, R. K.; Khaw, K. T.; Wareham, N. J.; Griffin, S. J. (2010) Estimating the population impact of screening strategies for identifying and treating people at high risk of cardiovascular disease: modelling study Bmj, 340 ,c1693 [Journal Article] Online
Abstract: OBJECTIVE: To estimate the potential population impact of different screening strategies for identifying and treating people at high risk of cardiovascular disease, including strategies using routine data for cardiovascular risk stratification, in light of the UK government's recommended national strategy to screen all adults aged 40-74 for cardiovascular risk. DESIGN: Modelling study using data from a prospective cohort, EPIC-Norfolk (European Prospective Investigation of Cancer-Norfolk). SETTING: An English county. PARTICIPANTS: 16,970 men and women aged 40-74 and free from cardiovascular disease and diabetes at baseline. MAIN OUTCOME MEASURES: The main outcomes were the population attributable fraction, the number needed to screen to prevent one new case of cardiovascular disease, the number needed to treat to prevent one new case of cardiovascular disease, and the number of new cardiovascular events that could be prevented. Relative risk reductions for estimated treatment effects were derived from meta-analyses of clinical trials or guidelines from the National Institute for Health and Clinical Excellence. RESULTS: 1362 cardiovascular events occurred over 183 586 person years of follow-up. Compared with the recommended government strategy, a stepwise screening approach using a simple risk score incorporating routine data could prevent a similar number (lower to upper estimates) of new cardiovascular events annually in the United Kingdom (26,789, 20,778 to 36,239) and 25,134 (19,450 to 34,134), respectively) but requiring only 60% of the population to be invited to attend a vascular risk assessment. A similar number of cardiovascular events (25,016, 19,563 to 33,372) could also be prevented by inviting everyone aged 50-74 for a vascular assessment. Using a participant completed Finnish diabetes risk score questionnaire or anthropometric cut-off points for risk prestratification was less effective. CONCLUSIONS: Compared with the UK government's recommended national strategy to screen all adults aged 40-74 for cardiovascular risk, an approach using routine data for cardiovascular risk stratification before inviting people at high risk for a vascular risk assessment may be similarly effective at preventing new cases of cardiovascular disease, with potential cost savings.
PubMed Accession Number :: 20418545.

Lee, D. C.; Sui, X.; Ortega, F. B.; Kim, Y. S.; Church, T. S.; Winett, R. A.; Ekelund, U.; Katzmarzyk, P. T.; Blair, S. N. (2010) Comparisons of leisure-time physical activity and cardiorespiratory fitness as predictors of all-cause mortality in men and women Br J Sports Med, , [Journal Article] Online
Abstract: Objective To examine the combined associations and relative contributions of leisure-time physical activity (PA) and cardiorespiratory fitness (CRF) with all-cause mortality. Design Prospective cohort study. Setting Aerobics centre longitudinal study. Participants 31 818 men and 10 555 women who received a medical examination during 1978-2002. Assessment of risk factors Leisure-time PA assessed by self-reported questionnaire; CRF assessed by maximal treadmill test. Main outcome measures All-cause mortality until 31 December 2003. Results There were 1492 (469 per 10 000) and 230 (218 per 10 000) deaths in men and women, respectively. PA and CRF were positively correlated in men (r=0.49) and women (r=0.47) controlling for age (p<0.001 for both). PA was inversely associated with mortality in multivariable Cox regression analysis among men, but the association was eliminated after further adjustment for CRF. No significant association of PA with mortality was observed in women. CRF was inversely associated with mortality in men and women, and the associations remained significant after further adjustment for PA. In the PA and CRF combined analysis, compared with the reference group "not meeting the recommended PA (<500 metabolic equivalent-minute/week) and unfit", the relative risks (95% CIs) of mortality were 0.62 (0.54 to 0.72) and 0.61 (0.44 to 0.86) in men and women "not meeting the recommended PA and fit", 0.96 (0.61 to 1.53) and 0.93 (0.33 to 2.58) in men and women "meeting the recommended PA and unfit" and 0.60 (0.51 to 0.70) and 0.56 (0.37 to 0.85) in men and women "meeting the recommended PA and fit", respectively. Conclusions CRF was more strongly associated with all-cause mortality than PA; therefore, improving CRF should be encouraged in unfit individuals to reduce risk of mortality and considered in the development of future PA guidelines.
PubMed Accession Number :: 20418526.

Corder, K.; van Sluijs, E. M. (2010) Invited Commentary: Comparing Physical Activity Across Countries--Current Strengths and Weaknesses Am J Epidemiol, 171 ,1065-1068 [Journal Article] Online
Abstract: Physical activity is thought to be important for various health outcomes, but population levels are suspected to be low. There is a lack of large-scale comparable data with which to assess temporal trends and make between-population comparisons. Continued increases in the use of objective monitoring, especially in longitudinal studies, would be very valuable in public health research, and both self-reported and objective data may help to start developing explanations regarding any observed population differences. There is much scope for more international surveillance of physical activity levels using historically comparable measurement tools, as well as making current data available for reanalysis. The continued use of objective measurement tools with transparent research protocols and data reduction strategies would also be beneficial for future research. Prospective objective physical activity data across different countries would allow us to learn from areas successful in maintaining or even increasing population physical activity levels. Physical activity surveillance using objective measures is needed worldwide, not only in Western countries but also in developing countries, as obesity and related metabolic disorders are a global problem, and it is therefore appropriate that the solution is similarly large scale in nature.
PubMed Accession Number :: 20406761.

Palla, L.; Higgins, J. P.; Wareham, N. J.; Sharp, S. J. (2010) Challenges in the Use of Literature-based Meta-Analysis to Examine Gene-Environment Interactions Am J Epidemiol, 171 ,1225-1232 [Journal Article] Online
Abstract: Statistical interactions between genes and environmental exposures with respect to disease outcomes may help to identify biologic mechanisms and pathways and inform behavioral interventions. The number of persons required for a single study to have sufficient statistical power to detect such interactions may be considered prohibitively large, making a meta-analysis of published literature an apparently attractive alternative. However, meta-analysis of gene-environment interactions using published literature is challenging, with the conclusions being likely to suffer from bias and lack of generalizability. The authors highlight these challenges and biases using an illustrative example: meta-analysis of interactions between the Pro12Ala variant of the peroxisome proliferator-activated receptor gamma (PPARgamma) gene and various diet and lifestyle factors in the risk of diabetes. The authors conclude that literature-based meta-analysis conducted to examine gene-environment interactions is unlikely to provide a meaningful quantitative conclusion. Alternative strategies are required, including analyses in scientific consortia established to assess main genetic effects, where individual participant data can be shared, allowing both greater power and consistency of analysis methods. However, these consortia are likely to be limited by lack of standardization of the measures of environmental factors. This issue may ultimately only be resolvable by the de novo establishment of large single or multicenter cohorts using comparable methods.
PubMed Accession Number :: 20406760.

Peters, T. M.; Shu, X. O.; Moore, S. C.; Xiang, Y. B.; Yang, G.; Ekelund, U.; Liu, D. K.; Tan, Y. T.; Ji, B. T.; Schatzkin, A. S.; Zheng, W.; Chow, W. H.; Matthews, C. E.; Leitzmann, M. F. (2010) Validity of a Physical Activity Questionnaire in Shanghai Med Sci Sports Exerc, , [Journal Article] Online
Abstract: PURPOSE:: In large epidemiologic studies, physical activity is often assessed using physical activity questionnaires (PAQs). As available PAQs may not capture the full range of physical activities in which urban Chinese adults engage, a PAQ was developed for this purpose. We examined the validity of this PAQ and the one-year stability of physical activity in 545 urban Shanghai adults. METHODS:: The PAQ was interview-administered twice, approximately one year apart, and participants also wore an accelerometer and completed a physical activity log (PA-log) for seven consecutive days every three months over this same year. The intra-class correlation coefficient (ICC) was used to evaluate stability of physical activity across questionnaire administrations, and Spearman correlation coefficients (rho) and mean differences and 95% limits of agreement were used to examine validity of the questionnaire compared against accelerometery and the PA-log. RESULTS:: When measured by accelerometry, estimates of time spent in moderate-to-vigorous physical activity were lower and of time spent sedentary were higher than when self-reported on the PAQ (p<0.001). Total physical activity (ICC=0.65) and physical activity domains (ICC=0.45-0.85) showed moderate to high stability across PAQ administrations. Total physical activity (rho=0.30), moderate-to-vigorous activity (rho=0.17), light activity (rho=0.36), and sedentary behavior (rho=0.16) assessed by PAQ and by accelerometry were significantly and positively correlated, and correlations of the PAQ with the PA-log (rho=0.36-0.85) were stronger than those observed with accelerometry. CONCLUSION:: The PAQ significantly overestimated time spent in moderate-to-vigorous activity and underestimated time spent in light activity and sedentary behaviour compared with accelerometry, but performed well at ranking participants according to physical activity level.
PubMed Accession Number :: 20404770.

Graffy, J.; Grant, J.; Williams, K.; Cohn, S.; Macbay, S.; Griffin, S.; Kinmonth, A. L. (2010) More than measurement: practice team experiences of screening for type 2 diabetes Fam Pract, 27 (4),386-94 [Journal Article] Online
Abstract: BACKGROUND: The feasibility, cost-effectiveness and best means to implement population screening for type 2 diabetes remain to be established. OBJECTIVE: To learn from the experiences of practice staff undertaking a diabetes screening programme in order to inform future screening initiatives. METHODS: Qualitative analysis of interviews with staff in six general practices in the 'ADDITION-Cambridge' trial; three randomly allocated to intensively manage screen-detected patients and three providing usual care. We conducted semi-structured interviews with seven nurses, four doctors, three health care assistants and four managers. Four researchers analysed the transcripts practice by practice, preparing vignettes and comparing interpretations. Participants commented on a summary report. RESULTS: Each practice team implemented the screening and intervention programme differently, depending on numbers at risk and decisions about staff contributions. Several emphasized the importance of administrative support. As they screened, they extended the reach of the programme, testing patients outside the target group if requested, checking other risk factors, providing health information and following up people with impaired glucose tolerance. Staff felt that patients accepted the screening and subsequent management as any other clinical activity. CONCLUSIONS: Although those developing screening programmes attempt to standardize them, primary care teams need to adapt the work to fit local circumstances. Staff need a sense of ownership, training, well-designed information technology systems and protected time. Furthermore, screening is more than measurement; at the individual level, it is a complete health care interaction, requiring individual explanations, advice on health-related behaviour and appropriate follow-up. The UK 'NHS Health Checks' programme should embrace these findings.
PubMed Accession Number :: 20403926.

O'Donovan, G.; Blazevich, A. J.; Boreham, C.; Cooper, A. R.; Crank, H.; Ekelund, U.; Fox, K. R.; Gately, P.; Giles-Corti, B.; Gill, J. M.; Hamer, M.; McDermott, I.; Murphy, M.; Mutrie, N.; Reilly, J. J.; Saxton, J. M.; Stamatakis, E. (2010) The ABC of Physical Activity for Health: a consensus statement from the British Association of Sport and Exercise Sciences J Sports Sci, 28 (6),573-91 [Journal Article] Online
Abstract: Our understanding of the relationship between physical activity and health is constantly evolving. Therefore, the British Association of Sport and Exercise Sciences convened a panel of experts to review the literature and produce guidelines that health professionals might use. In the ABC of Physical Activity for Health, A is for All healthy adults, B is for Beginners, and C is for Conditioned individuals. All healthy adults aged 18-65 years should aim to take part in at least 150 min of moderate-intensity aerobic activity each week, or at least 75 min of vigorous-intensity aerobic activity per week, or equivalent combinations of moderate- and vigorous-intensity activities. Moderate-intensity activities are those in which heart rate and breathing are raised, but it is possible to speak comfortably. Vigorous-intensity activities are those in which heart rate is higher, breathing is heavier, and conversation is harder. Aerobic activities should be undertaken in bouts of at least 10 min and, ideally, should be performed on five or more days a week. All healthy adults should also perform muscle-strengthening activities on two or more days a week. Weight training, circuit classes, yoga, and other muscle-strengthening activities offer additional health benefits and may help older adults to maintain physical independence. Beginners should work steadily towards meeting the physical activity levels recommended for all healthy adults. Even small increases in activity will bring some health benefits in the early stages and it is important to set achievable goals that provide success, build confidence, and increase motivation. For example, a beginner might be asked to walk an extra 10 min every other day for several weeks to slowly reach the recommended levels of activity for all healthy adults. It is also critical that beginners find activities they enjoy and gain support in becoming more active from family and friends. Conditioned individuals who have met the physical activity levels recommended for all healthy adults for at least 6 months may obtain additional health benefits by engaging in 300 min or more of moderate-intensity aerobic activity per week, or 150 min or more of vigorous-intensity aerobic activity each week, or equivalent combinations of moderate- and vigorous-intensity aerobic activities. Adults who find it difficult to maintain a normal weight and adults with increased risk of cardiovascular disease or type 2 diabetes may in particular benefit from going beyond the levels of activity recommended for all healthy adults and gradually progressing towards meeting the recommendations for conditioned individuals. Physical activity is beneficial to health with or without weight loss, but adults who find it difficult to maintain a normal weight should probably be encouraged to reduce energy intake and minimize time spent in sedentary behaviours to prevent further weight gain. Children and young people aged 5-16 years should accumulate at least 60 min of moderate-to-vigorous-intensity aerobic activity per day, including vigorous-intensity aerobic activities that improve bone density and muscle strength.
PubMed Accession Number :: 20401789.

Rankinen, T.; Roth, S. M.; Bray, M. S.; Loos, R.; Perusse, L.; Wolfarth, B.; Hagberg, J. M.; Bouchard, C. (2010) Advances in exercise, fitness, and performance genomics Med Sci Sports Exerc, 42 (5),835-46 [Journal Article] Online
Abstract: An annual review publication of the most significant articles in exercise, fitness, and performance genomics begins with this article, which covers 2 yr, 2008 and 2009. The review emphasizes the strongest articles as defined by sample size, quality of phenotype measurements, quality of the exercise program or physical activity exposure, study design, adjustment for multiple testing, quality of genotyping, and other related study characteristics. With this avowed focus on the highest quality articles, only a small number of published articles are reviewed. Among the most significant findings reported here are a brief overview of the first genome-wide association study of the genetic differences between exercisers and nonexercisers. In addition, the latest results on the actinin alpha 3 (ACTN3) R577X nonsense polymorphism are reviewed, emphasizing that no definitive conclusion can be reached at this time. Recent studies that have dealt with mitochondrial DNA haplogroups and endurance performance are described. Published reports indicating that physical activity may attenuate the effect of the fat mass and obesity associated (FTO) gene risk allele on body mass index are reviewed. Articles that have tested the contributions of specific genes to the response of glucose and insulin metabolism traits to regular exercise or physical activity level are considered and found to be generally inconclusive at this stage. Studies examining ethnic differences in the response of blood lipids and lipoproteins to exercise training cannot unequivocally relate these to apolipoprotein E (APOE) genotypes. Hemodynamic changes with exercise training were reported to be associated to sequence variation in kinesin heavy chain (KIF5B), but no replication study is available as of yet. We conclude from this first installment that exercise scientists need to prioritize high-quality research designs and that replication studies with large sample sizes are urgently needed.
PubMed Accession Number :: 20400881.

Liu, C.; Wu, Y.; Li, H.; Qi, Q.; Langenberg, C.; Loos, R. J.; Lin, X. (2010) MTNR1B rs10830963 is associated with fasting plasma glucose, HbA1C and impaired beta-cell function in Chinese Hans from Shanghai BMC Med Genet, 11 (1),59 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Genome-wide association studies (GWAS) in White Europeans have shown that genetic variation rs10830963 in melatonin receptor 1B gene (MTNR1B) is associated with fasting glucose and type 2 diabetes, which has also been replicated in several Asian populations. As a variant in the gene involved in the regulation of circadian rhythms, the effect of the variant on sleep status remains unknown. This study aimed to investigate the effects MTNR1B rs10830963 on fasting glucose, type 2 diabetes and sleep status in Chinese Hans. METHODS: MTNR1B rs10830963 was genotyped in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai, and tested for the associations with the risk of type 2 diabetes, diabetes-related traits and sleep status. RESULTS: We confirmed the associations of MTNR1B rs10830963 with fasting glucose (beta= 0.11 mmol/l, 95%CI [0.03, 0.18], P=0.005), glycated hemoglobin (HbA1c) (beta= 0.07%, 95%CI [0.02,0.12], P=0.004) and homeostasis model assessment of beta-cell function (HOMA-B) (beta=-5.01%, 95%CI [-8.24,-1.77], P=0.003) in the Shanghai, but not in the Beijing subpopulation (P[greater than or equal to]0.58). The effect size of MTNR1B rs10830963 on fasting glucose in Shanghai Chinese Hans was comparable to that reported from other Asian populations. We found no evidence of associations with type 2 diabetes (OR 1.05[0.90-1.23], P=0.54), homeostasis model assessment of insulin sensitivity (HOMA-S) (P= 0.86) or sleep status (P[greater than or equal to]0.44). CONCLUSIONS: A common variant in MTNR1B was associated with fasting glucose, HbA1C and HOMA-B but not with sleep status in Chinese Hans from Shanghai, strengthening the role of MTNR1B rs10830963 on fasting glycemia and impaired beta-cell function.
PubMed Accession Number :: 20398260.

Paddison, C. A.; Eborall, H. C.; French, D. P.; Kinmonth, A. L.; Prevost, A. T.; Griffin, S. J.; Sutton, S. (2010) Predictors of anxiety and depression among people attending diabetes screening: A prospective cohort study embedded in the ADDITION (Cambridge) randomized control trial Br J Health Psychol, , [Journal Article] Online
Abstract: Objective This study aimed to identify factors predicting anxiety and depression among people who attend primary care-based diabetes screening. Design A prospective cohort study embedded in the ADDITION (Cambridge) randomized control trial. Methods Participants (N=3,240) at risk of diabetes were identified from 10 primary care practices and invited to a stepwise screening programme as part of the ADDITION (Cambridge) trial. Main outcome measures were anxiety and depression at 12 months post-screening assessed using the Hospital Anxiety and Depression Scale (HADS). Results Hierarchical linear regressions showed that demographic, clinical, and psychological variables collectively accounted for 52% of the variance in HADS anxiety scores and 53% of the variance in HADS depression scores 12 months after diabetes screening. Screening outcome (positive or negative for diabetes) was not related to differences in anxiety or depression at 12 months. Higher number of self-reported (diabetes) symptoms after first attendance was associated with higher anxiety and depression at 12-month follow-up, after controlling for anxiety and depression after first attendance. Conclusion Participants in a diabetes screening programme showed low scores on anxiety and depression scales after first appointment and 1 year later. Diagnosis of diabetes was shown to have a limited psychological impact and may be less important than symptom perception in determining emotional outcomes after participation in diabetes screening.
PubMed Accession Number :: 20385038.

Chambers, J. C.; Zhang, W.; Lord, G. M.; van der Harst, P.; Lawlor, D. A.; Sehmi, J. S.; Gale, D. P.; Wass, M. N.; Ahmadi, K. R.; Bakker, S. J.; Beckmann, J.; Bilo, H. J.; Bochud, M.; Brown, M. J.; Caulfield, M. J.; Connell, J. M.; Cook, H. T.; Cotlarciuc, I.; Smith, G. D.; de Silva, R.; Deng, G.; Devuyst, O.; Dikkeschei, L. D.; Dimkovic, N.; Dockrell, M.; Dominiczak, A.; Ebrahim, S.; Eggermann, T.; Farrall, M.; Ferrucci, L.; Floege, J.; Forouhi, N. G.; Gansevoort, R. T.; Han, X.; Hedblad, B.; van der Heide, J. J.; Hepkema, B. G.; Hernandez-Fuentes, M.; Hypponen, E.; Johnson, T.; de Jong, P. E.; Kleefstra, N.; Lagou, V.; Lapsley, M.; Li, Y.; Loos, R. J.; Luan, J.; Luttropp, K.; Marechal, C.; Melander, O.; Munroe, P. B.; Nordfors, L.; Parsa, A.; Peltonen, L.; Penninx, B. W.; Perucha, E.; Pouta, A.; Prokopenko, I.; Roderick, P. J.; Ruokonen, A.; Samani, N. J.; Sanna, S.; Schalling, M.; Schlessinger, D.; Schlieper, G.; Seelen, M. A.; Shuldiner, A. R.; Sjogren, M.; Smit, J. H.; Snieder, H.; Soranzo, N.; Spector, T. D.; Stenvinkel, P.; Sternberg, M. J.; Swaminathan, R.; Tanaka, T.; Ubink-Veltmaat, L. J.; Uda, M.; Vollenweider, P.; Wallace, C.; Waterworth, D.; Zerres, K.; Waeber, G.; Wareham, N. J.; Maxwell, P. H.; McCarthy, M. I.; Jarvelin, M. R.; Mooser, V.; Abecasis, G. R.; Lightstone, L.; Scott, J.; Navis, G.; Elliott, P.; Kooner, J. S. (2010) Genetic loci influencing kidney function and chronic kidney disease Nat Genet, 42 ,373-375 [Journal Article] Online
Abstract: Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.
PubMed Accession Number :: 20383145.

Gradmark, A. M.; Rydh, A.; Renstrom, F.; De Lucia-Rolfe, E.; Sleigh, A.; Nordstrom, P.; Brage, S.; Franks, P. W. (2010) Computed tomography-based validation of abdominal adiposity measurements from ultrasonography, dual-energy X-ray absorptiometry and anthropometry Br J Nutr, 104 (4),582-588 [Journal Article] Online
Abstract: Large-scale aetiological studies of obesity and its pathological consequences require accurate measurements of adipose mass, distribution and subtype. Here, we compared the validity of three abdominal obesity assessment methods (dual-energy X-ray absorptiometry (DXA), ultrasound and anthropometry) against the gold-standard method of computed tomography (CT) in twenty-nine non-diseased middle-aged men (BMI 26.5 (sd 3.1) kg/m2) and women (BMI 25.5 (sd 3.2) kg/m2). Assessments of adipose mass (kg) and distribution (total subcutaneous (TSAT), superficial subcutaneous (SSAT), deep subcutaneous (DSAT) and visceral (VAT)) were obtained. Spearman's correlations were performed adjusted for age and sex. VAT area that was assessed using ultrasound (r 0.79; P < 0.0001) and waist circumference (r 0.85; P < 0.0001) correlated highly with VAT from CT, as did BMI (r 0.67; P < 0.0001) and DXA (r 0.70; P < 0.0001). DXA (r 0.72; P = 0.0004), BMI (r 0.71; P = 0.0003), waist circumference (r 0.86; P < 0.0001) and ultrasound (r 0.52; P = 0.015) were less strongly correlated with CT TSAT. None of the comparison measures of DSAT was strongly correlated with CT DSAT (all r approximately 0.50; P < 0.02). BMI (r 0.76; P < 0.0001), waist circumference (r 0.65; P = 0.002) and DXA (r 0.75; P < 0.0001) were all fairly strongly correlated with the CT measure of SSAT, whereas ultrasound yielded a weaker yet statistically significant correlation (r 0.48; P = 0.03). Compared with CT, visceral and subcutaneous adiposity can be assessed with reasonable validity using waist circumference and BMI, respectively. Ultrasound or DXA does not generally provide substantially better measures of these traits. Highly valid assessments of DSAT do not appear to be possible with surrogate measures. These findings may help guide the selection of measures for epidemiological studies of obesity.
PubMed Accession Number :: 20370942.

Lee, C. C.; Sharp, S. J.; Wexler, D. J.; Adler, A. I. (2010) Dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and diabetic nephropathy - cohort analysis of the Diabetes Control and Complications Trial (DCCT) Diabetes Care, 33 ,1454-1456 [Journal Article] Online
Abstract: AbstractObjective: To investigate the association between dietary n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) and the degree and development of albuminuria in type 1 diabetes. Methods: We analyzed longitudinal data from 1,436 participants in the Diabetes Control and Complications Trial. We defined average intake of eicosapentaenoic- and docosahexaenoic acid from diet histories. Urinary albumin excretion rates (UAER) were measured over 24 hours; incident albuminuria was considered the first occurrence of an UAER >40 mg/24 hr sustained for >/=1 year in normo-albuminuric individuals. Results: In a mean follow-up of 6.5 years, we observed a lower mean UAER [difference 22.7 mg/24 hr (95% CI 1.6, 43.8)] in the top vs. bottom third of dietary n-3 LC-PUFAs, but found no association with incident albuminuria. Conclusions: Dietary n-3 LC-PUFAs appear inversely associated with the degree, but not with the incidence of albuminuria in type 1 diabetes. These findings require further investigation in prospective studies.
PubMed Accession Number :: 20357378.

Kahn, R.; Alperin, P.; Eddy, D.; Borch-Johnsen, K.; Buse, J.; Feigelman, J.; Gregg, E.; Holman, R. R.; Kirkman, M. S.; Stern, M.; Tuomilehto, J.; Wareham, N. J. (2010) Age at initiation and frequency of screening to detect type 2 diabetes: a cost-effectiveness analysis Lancet, 375 ,1365-74 [Journal Article] Online
Abstract: BACKGROUND: No clinical trials have assessed the effects or cost-effectiveness of sequential screening strategies to detect new cases of type 2 diabetes. We used a mathematical model to estimate the cost-effectiveness of several screening strategies. METHODS: We used person-specific data from a representative sample of the US population to create a simulated population of 325 000 people aged 30 years without diabetes. We used the Archimedes model to compare eight simulated screening strategies for type 2 diabetes with a no-screening control strategy. Strategies differed in terms of age at initiation and frequency of screening. Once diagnosed, diabetes treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, myocardial infarction, stroke, and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). FINDINGS: Compared with no screening, all simulated screening strategies reduced the incidence of myocardial infarction (3-9 events prevented per 1000 people screened) and diabetes-related microvascular complications (3-9 events prevented per 1000 people), and increased the number of QALYs (93-194 undiscounted QALYs) added over 50 years. Most strategies prevented a significant number of simulated deaths (2-5 events per 1000 people). There was little or no effect of screening on incidence of stroke (0-1 event prevented per 1000 people). Five screening strategies had costs per QALY of about US$10 500 or less, whereas costs were much higher for screening started at 45 years of age and repeated every year ($15 509), screening started at 60 years of age and repeated every 3 years ($25 738), or a maximum screening strategy (screening started at 30 years of age and repeated every 6 months; $40 778). Several strategies differed substantially in the number of QALYs gained. Costs per QALY were sensitive to the disutility assigned to the state of having diabetes diagnosed with or without symptoms. INTERPRETATION: In the US population, screening for type 2 diabetes is cost effective when started between the ages of 30 years and 45 years, with screening repeated every 3-5 years. FUNDING: Novo Nordisk, Bayer Pharmaceuticals, and Pfizer.
PubMed Accession Number :: 20356621.

Dash, S.; Langenberg, C.; Fawcett, K. A.; Semple, R. K.; Romeo, S.; Sharp, S.; Sano, H.; Lienhard, G. E.; Rochford, J. J.; Howlett, T.; Massoud, A. F.; Hindmarsh, P.; Howell, S. J.; Wilkinson, R. J.; Lyssenko, V.; Groop, L.; Baroni, M. G.; Barroso, I.; Wareham, N. J.; S, O' Rahilly; Savage, D. B. (2010) Analysis of TBC1D4 in patients with severe insulin resistance Diabetologia, 53 ,1239-1242 [Journal Article] Online
PubMed Accession Number :: 20349035.

Arsenault, B. J.; Lemieux, I.; Despres, J. P.; Wareham, N. J.; Stroes, E. S.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2010) Comparison between Gradient Gel Electrophoresis and Nuclear Magnetic Resonance Spectroscopy in Estimating Coronary Heart Disease Risk Associated with LDL and HDL Particle Size Clin Chem, 56 ,789-798 [Journal Article] Online
Abstract: BACKGROUND: Gradient gel electrophoresis (GGE) and nuclear magnetic resonance (NMR) spectroscopy are both widely accepted methods for measuring LDL and HDL particle size. However, whether or not GGE- or NMR-measured LDL or HDL particle size predicts coronary heart disease (CHD) risk to a similar extent is currently unknown. METHODS: We used GGE and NMR to measure LDL and HDL particle size in a nested case-control study of 1025 incident cases of CHD and 1915 controls from the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study. The study sample included apparently healthy men and women age 45-79 years followed for an average of 6 years. RESULTS: Pearson correlation coefficients showed that the overall agreement between NMR and GGE was better for the measurement of HDL size (r = 0.78) than for LDL size (r = 0.47). The odds ratio for future CHD among participants in the bottom tertile of LDL size (smallest LDL particles) was 1.35 (95% CI, 1.12-1.63) for GGE and 1.74 (1.41-2.15) for NMR. For HDL size, these respective odds ratios were 1.41 (1.16-1.72) and 1.85 (1.47-2.32). After adjustment for potential confounders, the relationship between small LDL or HDL particles and CHD was no longer significant, irrespective of the method. CONCLUSIONS: In this prospective population study, we found that the relationships between NMR-measured LDL and HDL sizes and CHD risk were slightly higher than those obtained with GGE.
PubMed Accession Number :: 20348400.

Watkinson, C.; van Sluijs, E. M.; Sutton, S.; Marteau, T.; Griffin, S. J. (2010) Randomised controlled trial of the effects of physical activity feedback on awareness and behaviour in UK adults: the FAB study protocol [ISRCTN92551397] BMC Public Health, 10 (1),144 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: While there are increasing data implicating poor recognition of physical inactivity as a potential barrier to healthy behaviour change, the efficacy of feedback to promote physical activity is uncertain. Using a randomised controlled trial nested within a population-based cohort study, we plan to test three variations of physical activity feedback against a control group. Our primary objective is to assess the efficacy of physical activity feedback in promoting physical activity behaviour change. Secondary objectives are to determine the influence of feedback on physical activity awareness and cognitions, and to compare behavioural effects by type of feedback. Methods/ Design. We aim to recruit 500 healthy participants aged 30 to 55 years from the ongoing Fenland Study (Cambridge, UK). Following careful phenotyping during baseline measurement (anthropometric, clinical, body composition and fitness measurements, as well as questionnaires assessing self-reported and self-rated physical activity, psychosocial correlates of physical activity behaviour, diet, lifestyle and general health), participants wear a combined heart rate and movement sensor (Actiheart) for six continuous days and nights. After receipt of the physical activity data (around 2 weeks later), participants are randomly allocated to either a control group (no feedback) or one of three types of personalised physical activity feedback ('simple', 'visualised' or 'contextualised'), and complete repeat measures of self-rated physical activity and psychosocial correlates. Approximately five weeks after receiving feedback, all participants wear the Actiheart for another six-day follow-up period and complete repeat questionnaires. Values at outcome, adjusted for baseline, will be compared between randomised groups. DISCUSSION: Given the randomised trial design and use of objective measure of physical activity, this study is likely to provide valuable insights into the efficacy of a feedback intervention in changing physical activity behaviour, as well as the psychological mechanisms involved. Trial Registration: Current Controlled Trials: ISRCTN92551397.
PubMed Accession Number :: 20298560.

Lakshman, R. R.; Sharp, S. J.; Ong, K. K.; Forouhi, N. G. (2010) A novel school-based intervention to improve nutrition knowledge in children: cluster randomised controlled trial BMC Public Health, 10 (1),123 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Improving nutrition knowledge among children may help them to make healthier food choices. The aim of this study was to assess the effectiveness and acceptability of a novel educational intervention to increase nutrition knowledge among primary school children. METHODS: We developed a card game 'Top Grub' and a 'healthy eating' curriculum for use in primary schools. Thirty-eight state primary schools comprising 2519 children in years 5 and 6 (aged 9-11 years) were recruited in a pragmatic cluster randomised controlled trial. The main outcome measures were change in nutrition knowledge scores, attitudes to healthy eating and acceptability of the intervention by children and teachers. RESULTS: Twelve intervention and 13 control schools (comprising 1133 children) completed the trial. The main reason for non-completion was time pressure of the school curriculum. Mean total nutrition knowledge score increased by 1.1 in intervention (baseline to follow-up: 28.3 to 29.2) and 0.3 in control schools (27.3 to 27.6). Total nutrition knowledge score at follow-up, adjusted for baseline score, deprivation, and school size, was higher in intervention than in control schools (mean difference = 1.1; 95% CI: 0.05 to 2.16; p=0.042). At follow-up, more children in the intervention schools said they 'are currently eating a healthy diet' (39.6%) or 'would try to eat a healthy diet' (35.7%) than in control schools (34.4% and 31.7% respectively; chi-square test p<0.001). Most children (75.5%) enjoyed playing the game and teachers considered it a useful resource. CONCLUSIONS: The 'Top Grub' card game facilitated the enjoyable delivery of nutrition education in a sample of UK primary school age children. Further studies should determine whether improvements in nutrition knowledge are sustained and lead to changes in dietary behaviour.
PubMed Accession Number :: 20219104.

Warren, J. M.; Ekelund, U.; Besson, H.; Mezzani, A.; Geladas, N.; Vanhees, L. (2010) Assessment of physical activity - a review of methodologies with reference to epidemiological research: a report of the exercise physiology section of the European Association of Cardiovascular Prevention and Rehabilitation Eur J Cardiovasc Prev Rehabil, 17 (2),127-139 [Journal Article] Online
Abstract: Physical activity has a fundamental role in the prevention and treatment of chronic disease. The precise measurement of physical activity is key to many surveillance and epidemiological studies investigating trends and associations with disease. Public health initiatives aimed at increasing physical activity rely on the measurement of physical activity to monitor their effectiveness. Physical activity is multidimensional, and a complex behaviour to measure; its various domains are often misunderstood. Inappropriate or crude measures of physical activity have serious implications, and are likely to lead to misleading results and underestimate effect size. In this review, key definitions and theoretical aspects, which underpin the measurement of physical activity, are briefly discussed. Methodologies particularly suited for use in epidemiological research are reviewed, with particular reference to their validity, primary outcome measure and considerations when using each in the field. It is acknowledged that the choice of method may be a compromise between accuracy level and feasibility, but the ultimate choice of tool must suit the stated aim of the research. A framework is presented to guide researchers on the selection of the most suitable tool for use in a specific study.
PubMed Accession Number :: 20215971.

Ruchat, S. M.; Elks, C. E.; Loos, R. J.; Vohl, M. C.; Weisnagel, S. J.; Rankinen, T.; Bouchard, C.; Perusse, L. (2010) Evidence of Interaction between Type 2 Diabetes Susceptibility Genes and Dietary Fat Intake for Adiposity and Glucose Homeostasis-Related Phenotypes J Nutrigenet Nutrigenomics, 2 (4-5),225-234 [Journal Article] Online
Abstract: Background/Aims: Genome-wide association studies have led to the identification of several susceptibility genes for type 2 diabetes mellitus (T2DM). The objective of this study was to test the hypothesis that the associations between single nucleotide polymorphisms (SNPs) in these genes and adiposity and glucose homeostasis-related phenotypes are influenced by dietary fat intake. Methods: Thirty-three SNPs in 9 T2DM genes (CDKAL1, CDKN2A/B, HHEX, HNF1B, IGF2BP2, KCNJ11, SLC30A8, TCF7L2 and WFS1) were tested in a maximum of 669 subjects from the Quebec Family Study. Subjects were measured for several adiposity indices and underwent a 75-gram oral glucose tolerance test. Total fat intake was estimated from a 3-day dietary record. Results: We observed 13 significant (p </= 0.01) SNP-dietary fat interactions. Among them, IGF2BP2 rs4402960, alone or in interaction with dietary fat intake, influenced abdominal total fat (ATF: SNP effect, p = 0.006, interaction effect, p = 0.009) and abdominal visceral fat (AVF: SNP effect, p = 0.007, interaction effect, p = 0.01). Similarly, TCF7L2 rs12573128 alone or in interaction with dietary fat intake, influenced insulin sensitivity (SNP effect and interaction effect, p </= 0.008) and glucose tolerance (SNP effect p </= 0.009 and interaction effect, p </= 0.01). Conclusion: These results suggest that gene-dietary fat interactions may influence glucose homeostasis-related phenotypes and play an important role in determining the increased risk of diabetes associated with the T2DM susceptibility genes.
PubMed Accession Number :: 20215779.

Petry, C. J.; Lopez-Bermejo, A.; Diaz, M.; Sebastiani, G.; Ong, K. K.; de Zegher, F.; Dunger, D. B.; Ibanez, L. (2010) Association between a Common Variant near MC4R and Change in Body Mass Index Develops by Two Weeks of Age Horm Res Paediatr, 73 (4),275-280 [Journal Article] Online
Abstract: Background/Aims: The common polymorphism rs17782313 lying 188 kb downstream of the MC4R gene has recently been found to be unequivocally associated with body mass index (BMI) and obesity risk in adults and children. Our objective was to test the association between rs17782313 and neonatal weight gain in a contemporary population. Methods: This was a cross-sectional, hospital-based study using 278 healthy Caucasian newborns [142 girls; gestational age (mean +/- SD) 39.3 +/- 1.4 weeks, birth weight 3.1 +/- 0.6 kg]. Body composition was assessed by dual-energy X-ray absorptiometry (DXA) at approximately 13 days (range 9-20) and rs17782313 was genotyped by restriction fragment length polymorphism analysis. Results: rs17782313 was not associated with weight, length or ponderal index at birth. However, it was associated with changes in BMI (p = 0.0004) over the first 2 weeks of life and with body weight (p = 0.02) and BMI (p = 0.007) at age 2 weeks. Despite this, DXA measures of fat and lean mass failed to show any simple associations. Conclusion: Similar to other genetic variants associated with childhood and adult obesity, the association between rs17782313 genotype and body weight develops rapidly during the first 2 weeks of life, once caloric intake is regulated by the infant's appetite.
PubMed Accession Number :: 20215774.

Park, P.; Simmons, R. K.; Prevost, A. T.; Griffin, S. J. (2010) A Randomized Evaluation of Loss and Gain Frames in an Invitation to Screening for Type 2 Diabetes: Effects on Attendance, Anxiety and Self-rated Health J Health Psychol, 15 (2),196-204 [Journal Article] Online
Abstract: A randomized controlled trial in two general practices in Cambridgeshire compared the effect of loss and gain framed messages in an invitation to screening for type 2 diabetes on uptake and subsequent anxiety and self-rated health. High risk individuals aged 40-69 years were randomized to receive loss (n = 57) or gain (n = 59) framed screening invitations. A postal questionnaire was sent to all participants, including non-attenders, after six weeks. There were no significant differences in attendance, mean state anxiety, self-rated health or illness representation between the loss and gain frame arms. Framing of information in diabetes screening invitations does not influence uptake.
PubMed Accession Number :: 20207663.

Druet, C.; Ong, K.; Levy Marchal, C. (2010) Metabolic Syndrome in Children: Comparison of the International Diabetes Federation 2007 Consensus with an Adapted National Cholesterol Education Program Definition in 300 Overweight and Obese French Children Horm Res Paediatr, 73 (3),181-186 [Journal Article] Online
Abstract: Background/Aims: Former definitions of metabolic syndrome (MS) in children have been adapted from adult MS definitions using age-related thresholds for each biochemical component, whereas the International Diabetes Federation (IDF) definition is based on absolute values. We compared the IDF childhood MS definition (IDF-MS) to the adapted National Cholesterol Education Program (adapted-NCEP) definition in overweight children. Methods: 300 overweight and obese children were included with a median age of 11 years and BMI SDS of +4.7. Results: Below 10 years of age, the frequency of MS according to the adapted-NCEP-MS definition was 18.6%, and 86.1% had abdominal obesity. In children aged 10 to <16 years (n = 214), the frequency of IDF-MS was 8.9% compared to 14.5% by adapted-NCEP. IDF-MS children had a larger waist circumference, and higher triglycerides, fasting insulin and tended to be older than the intermediate severity group of children with MS only according to adapted-NCEP. Children with MS only according to adapted-NCEP (IDF-MS negative), differed from non-MS children in systolic blood pressure, triglycerides and high-density lipoprotein cholesterol. Conclusions: The recent IDF-MS criterion in children represents a more severe definition and appears to identify a group of children with higher fasting insulin than the adapted-MS definition which uses age-related thresholds (90th percentile).
PubMed Accession Number :: 20197670.

Ingelsson, E.; Langenberg, C.; Hivert, M. F.; Prokopenko, I.; Lyssenko, V.; Dupuis, J.; Magi, R.; Sharp, S.; Jackson, A. U.; Assimes, T. L.; Shrader, P.; Knowles, J. W.; Zethelius, B.; Abbasi, F. A.; Bergman, R. N.; Bergmann, A.; Berne, C.; Boehnke, M.; Bonnycastle, L. L.; Bornstein, S. R.; Buchanan, T. A.; Bumpstead, S. J.; Bottcher, Y.; Chines, P.; Collins, F. S.; Cooper, C. C.; Dennison, E. M.; Erdos, M. R.; Ferrannini, E.; Fox, C. S.; Graessler, J.; Hao, K.; Isomaa, B.; Jameson, K. A.; Kovacs, P.; Kuusisto, J.; Laakso, M.; Ladenvall, C.; Mohlke, K. L.; Morken, M. A.; Narisu, N.; Nathan, D. M.; Pascoe, L.; Payne, F.; Petrie, J. R.; Sayer, A. A.; Schwarz, P.; Scott, L. J.; Stringham, H. M.; Stumvoll, M.; Swift, A. J.; Syvanen, A. C.; Tuomi, T.; Tuomilehto, J.; Tonjes, A.; Valle, T. T.; Williams, G. H.; Lind, L.; Barroso, I.; Quertermous, T.; Walker, M.; Wareham, N. J.; Meigs, J. B.; McCarthy, M. I.; Groop, L.; Watanabe, R. M.; Florez, J. C. (2010) Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans Diabetes, 59 ,1266-1275 [Journal Article] Online
Abstract: AbstractObjective: Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. Research Design and Methods: We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTT), euglycemic clamps, insulin suppression tests or frequently-sampled intravenous glucose tolerance tests in non-diabetic humans (n=29,084). Results: The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index), at extremely persuasive levels of statistical significance (P=2.1x10(-71)). Defects in insulin-processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and FAM148B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. Conclusions: Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
PubMed Accession Number :: 20185807.

Vimaleswaran, K. S.; Loos, R. J. (2010) Progress in the genetics of common obesity and type 2 diabetes Expert Rev Mol Med, 12 ,e7 [Journal Article] Online
Abstract: The prevalence of obesity and diabetes, which are heritable traits that arise from the interactions of multiple genes and lifestyle factors, continues to rise worldwide, causing serious health problems and imposing a substantial economic burden on societies. For the past 15 years, candidate gene and genome-wide linkage studies have been the main genetic epidemiological approaches to identify genetic loci for obesity and diabetes, yet progress has been slow and success limited. The genome-wide association approach, which has become available in recent years, has dramatically changed the pace of gene discoveries. Genome-wide association is a hypothesis-generating approach that aims to identify new loci associated with the disease or trait of interest. So far, three waves of large-scale genome-wide association studies have identified 19 loci for common obesity and 18 for common type 2 diabetes. Although the combined contribution of these loci to the variation in obesity and diabetes risk is small and their predictive value is typically low, these recently identified loci are set to substantially improve our insights into the pathophysiology of obesity and diabetes. This will require integration of genetic epidemiological methods with functional genomics and proteomics. However, the use of these novel insights for genetic screening and personalised treatment lies some way off in the future.
PubMed Accession Number :: 20184785.

van Sluijs, E. M.; McMinn, A. (2010) Preventing obesity in primary schoolchildren Bmj, 340 ,c819 [Journal Article] Online
PubMed Accession Number :: 20179127.

Panter, J. R.; Jones, A. P.; Van Sluijs, E. M.; Griffin, S. J. (2010) Neighborhood, Route, and School Environments and Children's Active Commuting Am J Prev Med, 38 (3),268-278 [Journal Article] Online
Abstract: BACKGROUND: Walking and cycling to school represent an opportunity for children to achieve regular physical activity. These behaviors may be influenced by characteristics of the environment around homes and schools, yet few studies have quantified the potential associations between these two sets of factors. PURPOSE: This study aims to assess whether objectively measured characteristics of the neighborhood, route, and school environments are associated with active commuting to school among children, and it explores whether distance acts as a moderator in this association. METHODS: A cross-sectional study was conducted of 2012 children (899 boys and 1113 girls) aged 9-10 years attending 92 schools in the county of Norfolk, United Kingdom. Questionnaires were completed by children and parents during Summer 2007. Attributes around the home and children's route to school were assessed using a GIS. School environments were assessed using a newly developed school audit and via questionnaires completed by head teachers. Data were analyzed in 2008. RESULTS: Almost half of the children usually walked or cycled to school. Children who lived in a more deprived area and whose route to school was direct were less likely to walk or cycle to school, whereas those who had a higher density of roads in their neighborhood were more likely to walk. Further, children whose routes had a high density of streetlights were less likely to cycle to school. Distance did not moderate the observed associations. CONCLUSIONS: Objectively measured neighborhood and route factors are associated with walking and cycling to school. However, distance did not moderate the associations found here. Creating safe environments by improving urban design may influence children's commuting behavior. Intervention studies are needed to confirm the findings from this observational cross-sectional study.
PubMed Accession Number :: 20171528.

Webb, D. R.; Kamlesh, K.; Srinivasan, B.; Gray, L. J.; Taub, N.; Campbell, S.; Barnett, J.; Henson, J.; Hiles, S.; Farooqi, A.; Griffin, S. J.; Wareham, N. J.; Davies, M. J. (2010) Rationale and design of the ADDITION-Leicester study, a systematic screening programme and Randomised Controlled Trial of multi-factorial cardiovascular risk intervention in people with Type 2 Diabetes Mellitus detected by screening Trials, 11 (1),16 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Earlier diagnosis followed by multi-factorial cardiovascular risk intervention may improve outcomes in Type 2 Diabetes Mellitus (T2DM). Latent phase identification through screening requires structured, appropriately targeted population-based approaches. Providers responsible for implementing screening policy await evidence of clinical and cost effectiveness from randomised intervention trials in screen-detected T2DM cases. UK South Asians are at particularly high risk of abnormal glucose tolerance and T2DM. To be effective national screening programmes must achieve good coverage across the population by identifying barriers to the detection of disease and adapting to the delivery of earlier care. Here we describe the rationale and methods of a systematic community screening programme and randomised controlled trial of cardiovascular risk management within a UK multiethnic setting (ADDITION-Leicester). DESIGN: A single-blind cluster randomised, parallel group trial among people with screen-detected T2DM comparing a protocol driven intensive multi-factorial treatment with conventional care. METHODS: ADDITION-Leicester consists of community-based screening and intervention phases within 20 general practices coordinated from a single academic research centre. Screening adopts a universal diagnostic approach via repeated 75g-Oral Glucose Tolerance Tests within an eligible non-diabetic population of 66,320 individuals aged 40-75 years (25-75 years South Asian). Volunteers also provide detailed medical and family histories; complete health questionnaires, undergo anthropometric measures, lipid profiling and a proteinuria assessment. Primary outcome is reduction in modelled Coronary Heart Disease (UKPDS CHD) risk at five years. Seven thousand (30% of South Asian ethnic origin) volunteers over three years will be recruited to identify a screen-detected T2DM cohort (n=285) powered to detected a 6% relative difference (80% power, alpha 0.05) between treatment groups at one year. Randomisation will occur at practice-level with newly diagnosed T2DM cases receiving either conventional (according to current national guidelines) or intensive (algorithmic target-driven multi-factorial cardiovascular risk intervention) treatments. DISCUSSION: ADDITION-Leicester is the largest multiethnic (targeting >30% South Asian recruitment) community T2DM and vascular risk screening programme in the UK. By assessing feasibility and efficacy of T2DM screening, it will inform national disease prevention policy and contribute significantly to our understanding of the health care needs of UK South Asians. Trial registration: Clinicaltrial.gov (NCT00318032).
PubMed Accession Number :: 20170482.

McCormack, V.; Agudo, A.; Dahm, C.; Overvad, K.; Olsen, A.; Tjonneland, A.; Kaaks, R.; Boeing, H.; Manjer, J.; Almquist, M.; Hallmans, G.; Johansson, I.; Chirlaque, M.; Barricarte, A.; Dorronsoro, M.; Rodriguez, L.; Redondo, M.; Khaw, K.; Wareham, N.; Allen, N.; Key, T.; Riboli, E.; Boffetta, P. (2010) Cigar and pipe smoking and cancer risk in the european prospective investigation into cancer and nutrition Int J Cancer, 127 ,2402-2411 [Journal Article] Online
Abstract: The carcinogenicity of cigar and pipe smoking is established but the effect of detailed smoking characteristics is less well defined. We examined the effects on cancer incidence of exclusive cigar and pipe smoking, and in combination with cigarettes, among 102395 men from Denmark, Germany, Spain, Sweden and UK in the EPIC cohort. Hazard ratios (HR) and their 95% confidence intervals (CI) for cancer during a median 9 year follow-up from ages 35-70 years were estimated using proportional hazards models. Compared to never smokers, HR of cancers of lung, upper aero-digestive tract and bladder combined was 2.2 (95% CI: 1.3, 3.8) for exclusive cigar smokers (16 cases), 3.0 (2.1, 4.5) for exclusive pipe smokers (33 cases) and 5.3 (4.4, 6.4) for exclusive cigarette smokers (1069 cases). For each smoking type, effects were stronger in current than in ex-smokers, and in inhalers than in non-inhalers. Ever smokers of both cigarettes and cigars (HR 5.7 (4.4, 7.3), 120 cases) and cigarettes and pipes (5.1 (4.1, 6.4), 247 cases) had as high a raised risk as had exclusive cigarette smokers. In these smokers, the magnitude of the raised risk was smaller if they had switched to cigars or pipes only (i.e. quit cigarettes) and had not compensated with greater smoking intensity. Cigar and pipe smoking is not a safe alternative to cigarette smoking. The lower cancer risk of cigar and pipe smokers as compared to cigarette smokers is explained by lesser degree of inhalation and lower smoking intensity. (c) 2010 UICC.
PubMed Accession Number :: 20162568.

Wijndaele, K.; Healy, G. N.; Dunstan, D. W.; Barnet, A. G.; Salmon, J.; Shaw, J. E.; Zimmet, P. Z.; Owen, N. (2010) Increased Cardio-Metabolic Risk is Associated with Increased TV Viewing Time Med Sci Sports Exerc, 42 ,1511-1518 [Journal Article] Online
Abstract: PURPOSE:: Television viewing time, independent of leisure-time physical activity, has cross-sectional relationships with the metabolic syndrome and its individual components. We examined whether baseline and five-year changes in self-reported television viewing time are associated with changes in continuous biomarkers of cardio-metabolic risk (waist circumference, triglycerides, high density lipoprotein cholesterol, systolic and diastolic blood pressure, fasting plasma glucose; and a clustered cardio-metabolic risk score) in Australian adults. METHODS:: AusDiab is a prospective, population-based cohort study with biological, behavioral, and demographic measures collected in 1999-2000 and 2004-2005. Non-institutionalized adults aged >/= 25 years were measured at baseline (11,247; 55% of those completing an initial household interview); 6,400 took part in the five-year follow-up biomedical examination, and 3,846 met the inclusion criteria for this analysis. Multiple linear regression analysis was used and unstandardized B coefficients (95% CI) are provided. RESULTS:: Baseline television viewing time (10 hours/week unit) was not significantly associated with change in any of the biomarkers of cardio-metabolic risk. Increases in television viewing time over five years (10 hours/week unit) were associated with increases in: waist circumference (cm) (men: 0.43 (0.08, 0.78), P = 0.02; women: 0.68 (0.30, 1.05), P <0.001), diastolic blood pressure (mmHg) (women: 0.47 (0.02, 0.92), P = 0.04), and the clustered cardio-metabolic risk score (women: 0.03 (0.01, 0.05), P = 0.007). These associations were independent of baseline television viewing time and baseline and change in physical activity and other potential confounders. CONCLUSION:: These findings indicate that an increase in television viewing time is associated with adverse cardio-metabolic biomarker changes. Further prospective studies using objective measures of several sedentary behaviors are required to confirm causality of the associations found.
PubMed Accession Number :: 20139784.

Corder, K.; Brage, S.; Wright, A.; Ramachandran, A.; Snehalatha, C.; Yamuna, A.; Wareham, N. J.; Ekelund, U. (2010) Physical Activity Energy Expenditure of Adolescents in India Obesity (Silver Spring), 30 ,2212-2219 [Journal Article] Online
Abstract: Physical activity (PA) has rarely been quantified in adolescent populations undergoing economic transition; therefore relationships with disease still remain uncertain. This study assessed whether absolute PA energy expenditure (PAEE), PAEE/kg, and PAEE/kg(FFM) could be accurately estimated using accelerometry and a questionnaire in Indian adolescents and how these values compared to those of other populations. PAEE was assessed using doubly labeled water (DLW) in 30 adolescents from Chennai, India, over seven consecutive days, simultaneous with the measurement of PA using accelerometry and a previous-week recall questionnaire. Accelerometry counts (regression analysis) and questionnaire data were used to estimate PAEE; estimates were cross-validated using the Bland-Altman method. Accelerometry data and DLW-derived PAEE were visually compared to values from four North American and European populations. For boys, 49% of the variance in DLW-derived PAEE was explained with an equation including accelerometry counts and fat-free mass (FFM). Questionnaire-derived estimates did not contribute to the explained variance in DLW derived PAEE. The group-level PA of these Indian adolescents was successfully assessed using accelerometry, but not questionnaire. DLW-derived PAEE/kg(FFM) (mean (s.d.): 53.0 (27.5) kJ/kg(FFM)/day) was lower in this group than other adolescent populations in Europe and similar to those in North America. Additionally, four boys and none of the girls accumulated >/=60 min/day of accelerometry-derived moderate intensity activity, indicating low levels of PAEE and PA in these adolescents. Further research is necessary to investigate the association between PA and health outcomes in Indian adolescents.
PubMed Accession Number :: 20134412.

Vimaleswaran, K. S.; Franks, P. W.; Brage, S.; Grontved, A.; Wareham, N. J.; Ekelund, U.; Loos, R. J. (2010) Lack of Association Between PCK1 Polymorphisms and Obesity, Physical Activity, and Fitness in European Youth Heart Study (EYHS) Obesity (Silver Spring), 18 ,1975-1980 [Journal Article] Online
Abstract: Phosphoenolpyruvate carboxykinase-1 (PCK1) is the rate-limiting enzyme in the hepatic gluconeogenic pathway. Studies have shown that overexpression of Pck1 in mice results in obesity-related traits and higher levels of physical activity (PA). Therefore, our aims were to investigate whether common genetic variation in the PCK1 gene influences obesity-related traits, PA, and fitness, and to examine whether PA and fitness attenuate the influence of the PCK1 polymorphisms on obesity in children. Analyses were undertaken on data from Danish and Estonian children (958 boys and 1,104 girls) from the European Youth Heart Study (EYHS), a school-based, cross-sectional study of children (mean +/- s.d. age: 9.6 +/- 0.4 years) and adolescents (15.5 +/- 0.5 years). We genotyped eight polymorphisms that captured the common genetic variations in the PCK1 gene. The association between the PCK1 polymorphisms and BMI, waist circumference (WC), sum of four skinfolds, PA, and fitness was tested using an additive model adjusted for age, age-group, gender, maturity, and country. Interactions were tested by including interaction terms in the model. None of the polymorphisms were significantly associated with BMI, WC, sum of four skinfolds, PA, and fitness, and also with the risk of being overweight or obese (P > 0.05). The interactions between the polymorphisms and age-group, gender, PA, and fitness were not statistically significant. This is the first study to comprehensively examine the association of PCK1 polymorphisms with obesity, PA, and fitness. Despite strong evidence from animal studies, our study in the EYHS cohort failed to identify an association of PCK1 polymorphisms with obesity, PA, and fitness.
PubMed Accession Number :: 20134411.

Banim, P. J.; Luben, R. N.; Wareham, N. J.; Sharp, S. J.; Khaw, K. T.; Hart, A. R. (2010) Physical activity reduces the risk of symptomatic gallstones: a prospective cohort study Eur J Gastroenterol Hepatol, 22 ,983-988 [Journal Article] Online
Abstract: BACKGROUND AND AIMS: Physical activity may prevent gallstones formation by reducing bile stasis and plasma triglycerides and elevating high-density lipoprotein cholesterol levels. This prospective study investigated the relationship of physical activity and symptomatic gallstones in both sexes, using a questionnaire validated against physiological measurements. METHODS: A total of 25 639 volunteers, aged 40-74 years, were recruited into the European Prospective Investigation of Cancer, Norfolk and completed a questionnaire recording occupational and recreational physical activity. This questionnaire was validated earlier against measures of energy expenditure and cardio-respiratory fitness. Participants were ranked into four groups of physical activity. The cohort was monitored over 14 years for symptomatic gallstones. The primary outcome was hazard ratios (HR) of developing gallstones at 5 years, calculated using Cox regression modelling. HRs were adjusted for body mass index, alcohol, hormone replacement therapy and parity. Further analysis of a binary variable compared the highest level of physical activity against a combination of the lowest three levels. RESULTS: After 5 years of follow-up, 135 participants (69.6% women) developed symptomatic gallstones. Comparing the highest level of physical activity against the lowest three levels, the multivariable analysis at 5 years was HR=0.30 (95% confidence interval=0.14-0.64, P=0.002). After 14 years the findings were attenuated (HR=0.70, 95% confidence interval=0.49-1.01, P=0.055). CONCLUSION: The highest level of physical activity was associated with a 70% decreased risk of symptomatic gallstones after 5 years. This association may be causal as there are consistent experimental and epidemiological data for a protective effect. Physical activity should be accurately measured in studies investigating gallstones aetiology.
PubMed Accession Number :: 20130468.

Corder, K.; van Sluijs, E. M.; McMinn, A. M.; Ekelund, U.; Cassidy, A.; Griffin, S. J. (2010) Perception versus reality awareness of physical activity levels of british children Am J Prev Med, 38 (1),1-8 [Journal Article] Online
Abstract: BACKGROUND: Interventions to increase children's physical activity have had limited success. One reason may be that children and their parents overestimate children's levels of physical activity, although there is a small amount of data on this topic. PURPOSE: This study aims to assess awareness of physical activity levels among British school children aged 9-10 years and their parents. METHODS: Physical activity was measured using an accelerometer in a cross-sectional study of 1892 children (44% male; M age=10.3 years, SD=0.3) from 92 Norfolk schools (Sport, Physical Activity and Eating Behavior: Environmental Determinants in Young People [SPEEDY] study). Data were collected between April and July 2007 and analyzed in 2008. Inactive was defined as <60 minutes/day of moderate and vigorous physical activity. Agreement between physical activity perception (child- and parent-rated) and objective physical activity was assessed. Associations between biological (height, weight, fat mass index); parental (support, BMI, physical activity); and peer factors (support, objective physical activity) and child and parental physical activity awareness were studied using multinomial logistic regression. RESULTS: In all, 39% of girls and 18% of boys were inactive. A total of 80% of parents of inactive children wrongly thought that their child was sufficiently active. In all, 40% of inactive children overestimated their physical activity level. Compared to parents who accurately described their children as inactive, parents who overestimated were more likely to have girls (p=0.005), to have a child with a lower fat mass index (p<0.001), or to report more parental and peer support (p=0.014 and p<0.001, respectively). CONCLUSIONS: Most parents of inactive children wrongly consider their children to be sufficiently active; parents of children with a lower fat mass index appear to assume that their children are adequately active. Increasing awareness regarding health benefits of physical activity beyond weight control might help reverse misperceptions of physical activity levels and encourage behavior change.
PubMed Accession Number :: 20117551.

Chamnan, P.; Simmons, R. K.; Griffin, S. J. (2010) Which risk engines are best to assess CVD risk in diabetes? Nat Rev Endocrinol, 6 (2),2 p following 115 [Journal Article] Online
PubMed Accession Number :: 20104677.

Peng, Q.; Zhao, J.; Xue, F. (2010) PCA-based bootstrap confidence interval tests for gene-disease association involving multiple SNPs BMC Genet, 11 (1),6 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Genetic association study is currently the primary vehicle for identification and characterization of disease-predisposing variant(s) which usually involves multiple single-nucleotide polymorphisms (SNPs) available. However, SNP-wise association tests raise concerns over multiple testing. Haplotype-based methods have the advantage of being able to account for correlations between neighbouring SNPs, yet assuming Hardy-Weinberg equilibrium (HWE) and potentially large number degrees of freedom can harm its statistical power and robustness. Approaches based on principal component analysis (PCA) are preferable in this regard but their performance varies with methods of extracting principal components (PCs). RESULTS: PCA-based bootstrap confidence interval test (PCA-BCIT), which directly uses the PC scores to assess gene-disease association, was developed and evaluated for three ways of extracting PCs, i.e., cases only(CAES), controls only(COES) and cases and controls combined(CES). Extraction of PCs with COES is preferred to that with CAES and CES. Performance of the test was examined via simulations as well as analyses on data of rheumatoid arthritis and heroin addiction, which maintains nominal level under null hypothesis and showed comparable performance with permutation test. CONCLUSIONS: PCA-BCIT is a valid and powerful method for assessing gene-disease association involving multiple SNPs.
PubMed Accession Number :: 20100356.

Borch-Johnsen, K.; Wareham, N. (2010) The rise and fall of the metabolic syndrome Diabetologia, 53 (4),597-599 [Journal Article] Online
PubMed Accession Number :: 20084362.

Skidmore, P.; Welch, A.; van Sluijs, E.; Jones, A.; Harvey, I.; Harrison, F.; Griffin, S.; Cassidy, A. (2010) Impact of neighbourhood food environment on food consumption in children aged 9-10 years in the UK SPEEDY (Sport, Physical Activity and Eating behaviour: Environmental Determinants in Young people) study Public Health Nutr, 13 ,1022-1030 [Journal Article] Online
Abstract: OBJECTIVE: Poor diet in childhood increases risk of obesity but the relationship between access to food and children's food choice is underexplored. We determined relationships between distance to and density of food outlets on children's food choice. DESIGN: Children (n 1721) aged 9-10 years who participated in a cross-sectional study from a sample of state and private schools across urban and rural areas. Food consumption was reported using a short validated FFQ. A Geographic Information System was used to determine proximity to local food outlets. Multivariable regression analyses were performed to determine associations between food consumption and distance to and density of local food outlets. SETTING: Norfolk, England. SUBJECTS: Boys (n 754) and girls (n 967) aged 9-10 years. RESULTS: The impact of distance to or density of food outlets on food choice was small after adjustment. Living further away from a supermarket increased portions of fruit (0.11 portions/week per 1 km increase in distance to nearest supermarket, P < 0.05) and vegetables (0.11 portions/week, P < 0.05) consumed. Living closer to convenience stores was also associated with an increased consumption of crisps, chocolate and white bread. Density of supermarkets was associated with both an increase in vegetable intake (0.31 portions/week, P < 0.05) and unhealthy foods. CONCLUSIONS: Distance to and density of food outlets are both associated with children's food choice, although the impact appears to be small and the relationship is complex. However, the effects of individual foods combined could be important, particularly as even small differences in intake can impact on body weight over time.
PubMed Accession Number :: 20082745.

Dupuis, J.; Langenberg, C.; Prokopenko, I.; Saxena, R.; Soranzo, N.; Jackson, A. U.; Wheeler, E.; Glazer, N. L.; Bouatia-Naji, N.; Gloyn, A. L.; Lindgren, C. M.; Magi, R.; Morris, A. P.; Randall, J.; Johnson, T.; Elliott, P.; Rybin, D.; Thorleifsson, G.; Steinthorsdottir, V.; Henneman, P.; Grallert, H.; Dehghan, A.; Hottenga, J. J.; Franklin, C. S.; Navarro, P.; Song, K.; Goel, A.; Perry, J. R.; Egan, J. M.; Lajunen, T.; Grarup, N.; Sparso, T.; Doney, A.; Voight, B. F.; Stringham, H. M.; Li, M.; Kanoni, S.; Shrader, P.; Cavalcanti-Proenca, C.; Kumari, M.; Qi, L.; Timpson, N. J.; Gieger, C.; Zabena, C.; Rocheleau, G.; Ingelsson, E.; An, P.; O'Connell, J.; Luan, J.; Elliott, A.; McCarroll, S. A.; Payne, F.; Roccasecca, R. M.; Pattou, F.; Sethupathy, P.; Ardlie, K.; Ariyurek, Y.; Balkau, B.; Barter, P.; Beilby, J. P.; Ben-Shlomo, Y.; Benediktsson, R.; Bennett, A. J.; Bergmann, S.; Bochud, M.; Boerwinkle, E.; Bonnefond, A.; Bonnycastle, L. L.; Borch-Johnsen, K.; Bottcher, Y.; Brunner, E.; Bumpstead, S. J.; Charpentier, G.; Chen, Y. D.; Chines, P.; Clarke, R.; Coin, L. J.; Cooper, M. N.; Cornelis, M.; Crawford, G.; Crisponi, L.; Day, I. N.; de Geus, E. J.; Delplanque, J.; Dina, C.; Erdos, M. R.; Fedson, A. C.; Fischer-Rosinsky, A.; Forouhi, N. G.; Fox, C. S.; Frants, R.; Franzosi, M. G.; Galan, P.; Goodarzi, M. O.; Graessler, J.; Groves, C. J.; Grundy, S.; Gwilliam, R.; Gyllensten, U.; Hadjadj, S.; Hallmans, G.; Hammond, N.; Han, X.; Hartikainen, A. L.; Hassanali, N.; Hayward, C.; Heath, S. C.; Hercberg, S.; Herder, C.; Hicks, A. A.; Hillman, D. R.; Hingorani, A. D.; Hofman, A.; Hui, J.; Hung, J.; Isomaa, B.; Johnson, P. R.; Jorgensen, T.; Jula, A.; Kaakinen, M.; Kaprio, J.; Kesaniemi, Y. A.; Kivimaki, M.; Knight, B.; Koskinen, S.; Kovacs, P.; Kyvik, K. O.; Lathrop, G. M.; Lawlor, D. A.; Le Bacquer, O.; Lecoeur, C.; Li, Y.; Lyssenko, V.; Mahley, R.; Mangino, M.; Manning, A. K.; Martinez-Larrad, M. T.; McAteer, J. B.; McCulloch, L. J.; McPherson, R.; Meisinger, C.; Melzer, D.; Meyre, D.; Mitchell, B. D.; Morken, M. A.; Mukherjee, S.; Naitza, S.; Narisu, N.; Neville, M. J.; Oostra, B. A.; Orru, M.; Pakyz, R.; Palmer, C. N.; Paolisso, G.; Pattaro, C.; Pearson, D.; Peden, J. F.; Pedersen, N. L.; Perola, M.; Pfeiffer, A. F.; Pichler, I.; Polasek, O.; Posthuma, D.; Potter, S. C.; Pouta, A.; Province, M. A.; Psaty, B. M.; Rathmann, W.; Rayner, N. W.; Rice, K.; Ripatti, S.; Rivadeneira, F.; Roden, M.; Rolandsson, O.; Sandbaek, A.; Sandhu, M.; Sanna, S.; Sayer, A. A.; Scheet, P.; Scott, L. J.; Seedorf, U.; Sharp, S. J.; Shields, B.; Sigurethsson, G.; Sijbrands, E. J.; Silveira, A.; Simpson, L.; Singleton, A.; Smith, N. L.; Sovio, U.; Swift, A.; Syddall, H.; Syvanen, A. C.; Tanaka, T.; Thorand, B.; Tichet, J.; Tonjes, A.; Tuomi, T.; Uitterlinden, A. G.; van Dijk, K. W.; van Hoek, M.; Varma, D.; Visvikis-Siest, S.; Vitart, V.; Vogelzangs, N.; Waeber, G.; Wagner, P. J.; Walley, A.; Walters, G. B.; Ward, K. L.; Watkins, H.; Weedon, M. N.; Wild, S. H.; Willemsen, G.; Witteman, J. C.; Yarnell, J. W.; Zeggini, E.; Zelenika, D.; Zethelius, B.; Zhai, G.; Zhao, J. H.; Zillikens, M. C.; Borecki, I. B.; Loos, R. J.; Meneton, P.; Magnusson, P. K.; Nathan, D. M.; Williams, G. H.; Hattersley, A. T.; Silander, K.; Salomaa, V.; Smith, G. D.; Bornstein, S. R.; Schwarz, P.; Spranger, J.; Karpe, F.; Shuldiner, A. R.; Cooper, C.; Dedoussis, G. V.; Serrano-Rios, M.; Morris, A. D.; Lind, L.; Palmer, L. J.; Hu, F. B.; Franks, P. W.; Ebrahim, S.; Marmot, M.; Kao, W. H.; Pankow, J. S.; Sampson, M. J.; Kuusisto, J.; Laakso, M.; Hansen, T.; Pedersen, O.; Pramstaller, P. P.; Wichmann, H. E.; Illig, T.; Rudan, I.; Wright, A. F.; Stumvoll, M.; Campbell, H.; Wilson, J. F.; Bergman, R. N.; Buchanan, T. A.; Collins, F. S.; Mohlke, K. L.; Tuomilehto, J.; Valle, T. T.; Altshuler, D.; Rotter, J. I.; Siscovick, D. S.; Penninx, B. W.; Boomsma, D. I.; Deloukas, P.; Spector, T. D.; Frayling, T. M.; Ferrucci, L.; Kong, A.; Thorsteinsdottir, U.; Stefansson, K.; van Duijn, C. M.; Aulchenko, Y. S.; Cao, A.; Scuteri, A.; Schlessinger, D.; Uda, M.; Ruokonen, A.; Jarvelin, M. R.; Waterworth, D. M.; Vollenweider, P.; Peltonen, L.; Mooser, V.; Abecasis, G. R.; Wareham, N. J.; Sladek, R.; Froguel, P.; Watanabe, R. M.; Meigs, J. B.; Groop, L.; Boehnke, M.; McCarthy, M. I.; Florez, J. C.; Barroso, I. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk Nat Genet, 42 (2),105-116 [Journal Article] Online
Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
PubMed Accession Number :: 20081858.

Saxena, R.; Hivert, M. F.; Langenberg, C.; Tanaka, T.; Pankow, J. S.; Vollenweider, P.; Lyssenko, V.; Bouatia-Naji, N.; Dupuis, J.; Jackson, A. U.; Kao, W. H.; Li, M.; Glazer, N. L.; Manning, A. K.; Luan, J.; Stringham, H. M.; Prokopenko, I.; Johnson, T.; Grarup, N.; Boesgaard, T. W.; Lecoeur, C.; Shrader, P.; O'Connell, J.; Ingelsson, E.; Couper, D. J.; Rice, K.; Song, K.; Andreasen, C. H.; Dina, C.; Kottgen, A.; Le Bacquer, O.; Pattou, F.; Taneera, J.; Steinthorsdottir, V.; Rybin, D.; Ardlie, K.; Sampson, M.; Qi, L.; van Hoek, M.; Weedon, M. N.; Aulchenko, Y. S.; Voight, B. F.; Grallert, H.; Balkau, B.; Bergman, R. N.; Bielinski, S. J.; Bonnefond, A.; Bonnycastle, L. L.; Borch-Johnsen, K.; Bottcher, Y.; Brunner, E.; Buchanan, T. A.; Bumpstead, S. J.; Cavalcanti-Proenca, C.; Charpentier, G.; Chen, Y. D.; Chines, P. S.; Collins, F. S.; Cornelis, M.; G, J. Crawford; Delplanque, J.; Doney, A.; Egan, J. M.; Erdos, M. R.; Firmann, M.; Forouhi, N. G.; Fox, C. S.; Goodarzi, M. O.; Graessler, J.; Hingorani, A.; Isomaa, B.; Jorgensen, T.; Kivimaki, M.; Kovacs, P.; Krohn, K.; Kumari, M.; Lauritzen, T.; Levy-Marchal, C.; Mayor, V.; McAteer, J. B.; Meyre, D.; Mitchell, B. D.; Mohlke, K. L.; Morken, M. A.; Narisu, N.; Palmer, C. N.; Pakyz, R.; Pascoe, L.; Payne, F.; Pearson, D.; Rathmann, W.; Sandbaek, A.; Sayer, A. A.; Scott, L. J.; Sharp, S. J.; Sijbrands, E.; Singleton, A.; Siscovick, D. S.; Smith, N. L.; Sparso, T.; Swift, A. J.; Syddall, H.; Thorleifsson, G.; Tonjes, A.; Tuomi, T.; Tuomilehto, J.; Valle, T. T.; Waeber, G.; Walley, A.; Waterworth, D. M.; Zeggini, E.; Zhao, J. H.; Illig, T.; Wichmann, H. E.; Wilson, J. F.; van Duijn, C.; Hu, F. B.; Morris, A. D.; Frayling, T. M.; Hattersley, A. T.; Thorsteinsdottir, U.; Stefansson, K.; Nilsson, P.; Syvanen, A. C.; Shuldiner, A. R.; Walker, M.; Bornstein, S. R.; Schwarz, P.; Williams, G. H.; Nathan, D. M.; Kuusisto, J.; Laakso, M.; Cooper, C.; Marmot, M.; Ferrucci, L.; Mooser, V.; Stumvoll, M.; Loos, R. J.; Altshuler, D.; Psaty, B. M.; Rotter, J. I.; Boerwinkle, E.; Hansen, T.; Pedersen, O.; Florez, J. C.; McCarthy, M. I.; Boehnke, M.; Barroso, I.; Sladek, R.; Froguel, P.; Meigs, J. B.; Groop, L.; Wareham, N. J.; Watanabe, R. M. (2010) Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge Nat Genet, 42 (2),142-148 [Journal Article] Online
Abstract: Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).
PubMed Accession Number :: 20081857.

Vimaleswaran, K. S.; Zhao, J. H.; Wainwright, N. W.; Surtees, P. G.; Wareham, N. J.; Loos, R. J. (2010) Association between serotonin 5-HT-2C receptor gene (HTR2C) polymorphisms and obesity- and mental health-related phenotypes in a large population-based cohort Int J Obes (Lond), 34 ,1028-1033 [Journal Article] Online
Abstract: Objective:Studies have shown that common single-nucleotide polymorphisms (SNPs) in the serotonin 5-HT-2C receptor (HTR2C) are associated with antipsychotic agent-induced weight gain and the development of behavioural and psychological symptoms. We aimed to analyse whether variation in the HTR2C is associated with obesity- and mental health-related phenotypes in a large population-based cohort.Method:Six tagSNPs, which capture all common genetic variation in the HTR2C gene, were genotyped in 4978 men and women from the European Prospective Investigation into Cancer (EPIC)-Norfolk study, an ongoing prospective population-based cohort study in the United Kingdom. To confirm borderline significant associations, the -759C/T SNP (rs3813929) was genotyped in the remaining 16 003 individuals from the EPIC-Norfolk study. We assessed social and psychological circumstances using the Health and Life Experiences Questionnaire. Genmod models were used to test associations between the SNPs and the outcomes. Logistic regression was performed to test for association of SNPs with obesity- and mental health- related phenotypes.Results:Of the six HTR2C SNPs, only the T allele of the -759C/T SNP showed borderline significant associations with higher body mass index (BMI) (0.23 kg m(-2); (95% confidence interval (CI): 0.01-0.44); P=0.051) and increased risk of lifetime major depressive disorder (MDD) (Odds ratio (OR): 1.13 (95% CI: 1.01-1.22), P=0.02). The associations between the -759C/T and BMI and lifetime MDD were independent. As associations only achieved borderline significance, we aimed to validate our findings on the -759C/T SNP in the full EPIC-Norfolk cohort (n=20 981). Although the association with BMI remained borderline significant (beta=0.20 kg m(-2); 95% CI: 0.04-0.44, P=0.09), that with lifetime MDD (OR: 1.01; 95% CI: 0.94-1.09, P=0.73) was not replicated.Conclusions:Our findings suggest that common HTR2C gene variants are unlikely to have a major role in obesity- and mental health-related traits in the general population.International Journal of Obesity advance online publication, 12 January 2010; doi:10.1038/ijo.2009.292.
PubMed Accession Number :: 20065966.

Huerta, J. M.; Navarro, C.; Chirlaque, M. D.; Tormo, M. J.; Steindorf, K.; Buckland, G.; Carneiro, F.; Johnsen, N. F.; Overvad, K.; Stegger, J.; Tjonneland, A.; Boutron-Ruault, M. C.; Clavel-Chapelon, F.; Morois, S.; Boeing, H.; Kaaks, R.; Rohrmann, S.; Vigl, M.; Lagiou, P.; Trichopoulos, D.; Trichopoulou, A.; Bas Bueno-de-Mesquita, H.; Monninkhof, E. M.; Numans, M. E.; Peeters, P. H.; Mattiello, A.; Pala, V.; Palli, D.; Tumino, R.; Vineis, P.; Agudo, A.; Ardanaz, E.; Arriola, L.; Molina-Montes, E.; Rodriguez, L.; Lindkvist, B.; Manjer, J.; Stenling, R.; Lund, E.; Crowe, F. L.; Key, T. J.; Khaw, K. T.; Wareham, N. J.; Jenab, M.; Norat, T.; Romaguera, D.; Riboli, E.; Gonzalez, C. A. (2010) Prospective study of physical activity and risk of primary adenocarcinomas of the oesophagus and stomach in the EPIC (European Prospective Investigation into Cancer and nutrition) cohort Cancer Causes Control, 21 ,657-669 [Journal Article] Online
Abstract: OBJECTIVE: To analyse the association between types of physical activity (occupational, recreational and household, vigorous and overall) and risk of primary oesophageal (OAC) or gastric adenocarcinoma (GAC). METHODS: From nine European countries, 420,449 participants were recruited between 1991 and 2000 and followed-up for a mean of 8.8 years to register incident GAC and OAC. Information on physical activity (PA), diet, lifestyle and health-related variables was obtained at baseline. Helicobacter pylori infection status was considered in a subset of 1,211 participants. Analyses were repeated by tumour site (cardia/non-cardia) and histological type (intestinal/diffuse). RESULTS: During the follow-up, 410 GAC and 80 OAC occurred. A lower risk of overall and non-cardia GAC was found for increasing levels of a PA index which combined occupational PA with weekly time spent in sports and cycling. The hazard ratio (HR) of GAC was 0.69, 95% CI: 0.50-0.94, for the comparison between active and inactive participants according to the PA index (HR = 0.44, 95% CI:0.26-0.74, for non-cardia GAC). No effect was found for cardia tumours or histological subtypes of GAC. PA of any kind was not associated with OAC. CONCLUSIONS: Overall and distal (non-cardia) gastric tumours were inversely associated with time spent on cycling and sports and a total PA index. No association was found for any type of PA and risk of cardia cancers of the stomach.
PubMed Accession Number :: 20052611.

Finucane, F. M.; Sharp, S. J.; Purslow, L. R.; Horton, K.; Horton, J.; Savage, D. B.; Brage, S.; Besson, H.; De Lucia Rolfe, E.; Sleigh, A.; Martin, H. J.; Aihie Sayer, A.; Cooper, C.; Ekelund, U.; Griffin, S. J.; Wareham, N. J. (2010) The effects of aerobic exercise on metabolic risk, insulin sensitivity and intrahepatic lipid in healthy older people from the Hertfordshire Cohort Study: a randomised controlled trial Diabetologia, 53 (4),624-631 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: We sought to determine the effect of an aerobic exercise intervention on clustered metabolic risk and related outcomes in healthy older adults in a single-centre, explanatory randomised controlled trial. METHODS: Participants from the Hertfordshire Cohort Study (born 1931-1939) were randomly assigned to 36 supervised 1 h sessions on a cycle ergometer over 12 weeks or to a non-intervention control group. Randomisation and group allocation were conducted by the study co-ordinator, using a software programme. Those with prevalent diabetes, unstable ischaemic heart disease or poor mobility were excluded. All data were collected at our clinical research facility in Cambridge. Components of the metabolic syndrome were used to derive a standardised composite metabolic risk score (zMS) as the primary outcome. Trial status: closed to follow-up. RESULTS: We randomised 100 participants (50 to the intervention, 50 to the control group). Mean age was 71.4 (range 67.4-76.3) years. Overall, 96% of participants attended for follow-up measures. There were no serious adverse events. Using an intention-to-treat analysis, we saw a non-significant reduction in zMS in the exercise group compared with controls (0.07 [95% CI -0.03, 0.17], p = 0.19). However, the exercise group had significantly decreased weight, waist circumference and intrahepatic lipid, with increased aerobic fitness and a 68% reduction in prevalence of abnormal glucose metabolism (OR 0.32 [95% CI 0.11-0.92], p = 0.035) compared with controls. Results were similar in per-protocol analyses. CONCLUSIONS/INTERPRETATION: Enrolment in a supervised aerobic exercise intervention led to weight loss, increased fitness and improvements in some but not all metabolic outcomes. In appropriately screened older individuals, such interventions appear to be safe. TRIAL REGISTRATION: Controlled-trials.com ISRCTN60986572 FUNDING: Medical Research Council.
PubMed Accession Number :: 20052455.

Hoeft, B.; Linseisen, J.; Beckmann, L.; Muller-Decker, K.; Canzian, F.; Husing, A.; Kaaks, R.; Vogel, U.; Jakobsen, M. U.; Overvad, K.; Hansen, R. D.; Knuppel, S.; Boeing, H.; Trichopoulou, A.; Yvoni, K.; Trichopoulos, D.; Berrino, F.; Palli, D.; Panico, S.; Tumino, R.; Bueno-de-Mesquita, H. B.; van Duijnhoven, F. J.; van Gils, C. H.; Peeters, P. H.; Dumeaux, V.; Lund, E.; Huerta Castano, J. M.; Munoz, X.; Rodriguez, L.; Barricarte, A.; Manjer, J.; Jirstrom, K.; Van Guelpen, B.; Hallmans, G.; Spencer, E. A.; Crowe, F. L.; Khaw, K. T.; Wareham, N.; Morois, S.; Boutron-Ruault, M. C.; Clavel-Chapelon, F.; Chajes, V.; Jenab, M.; Boffetta, P.; Vineis, P.; Mouw, T.; Norat, T.; Riboli, E.; Nieters, A. (2010) Polymorphisms in fatty acid metabolism-related genes are associated with colorectal cancer risk Carcinogenesis, 31 (3),466-72 [Journal Article] Online
Abstract: Colorectal cancer is the third most common malignant tumor and the fourth-leading cause of cancer death worldwide. The crucial role of fatty acids for a number of important biological processes suggests a more in depth analysis of inter-individual differences in fatty acid metabolizing genes as contributing factor to colon carcinogenesis. We examined the association between genetic variability in 43 fatty acid metabolism-related genes and colorectal risk in 1225 CRC cases and 2032 controls participating in the European Prospective Investigation into Cancer and Nutrition study. 392 single nucleotide polymorphisms were selected using pairwise tagging with an r(2) cutoff of 0.8 and a minor allele frequency of >5%. Conditional logistic regression models were used to estimate odds ratios and corresponding 95% confidence intervals. Haplotype analysis was performed using a generalized linear model framework. On the genotype level, HPGD, PLA2G6, and TRPV3 were associated with higher risk for colorectal cancer, while PTGER2 was associated with lower colorectal cancer risk. A significant inverse association (p < 0.006) was found for PTGER2 GGG haplotype while HPGD AGGAG and PLA2G3 CT haplotypes were significantly (p < 0.001 and p = 0.003, respectively) associated with higher risk of colorectal cancer. Based on these data we present for the first time the association of HPGD variants with colorectal cancer risk. Our results support the key role of prostanoid signaling in colon carcinogenesis and suggest a relevance of genetic variation in fatty acid metabolism-related genes and colorectal cancer risk.
PubMed Accession Number :: 20042636.

Green, A. Q.; Krishnan, S.; Finucane, F. M.; Rayman, G. (2010) Altered C-fiber function as an indicator of early peripheral neuropathy in individuals with impaired glucose tolerance Diabetes Care, 33 (1),174-6 [Journal Article] Online
Abstract: OBJECTIVE: This study explored the importance of glycemic burden compared with features of the metabolic syndrome in the pathogenesis of diabetic neuropathy by comparing C-fiber function in people with type 1 diabetes to that in people with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: The axon reflex-elicited flare areas (LDIflares) were measured with a laser Doppler imager (LDI) in age-, height-, and BMI-matched groups with IGT (n = 14) and type 1 diabetes (n = 16) and in healthy control subjects (n = 16). RESULTS: The flare area was reduced in the IGT group compared with the control (2.78 +/- 1.1 vs. 5.23 +/- 1.7 cm(2), P = 0.0001) and type 1 diabetic (5.16 +/- 2.3 cm(2), P = 0.002) groups, whereas the flare area was similar in the type 1 diabetic and control groups. CONCLUSIONS: This technique suggests that small-fiber neuropathy is a feature of IGT. The absence of similar small-fiber neuropathy in those with longstanding type 1 diabetes suggests that glycemia may not be the major determinant of small-fiber neuropathy in IGT.
PubMed Accession Number :: 20040675.

Fawcett, K. A.; Wheeler, E.; Morris, A. P.; Ricketts, S. L.; Hallmans, G.; Rolandsson, O.; Daly, A.; Wasson, J.; Permutt, A.; Hattersley, A. T.; Glaser, B.; Franks, P. W.; McCarthy, M. I.; Wareham, N. J.; Sandhu, M. S.; Barroso, I. (2010) Detailed investigation of the role of common and low frequency WFS1 variants in type 2 diabetes risk Diabetes, 59 (3),741-746 [Journal Article] Online
Abstract: Objective: WFS1 (Wolfram Syndrome 1) SNPs are associated with risk of type 2 diabetes (T2D). Here, we aimed to refine this association, and investigate the role of low frequency WFS1 variants in T2D risk. Research design and methods: For fine-mapping, we sequenced WFS1 exons, splice junctions and conserved non-coding sequences in 24 T2D cases and 68 controls, selected tagging SNPs, and genotyped these in 959 UK T2D cases and 1386 controls. The same genomic regions were sequenced in 1235 T2D cases and 1668 controls to compare the frequency of rarer variants between cases and controls. Results: Of 31 tagging SNPs, the strongest associated was the previously untested 3' UTR rs1046320 (P=0.008); OR=0.84, P=6.59 x 10(-7) on further replication in 3753 cases and 4198 controls. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r(2)=0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (MAF<0.01) non-synonymous variants between T2D cases and controls (P=0.79). Two intermediate frequency (MAF 0.01-0.05) non-synonymous changes also showed no statistical association with T2D. Conclusion: We identified six highly correlated SNPs that show strong and comparable associations with risk of T2D association but further refinement of these associations will require large sample sizes (>100,000), or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on T2D risk in white UK populations, highlighting the complexities of undertaking association studies with low frequency variants identified by re-sequencing.
PubMed Accession Number :: 20028947.

Sofat, R.; Hingorani, A. D.; Smeeth, L.; Humphries, S. E.; Talmud, P. J.; Cooper, J.; Shah, T.; Sandhu, M. S.; Ricketts, S. L.; Boekholdt, S. M.; Wareham, N.; Khaw, K. T.; Kumari, M.; Kivimaki, M.; Marmot, M.; Asselbergs, F. W.; van der Harst, P.; Dullaart, R. P.; Navis, G.; van Veldhuisen, D. J.; Van Gilst, W. H.; Thompson, J. F.; McCaskie, P.; Palmer, L. J.; Arca, M.; Quagliarini, F.; Gaudio, C.; Cambien, F.; Nicaud, V.; Poirer, O.; Gudnason, V.; Isaacs, A.; Witteman, J. C.; van Duijn, C. M.; Pencina, M.; Vasan, R. S.; D'Agostino, R. B., Sr.; Ordovas, J.; Li, T. Y.; Kakko, S.; Kauma, H.; Savolainen, M. J.; Kesaniemi, Y. A.; Sandhofer, A.; Paulweber, B.; Sorli, J. V.; Goto, A.; Yokoyama, S.; Okumura, K.; Horne, B. D.; Packard, C.; Freeman, D.; Ford, I.; Sattar, N.; McCormack, V.; Lawlor, D. A.; Ebrahim, S.; Smith, G. D.; Kastelein, J. J.; Deanfield, J.; Casas, J. P. (2010) Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms Circulation, 121 (1),52-62 [Journal Article] Online
Abstract: BACKGROUND: -Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results-We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI -0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI -0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions-Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.
PubMed Accession Number :: 20026784.

Du, H.; van der, A. Dl; Boshuizen, H. C.; Forouhi, N. G.; Wareham, N. J.; Halkjaer, J.; Tjonneland, A.; Overvad, K.; Jakobsen, M. U.; Boeing, H.; Buijsse, B.; Masala, G.; Palli, D.; Sorensen, T. I.; Saris, W. H.; Feskens, E. J. (2010) Dietary fiber and subsequent changes in body weight and waist circumference in European men and women Am J Clin Nutr, 91 ,329-36 [Journal Article] Online
Abstract: BACKGROUND: Dietary fiber may play a role in obesity prevention. Until now, the role that fiber from different sources plays in weight change had rarely been studied. Objective: Our aim was to investigate the association of total dietary fiber, cereal fiber, and fruit and vegetable fiber with changes in weight and waist circumference. DESIGN: We conducted a prospective cohort study with 89,432 European participants, aged 20-78 y, who were free of cancer, cardiovascular disease, and diabetes at baseline and who were followed for an average of 6.5 y. Dietary information was collected by using validated country-specific food-frequency questionnaires. Multiple linear regression analysis was performed in each center studied, and estimates were combined by using random-effect meta-analyses. Adjustments were made for follow-up duration, other dietary variables, and baseline anthropometric, demographic, and lifestyle factors. RESULTS: Total fiber was inversely associated with subsequent weight and waist circumference change. For a 10-g/d higher total fiber intake, the pooled estimate was -39 g/y (95% CI: -71, -7 g/y) for weight change and -0.08 cm/y (95% CI: -0.11, -0.05 cm/y) for waist circumference change. A 10-g/d higher fiber intake from cereals was associated with -77 g/y (95% CI: -127, -26 g/y) weight change and -0.10 cm/y (95% CI: -0.18, -0.02 cm/y) waist circumference change. Fruit and vegetable fiber was not associated with weight change but had a similar association with waist circumference change when compared with intake of total dietary fiber and cereal fiber. CONCLUSION: Our finding may support a beneficial role of higher intake of dietary fiber, especially cereal fiber, in prevention of body-weight and waist circumference gain.
PubMed Accession Number :: 20016015.

Simmons, R. K.; Alberti, K. G.; Gale, E. A.; Colagiuri, S.; Tuomilehto, J.; Qiao, Q.; Ramachandran, A.; Tajima, N.; Brajkovich Mirchov, I.; Ben-Nakhi, A.; Reaven, G.; Hama Sambo, B.; Mendis, S.; Roglic, G. (2010) The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation Diabetologia, 53 (4),600-605 [Journal Article] Online
Abstract: This article presents the conclusions of a WHO Expert Consultation that evaluated the utility of the 'metabolic syndrome' concept in relation to four key areas: pathophysiology, epidemiology, clinical work and public health. The metabolic syndrome is a concept that focuses attention on complex multifactorial health problems. While it may be considered useful as an educational concept, it has limited practical utility as a diagnostic or management tool. Further efforts to redefine it are inappropriate in the light of current knowledge and understanding, and there is limited utility in epidemiological studies in which different definitions of the metabolic syndrome are compared. Metabolic syndrome is a pre-morbid condition rather than a clinical diagnosis, and should thus exclude individuals with established diabetes or known cardiovascular disease (CVD). Future research should focus on: (1) further elucidation of common metabolic pathways underlying the development of diabetes and CVD, including those clustering within the metabolic syndrome; (2) early-life determinants of metabolic risk; (3) developing and evaluating context-specific strategies for identifying and reducing CVD and diabetes risk, based on available resources; and (4) developing and evaluating population-based prevention strategies.
PubMed Accession Number :: 20012011.

Repapi, E.; Sayers, I.; Wain, L. V.; Burton, P. R.; Johnson, T.; Obeidat, M.; Zhao, J. H.; Ramasamy, A.; Zhai, G.; Vitart, V.; Huffman, J. E.; Igl, W.; Albrecht, E.; Deloukas, P.; Henderson, J.; Granell, R.; McArdle, W. L.; Rudnicka, A. R.; Barroso, I.; Loos, R. J.; Wareham, N. J.; Mustelin, L.; Rantanen, T.; Surakka, I.; Imboden, M.; Wichmann, H. E.; Grkovic, I.; Jankovic, S.; Zgaga, L.; Hartikainen, A. L.; Peltonen, L.; Gyllensten, U.; Johansson, A.; Zaboli, G.; Campbell, H.; Wild, S. H.; Wilson, J. F.; Glaser, S.; Homuth, G.; Volzke, H.; Mangino, M.; Soranzo, N.; Spector, T. D.; Polasek, O.; Rudan, I.; Wright, A. F.; Heliovaara, M.; Ripatti, S.; Pouta, A.; Naluai, A. T.; Olin, A. C.; Toren, K.; Cooper, M. N.; James, A. L.; Palmer, L. J.; Hingorani, A. D.; Wannamethee, S. G.; Whincup, P. H.; Smith, G. D.; Ebrahim, S.; McKeever, T. M.; Pavord, I. D.; Macleod, A. K.; Morris, A. D.; Porteous, D. J.; Cooper, C.; Dennison, E.; Shaheen, S.; Karrasch, S.; Schnabel, E.; Schulz, H.; Grallert, H.; Bouatia-Naji, N.; Delplanque, J.; Froguel, P.; Blakey, J. D.; Britton, J. R.; Morris, R. W.; Holloway, J. W.; Lawlor, D. A.; Hui, J.; Nyberg, F.; Jarvelin, M. R.; Jackson, C.; Kahonen, M.; Kaprio, J.; Probst-Hensch, N. M.; Koch, B.; Hayward, C.; Evans, D. M.; Elliott, P.; Strachan, D. P.; Hall, I. P.; Tobin, M. D. (2010) Genome-wide association study identifies five loci associated with lung function Nat Genet, 42 (1),36-44 [Journal Article] Online
Abstract: Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n </= 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n </= 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
PubMed Accession Number :: 20010834.

Vimaleswaran, K. S.; Radha, V.; Ghosh, S.; Majumder, P. P.; Rao, M. R.; Mohan, V. (2010) A Haplotype at the UCP1 Gene Locus Contributes to Genetic Risk for Type 2 Diabetes in Asian Indians (CURES-72) Metab Syndr Relat Disord, 8 (1),63-68 [Journal Article] Online
Abstract: Background: The gene encoding for uncoupling protein-1 (UCP1) is considered to be a candidate gene for type 2 diabetes because of its role in thermogenesis and energy expenditure. The objective of the study was to examine whether genetic variations in the UCP1 gene are associated with type 2 diabetes and its related traits in Asian Indians. Methods: The study subjects, 810 type 2 diabetic subjects and 990 normal glucose tolerant (NGT) subjects, were chosen from the Chennai Urban Rural Epidemiological Study (CURES), an ongoing population-based study in southern India. The polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies. Results: The three polymorphisms, namely -3826A-->G, an A-->C transition in the 5'-untranslated region (UTR) and Met229Leu, were not associated with type 2 diabetes. However, the frequency of the A-C-Met (-3826A-->G-5'UTR A-->C-Met229Leu) haplotype was significantly higher among the type 2 diabetic subjects (2.67%) compared with the NGT subjects (1.45%, P < 0.01). The odds ratio for type 2 diabetes for the individuals carrying the haplotype A-C-Met was 1.82 (95% confidence interval, 1.29-2.78, P = 0.009). Conclusions: The haplotype, A-C-Met, in the UCP1 gene is significantly associated with the increased genetic risk for developing type 2 diabetes in Asian Indians.
PubMed Accession Number :: 19943796.

Perry, J. R.; Weedon, M. N.; Langenberg, C.; Jackson, A. U.; Lyssenko, V.; Sparso, T.; Thorleifsson, G.; Grallert, H.; Ferrucci, L.; Maggio, M.; Paolisso, G.; Walker, M.; Palmer, C. N.; Payne, F.; Young, E.; Herder, C.; Narisu, N.; Morken, M. A.; Bonnycastle, L. L.; Owen, K. R.; Shields, B.; Knight, B.; Bennett, A.; Groves, C. J.; Ruokonen, A.; Jarvelin, M. R.; Pearson, E.; Pascoe, L.; Ferrannini, E.; Bornstein, S. R.; Stringham, H. M.; Scott, L. J.; Kuusisto, J.; Nilsson, P.; Neptin, M.; Gjesing, A. P.; Pisinger, C.; Lauritzen, T.; Sandbaek, A.; Sampson, M.; Zeggini, E.; Lindgren, C. M.; Steinthorsdottir, V.; Thorsteinsdottir, U.; Hansen, T.; Schwarz, P.; Illig, T.; Laakso, M.; Stefansson, K.; Morris, A. D.; Groop, L.; Pedersen, O.; Boehnke, M.; Barroso, I.; Wareham, N. J.; Hattersley, A. T.; McCarthy, M. I.; Frayling, T. M. (2010) Genetic evidence that raised Sex Hormone Binding Globulin (SHBG) levels reduce the risk of type 2 diabetes Hum Mol Genet, 19 ,535-544 [Journal Article] Online
Abstract: Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased, or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941 that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27,657 type 2 diabetes patients and 58,481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes, odds ratio 0.94 (95%CI: 0.91, 0.97), p=2x10(-5), with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected [odds ratio 0.92 (95%CI: 0.88-0.96)], given the SHBG-SNP versus SHBG-levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG-levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
PubMed Accession Number :: 19933169.

Dossus, L.; Allen, N.; Kaaks, R.; Bakken, K.; Lund, E.; Tjonneland, A.; Olsen, A.; Overvad, K.; Clavel-Chapelon, F.; Fournier, A.; Chabbert-Buffet, N.; Boeing, H.; Schutze, M.; Trichopoulou, A.; Trichopoulos, D.; Lagiou, P.; Palli, D.; Krogh, V.; Tumino, R.; Vineis, P.; Mattiello, A.; Bueno-de-Mesquita, H. B.; Onland-Moret, N. C.; Peeters, P. H.; Dumeaux, V.; Redondo, M. L.; Duell, E.; Sanchez-Cantalejo, E.; Arriola, L.; Chirlaque, M. D.; Ardanaz, E.; Manjer, J.; Borgquist, S.; Lukanova, A.; Lundin, E.; Khaw, K. T.; Wareham, N.; Key, T.; Chajes, V.; Rinaldi, S.; Slimani, N.; Mouw, T.; Gallo, V.; Riboli, E. (2010) Reproductive risk factors and endometrial cancer: The European prospective investigation into cancer and nutrition Int J Cancer, 127 ,442-451 [Journal Article] Online
Abstract: Endometrial cancer risk has been associated with reproductive factors (age at menarche, age at menopause, parity, age at first and last birth, time since last birth, and use of oral contraceptives). However, these factors are closely inter-related and whether they act independently still requires clarification. We conducted a study to examine the association of menstrual and reproductive variables with the risk of endometrial cancer among the European Prospective Investigation into Cancer and nutrition (EPIC).Among the 302,618 women eligible for the study, 1,017 incident endometrial cancer cases were identified. A reduction in endometrial cancer risk was observed in women with late menarche, early menopause, past oral contraceptive (OC) use, high parity, and a shorter time since last full term pregnancy (FTP). No association was observed for duration of breast-feeding after adjustment for number of FTP, or for abortion (spontaneous or induced). After mutual adjustment, late age at menarche, early age at menopause and duration of OC use showed similar risk reductions of 7-8% per year of menstrual life, whereas the decreased risk associated with cumulative duration of full-term pregnancies was stronger (22% per year).In conclusion, our findings confirmed a reduction in risk of endometrial cancer with factors associated with a lower cumulative exposure to estrogen and/or higher exposure to progesterone, such as increasing number of full-term pregnancies and shorter menstrual lifespan and therefore support an important role of hormonal mechanisms in endometrial carcinogenesis. (c) 2009 UICC.
PubMed Accession Number :: 19924816.

Freitas, R. N.; Khaw, K. T.; Wu, K.; Bowman, R.; Jeffery, H.; Luben, R.; Wareham, N. J.; Rodwell, S. (2010) HMGCR gene polymorphism is associated with stroke risk in the EPIC-Norfolk study Eur J Cardiovasc Prev Rehabil, 17 ,89-93 [Journal Article] Online
Abstract: BACKGROUND: Earlier, a G/T single nucleotide polymorphism (SNP) in the HMGCR gene was shown to significantly reduce the overall serum lipids response to pravastatin. This study aimed to investigate the relationship of the rs17238540 SNP with coronary heart disease, stroke and cardiovascular disease risk. DESIGN: Cross-sectional study from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort. METHODS: Genotype was determined by pyrosequencing 23 011 participants, for whom clinical and biochemical data were available. Baseline risk factors according to genotype were evaluated, and the risk for fatal and nonfatal stroke, ischaemic heart disease and all types of cardiovascular diseases were assessed by logistic regression after approximately 11 years of follow-up. RESULTS: The G allele carriers presented 1.4 mmHg higher systolic blood pressure and 0.8 mmHg higher diastolic blood pressure than those who were TT carriers. They also presented higher risk of prevalent total (odds ratio: 1.44, 95% confidence interval: 1.05-1.97, P = 0.025) and nonfatal (odds ratio: 1.56, 95% confidence interval: 1.12-2.17, P = 0.009) stroke events compared with the TT individuals in the multivariate models. CONCLUSION: An association between the rs17238540 SNP and stroke risk was observed, independent of the effect of the SNP on the blood pressure. The possible mechanisms involved, besides the effect on blood pressure, might be related to pleiotropic functions of the HMGCR, and remain to be explored.
PubMed Accession Number :: 19923996.

Arsenault, B. J.; Rana, J. S.; Lemieux, I.; Despres, J. P.; Kastelein, J. J.; Boekholdt, S. M.; Wareham, N. J.; Khaw, K. T. (2010) Physical inactivity, abdominal obesity and risk of coronary heart disease in apparently healthy men and women Int J Obes (Lond), 34 ,340-347 [Journal Article] Online
Abstract: Objective:To test the hypothesis that for any given body mass index (BMI) category, active individuals would have a smaller waist circumference than inactive individuals. Our second objective was to examine the respective contribution of waist circumference and physical inactivity on coronary heart disease (CHD) risk.Design:Prospective, population-based study with an 11.4-year follow-up.Subjects:A total of 21 729 men and women aged 45-79 years, residing in Norfolk, UK.Methods:During follow-up, 2191 CHD events were recorded. Physical activity was evaluated using a validated lifestyle questionnaire that takes into account both leisure-time and work-related physical activity. Waist circumference was measured and BMI was calculated for each participant.Results:For both men and women, we observed that within each BMI category (<25.0, 25-30 and >/=30.0 kg m(-2)), active participants had a lower waist circumference than inactive participants (P<0.001). In contrast, within each waist circumference tertile, BMI did not change across physical activity categories (except for women with an elevated waist circumference). Compared with active men with a low waist circumference, inactive men with an elevated waist circumference had a hazard ratio (HR) for future CHD of 1.74 (95% confidence interval (CI), 1.34-2.27) after adjusting for age, smoking, alcohol intake and parental history of CHD. In the same model and after further adjusting for hormone replacement therapy use, compared with active women with a low waist circumference, inactive women with an elevated waist circumference had an HR for future CHD of 4.00 (95% CI, 2.04-7.86).Conclusion:In any BMI category, inactive participants were characterized by an increased waist circumference, a marker of abdominal adiposity, compared with active individuals. Physical inactivity and abdominal obesity were both independently associated with an increased risk of future CHD.International Journal of Obesity advance online publication, 17 November 2009; doi:10.1038/ijo.2009.229.
PubMed Accession Number :: 19918249.

Chamnan, P.; Shine, B. S.; Haworth, C. S.; Bilton, D.; Adler, A. I. (2010) Diabetes as a Determinant of Mortality in Cystic Fibrosis Diabetes Care, 33 ,311-316 [Journal Article] Online
Abstract: Background: Diabetes is increasingly common in cystic fibrosis (CF), but little exists describing its influence on mortality. Using national UK data, this study documents diabetes-specific mortality rates, estimates the impact of diabetes on survival, and estimates population attributable fractions. Methods: This retrospective cohort study identified 8,029 individuals aged 0-65 years from the UK CF Registry (1996-2005). 5,892 patients were included in analyses of mortality rates and 4,234 in analyses of risk factors. We calculated age-adjusted mortality rates using Poisson regression, standardized mortality ratios using the population of England and Wales, and relative risks using proportional hazards modeling. Findings: During 17,672 person-years of follow-up, 393 subjects died. The age-adjusted mortality rate was 1.8/100 person-years (95% CI 1.6 to 2.0). The age-adjusted mortality rates per 100 person-years were 2.0 (CI 1.8 to 2.4) in women and 1.6 (95% CI 1.4 to 1.9) in males, and 4.2 (95% CI 3.4-5.1) in individuals with diabetes vs 1.5 (95% CI 1.3 to 1.7) in those without diabetes. Independent risk factors for death included diabetes (hazard ratio, 95% confidence interval, 1.31 (1.03 to 1.67), female sex (1.71, 1.36 to 2.14) plus poorer pulmonary function, lower body mass index, B. cepacia infection, absence of S. aureus infection, allergic bronchopulmonary aspergillosis, liver disease, prior organ transplantation, and corticosteroid use. Interpretation: Individuals with CF die earlier with diabetes, which, if delayed or better treated, might reasonably extend survival, and merits testing.
PubMed Accession Number :: 19918014.

Simmons, R. K.; Unwin, N.; Griffin, S. J. (2010) International Diabetes Federation: An update of the evidence concerning the prevention of type 2 diabetes Diabetes Res Clin Pract, 87 (2),143-149 [Journal Article] Online
Abstract: This article aims to provide an updated summary of diabetes prevention efforts by reviewing relevant literature published between 2007 and 2009. These include results from the long-term follow-up of diabetes prevention trials and the roll-out of community-based interventions in "real world" settings. Some countries have begun to implement population-based strategies for chronic disease prevention, but investment in developing and evaluating population-level interventions remains inadequate. By focussing on the "small change" approach and involving a number of different agencies, it may be possible to shift the population distribution of risk factors for diabetes and cardiovascular disease in a favourable direction. The cost-effectiveness of primary prevention strategies for type 2 diabetes has not been universally demonstrated. Some of the uncertainties relating to screening for diabetes have now been resolved but longer-term data on hard cardiovascular outcomes are still needed. In summary, individual countries should aim to develop and evaluate cost-effective, setting-specific diabetes risk identification and prevention strategies based on available resources. These should be linked to initiatives aimed at reducing the burden of cardiovascular disease, and complemented with population-based strategies focusing on the control and reduction of behavioural and cardiovascular risk factors by targeting their key determinants.
PubMed Accession Number :: 19913319.

Jones, A. P.; van Sluijs, E. M.; Ness, A. R.; Haynes, R.; Riddoch, C. J. (2010) Physical activity in children: Does how we define neighbourhood matter? Health Place, 16 ,236-241 [Journal Article] Online
Abstract: Physical activity levels in children are low and factors in the neighbourhood are believed to be influential. However, uncertainty remains about how best to define the neighbourhood. We therefore sought to study the role of area definition on neighbourhood variations in child physical activity using data collected at age 11 from the Avon Longitudinal Study of Parents and Children, UK. We found the effect of neighbourhood of residence on variations in PA was small, explaining under 3% of variance at best, and was not strongly dependent on the manner by which the neighbourhood was defined. Our results suggest that while characteristics of local environments may be important determinants of activity, the delineation of neighbourhoods based on shared social or physical characteristics may not best capture the local influences.
PubMed Accession Number :: 19906555.

Lee, C. T.; Gayton, E. L.; Beulens, J. W.; Flanagan, D. W.; Adler, A. I. (2010) Micronutrients and Diabetic Retinopathy A Systematic Review Ophthalmology, 117 (1),71-78 [Journal Article] Online
Abstract: BACKGROUND: We have evaluated the evidence for the association between intake and blood levels of micronutrients and diabetic retinopathy. Treatment for diabetic retinopathy requires significant clinical input and specialist ophthalmologic care. Micronutrients, including vitamin C, vitamin E, and magnesium, may interfere with pathologic mechanisms of diabetic retinopathy and potentially alter its risk. METHODS: We conducted a search of epidemiologic literature in PubMed and Embase from 1988 to May 2008, using keywords for exposures, including magnesium, ascorbic acid, alpha-tocopherol and antioxidants, and outcomes, including diabetic retinopathy. Two authors independently extracted data and assessed the quality of the studies using the Newcastle-Ottawa Scale. The overall quality of evidence was graded as I (highest), II, or III (lowest). RESULTS: Of the 766 studies identified, we reviewed 15 studies, comprising 4094 individuals. For vitamin C, hospital-based studies reported an inverse association between plasma levels with retinopathy, whereas population-based studies showed no association between dietary intake and retinopathy. For vitamin E, there was no association with dietary intake or plasma levels and retinopathy. For magnesium, a single prospective analysis showed an association between low levels in plasma and progression of retinopathy, but cross-sectional studies reported inconsistent results. In the assessment of quality, population-based studies had higher ratings than hospital-based studies. CONCLUSIONS: The evidence suggests that dietary intake or plasma levels of vitamins C and E and magnesium do not seem to be associated with diabetic retinopathy. Because of differences in study designs and measurement of micronutrients, incomplete ascertainment of retinopathy, and residual confounding, these findings require confirmation. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.
PubMed Accession Number :: 19900709.

Gayathri, S. B.; Radha, V.; Vimaleswaran, K. S.; Mohan, V. (2010) Association of the PPARGC1A Gene Polymorphism With Diabetic Nephropathy in an Asian Indian Population (CURES-41) Metab Syndr Relat Disord, 8 (2),119-126 [Journal Article] Online
Abstract: Background: The aim of this study was to evaluate the association of polymorphisms of the peroxisome proliferator-activated receptor gamma (PPARG) gene and peroxisome proliferators-activated receptor gamma co-activator 1 alpha (PPARGC1A) gene with diabetic nephropathy (DN) in Asian Indians. Methods: Six common polymorphisms, 3 of the PPARG gene [-1279G/A, Pro12Ala, and His478His (C/T)] and 3 of the PPARGC1A gene (Thr394Thr, Gly482Ser, and +A2962G) were studied in 571 normal glucose-tolerant (NGT) subjects, 255 type 2 diabetic (T2D) subjects without nephropathy, and 141 DN subjects. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing. Logistic regression analysis was performed to assess the covariables associated with DN. Results: Among the 6 polymorphisms examined, only the Gly482Ser of the PPARGC1A gene was significantly associated with DN. The genotype frequency of Ser/Ser genotype of the PPARGC1A gene was 8.8% (50/571) in NGT subjects, 7.8% (20/255) in T2D subjects, and 29.8% (42/141) in DN subjects. The odds ratios (ORs) for DN for the susceptible Gly/Ser and Ser/Ser genotype after adjusting for age, sex, body mass index, and duration of diabetes were 2.14 [95% confidence interval (CI), 1.23-3.72; P = 0.007] and 8.01 (95% CI, 3.89-16.47; P < 0.001), respectively. The unadjusted OR for DN for the XA genotype of the Thr394Thr polymorphism was 1.87 (95% CI, 1.20-2.92; P = 0.006) compared to T2D subjects. However, the significance was lost (P = 0.061) when adjusted for age, sex, BMI, and duration of diabetes. The +A2962G of PPARGC1A and the 3 polymorphisms of PPARG were not associated with DN. Conclusion: The Gly482Ser polymorphism of the PPARGC1A gene is associated with DN in Asian Indians.
PubMed Accession Number :: 19900151.

Besson, H.; Brage, S.; Jakes, R. W.; Ekelund, U.; Wareham, N. J. (2010) Estimating physical activity energy expenditure, sedentary time, and physical activity intensity by self-report in adults Am J Clin Nutr, 91 ,106-114 [Journal Article] Online
Abstract: BACKGROUND: Few questionnaires that assess usual physical activity have been reported to be valid for all different subdimensions of physical activity. OBJECTIVE: The objective was to assess the validity and reliability of the Recent Physical Activity Questionnaire (RPAQ), which assesses usual physical activity (PA) in 4 domains (work, travel, recreation, and domestic life). DESIGN: Total energy expenditure (TEE) was measured for 14 d by using the doubly labeled water (DLW) technique combined with a measure of resting metabolic rate to yield PA energy expenditure (PAEE) in 25 men and 25 women. Simultaneously, intensity of activity was measured by using combined heart rate and movement sensing for 11 d. Repeatability of the RPAQ was assessed in an independent sample of 71 women and 60 men aged 31-57 y. RESULTS: Estimated TEE and PAEE were significantly associated with criterion measures (TEE: r = 0.67; PAEE: r = 0.39) with mean (+/-SD) biases of -3452 +/- 2025 kJ/d and -13 +/- 24 kJ . d(-1) . kg(-1). The correlation between self-reported and measured time spent was significant for vigorous PA (r = 0.70) and marginally insignificant for sedentary time (r = 0.27, P = 0.06). The mean biases were relatively small for sedentary time and vigorous PA: 0.7 +/- 2.8 h/d and + 12 +/- 24 min/d, respectively. The intraclass correlation coefficient for repeatability of total PAEE (kJ/d) was 0.76 (P < 0.0001). CONCLUSION: The RPAQ is the first questionnaire with demonstrated validity for ranking individuals according to their time spent at vigorous-intensity activity and overall energy expenditure.
PubMed Accession Number :: 19889820.

Hardy, R.; Wills, A. K.; Wong, A.; Elks, C. E.; Wareham, N. J.; Loos, R. J.; Kuh, D.; Ong, K. K. (2010) Life course variations in the associations between FTO and MC4R gene variants and body size Hum Mol Genet, 19 ,545-552 [Journal Article] Online
Abstract: The timing of associations between common genetic variants for weight or BMI across the life course may provide insights into the aetiology of obesity. We genotyped variants in FTO (rs9939609) and near MC4R (rs17782313) in 1240 men and 1239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2-20 years) or adulthood (20-53 years). The association between FTO rs9939609 and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; 95% CI: 0.003 to 0.010, p<0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele, 0.08 to 0.19), and then weakened during adulthood (-0.003 SDS/A-allele/year, -0.005 to -0.001, p=0.001). MC4R rs17782313 showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/year/C-allele; 0.001 to 0.008, p=0.006), peaked at age 20 years (0.13 SDS/C-allele, 0.07 to 0.18), and weakened during adulthood (-0.002 SDS/C-allele/year, -0.004 to 0.000, p=0.05). In conclusion, genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age. Studies of the aetiology of obesity spanning different age groups may identify age-specific determinants of weight gain.
PubMed Accession Number :: 19880856.

Vimaleswaran, K. S.; Radha, V.; Jayapriya, M. G.; Ghosh, S.; Majumder, P. P.; Rao, M. R.; Mohan, V. (2010) Evidence for an association with type 2 diabetes mellitus at the PPARG locus in a South Indian population Metabolism, 59 (4),457-462 [Journal Article] Online
Abstract: Peroxisome proliferator-activated receptor-gamma2 (PPARG2) is a nuclear hormone receptor of ligand-dependent transcription factor involved in adipogenesis and a molecular target of the insulin sensitizers thiazolidinediones. We addressed the question of whether the 3 variants (-1279G/A, Pro12Ala, and His478His) in the PPARG2 gene are associated with type 2 diabetes mellitus and its related traits in a South Indian population. The study subjects (1000 type 2 diabetes mellitus and 1000 normal-glucose-tolerant subjects) were chosen randomly from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The variants were screened by single-stranded conformational variant, direct sequencing, and restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotypic frequencies. The -1279G/A, Pro12Ala, and His478His variants of the PPARG2 gene were not associated with type 2 diabetes mellitus. However, the 2-loci analyses showed that, in the presence of Pro/Pro genotype of the Pro12Ala variant, the -1279G/A promoter variant showed increased susceptibility to type 2 diabetes mellitus (odds ratio, 2.092; 95% confidence interval, 1.22-3.59; P = .008), whereas in the presence of 12Ala allele, the -1279G/A showed a protective effect against type 2 diabetes mellitus (odds ratio, 0.270; 95% confidence interval, 0.15-0.49; P < .0001). The 3-loci haplotype analysis showed that the A-Ala-T (-1279G/A-Pro12Ala-His478His) haplotype was associated with a reduced risk of type 2 diabetes mellitus (P < .0001). Although our data indicate that the PPARG2 gene variants, independently, have no association with type 2 diabetes mellitus, the 2-loci genotype analysis involving -1279G/A and Pro12Ala variants and the 3-loci haplotype analysis have shown a significant association with type 2 diabetes mellitus in this South Indian population.
PubMed Accession Number :: 19846173.

Li, S.; Zhao, J. H.; Luan, J.; Luben, R. N.; Rodwell, S. A.; Khaw, K. T.; Ong, K. K.; Wareham, N. J.; Loos, R. J. (2010) Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies Am J Clin Nutr, 91 (1),184-90 [Journal Article] Online
Abstract: BACKGROUND: Large-scale genome-wide association studies have identified 12 genetic loci that are robustly associated with body mass index (BMI). OBJECTIVES: We examined associations and compared effect sizes of these newly identified obesity susceptibility loci with various anthropometric traits and assessed their cumulative effects and predictive value for obesity risk. DESIGN: We genotyped 12 single nucleotide polymorphisms (SNPs) from each locus in 20,431 individuals (age: 39-79 y) from the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. General linear model and logistic regression were used to examine associations, and the area under the receiver operating characteristic curve (AUC) was used to assess the predictive value of these variants for obesity risk. RESULTS: Effect sizes of the risk alleles ranged between 0.058 and 0.329 for BMI (in kg/m(2)), between 0.094 and 0.866 kg for weight, and between 0.085 and 0.819 cm for waist circumference, with rs1121980 (FTO locus) showing the largest effect. Risk alleles of rs7132908 (FAIM2 locus) and rs17782313 (MC4R locus) were also associated with taller height. On average, each additional risk allele was associated with increases of 0.149 in BMI (P = 1.54E-22), 0.444 kg in body weight (P = 9.88E-22), and 0.357 cm in waist circumference (P = 1.10E-18) and 10.8% (P = 9.83E-16) and 5.5% (P = 3.38E-10) increased risks of obesity and overweight, respectively. All SNPs combined explained 0.9% of BMI variation, with an AUC of 0.574 (95% CI: 0.559, 0.590) for prediction of obesity. CONCLUSIONS: Common variants for BMI have small effects on obesity measures and show different association patterns with anthropometric traits, with the largest effect shown for the FTO locus. These variants have cumulative effects, yet their predictive value for obesity risk is limited.
PubMed Accession Number :: 19812171.

Petry, C. J.; Evans, M. L.; Wingate, D. L.; Ong, K. K.; Reik, W.; Constancia, M.; Dunger, D. B. (2010) Raised Late Pregnancy Glucose Concentrations in Mice carrying Pups with Targeted Disruption of H19{Delta}13 Diabetes, 59 (1), [Journal Article] Online
Abstract: Objective: We have hypothesised that variation in imprinted growth promoting fetal genes may affect maternal glucose concentrations in pregnancy. In order to test this hypothesis we evaluated the effects of fetal disruption of murine H19(Delta13) on maternal glucose concentrations in pregnancy. Research Design and Methods: Experimental mice were pregnant females, who had inherited the disrupted H19(Delta13) from their fathers so were phenotypically wild type due to imprinting, where approximately half of their litter were null for H19(Delta13) through maternal inheritance of the disrupted gene. In control mice approximately half the litter paternally-inherited the disrupted H19(Delta13), so the pups were either genetically wild type or phenotypically wild type due to imprinting. Blood glucose concentrations were assessed by intra-peritoneal glucose tolerance tests on days 1, 16 and 18 of pregnancy. Results: There were no differences in the glucose concentrations of control and experimental pregnant mice at day 1 (e1). However at e16 mothers carrying H19(Delta13)-null pups had a significantly higher area under the glucose tolerance test curves than controls (1845 +/- 378 v. 1386 +/- 107 mmol.min/L (p=0.01)) in association with increasing pregnancy-related insulin resistance. Although this difference lessened towards term, overall mothers of maternally-inherited H19(Delta13) mutants had significantly higher glucose concentrations during the last trimester (1602 +/- 321 (n=17) v. 1359 +/- 147 (n=18) mmol.min/L (p=0.009)). Conclusions: This study provides evidence that maternal glucose concentrations in pregnant mice can be affected by targeted disruption of fetal H19(Delta13). This implies that variable fetal IGF2 expression could affect risk for gestational diabetes.
PubMed Accession Number :: 19794064.

Wang, J.; Williams, M.; Rush, E.; Crook, N.; Forouhi, N. G.; Simmons, D. (2010) Mapping the availability and accessibility of healthy food in rural and urban New Zealand - Te Wai o Rona: Diabetes Prevention Strategy Public Health Nutr, 13 ,1049-1055 [Journal Article] Online
Abstract: OBJECTIVE: Uptake of advice for lifestyle change for obesity and diabetes prevention requires access to affordable 'healthy' foods (high in fibre/low in sugar and fat). The present study aimed to examine the availability and accessibility of 'healthy' foods in rural and urban New Zealand. DESIGN: We identified and visited ('mapped') 1230 food outlets (473 urban, 757 rural) across the Waikato/Lakes areas (162 census areas within twelve regions) in New Zealand, where the Te Wai O Rona: Diabetes Prevention Strategy was underway. At each site, we assessed the availability of 'healthy' foods (e.g. wholemeal bread) and compared their cost with those of comparable 'regular' foods (e.g. white bread). RESULTS: Healthy foods were generally more available in urban than rural areas. In both urban and rural areas, 'healthy' foods were more expensive than 'regular' foods after adjusting for the population and income level of each area. For instance, there was an increasing price difference across bread, meat, poultry, with the highest difference for sugar substitutes. The weekly family cost of a 'healthy' food basket (without sugar) was 29.1 % more expensive than the 'regular' basket ($NZ 176.72 v. $NZ 136.84). The difference between the 'healthy' and 'regular' basket was greater in urban ($NZ 49.18) than rural areas ($NZ 36.27) in adjusted analysis. CONCLUSIONS: 'Healthy' foods were more expensive than 'regular' choices in both urban and rural areas. Although urban areas had higher availability of 'healthy' foods, the cost of changing to a healthy diet in urban areas was also greater. Improvement in the food environment is needed to support people in adopting healthy food choices.
PubMed Accession Number :: 19781125.

De Lucia Rolfe, E.; Sleigh, A.; Finucane, F. M.; Brage, S.; Stolk, R. P.; Cooper, C.; Sharp, S. J.; Wareham, N. J.; Ong, K. K. (2010) Ultrasound Measurements of Visceral and Subcutaneous Abdominal Thickness to Predict Abdominal Adiposity Among Older Men and Women Obesity (Silver Spring), 18 ,625-631 [Journal Article] Online
Abstract: Accurate measures of visceral and abdominal subcutaneous fat are essential for investigating the pathophysiology of obesity. Classical anthropometric measures such as waist and hip circumference cannot distinguish between these two fat depots. Direct imaging methods such as computed tomography and magnetic resonance imaging (MRI) are restricted in large-scale studies due to practical and ethical issues. We aimed to establish whether ultrasound is a valid alternative method to MRI for the quantitative assessment of abdominal fat depots in older individuals. The study population comprised 74 white individuals (41 men and 33 women, aged 67-76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial. Anthropometry included height, weight, waist and hip circumferences. Abdominal fat was measured by ultrasound in two compartments: visceral fat defined as the depth from the peritoneum to the lumbar spine; and subcutaneous fat defined as the depth from the skin to the abdominal muscles and compared to reference measures by MRI (10-mm single-slice image). Ultrasound measures were positively correlated with MRI measures of visceral and subcutaneous fat (visceral: r = 0.82 and r = 0.80 in men and women, respectively; subcutaneous: r = 0.63 and 0.68 in men and women, respectively). In multiple regression models, the addition of ultrasound measures significantly improved the prediction of visceral fat and subcutaneous fat in both men and women over and above the contribution of standard anthropometric variables. In conclusion, ultrasound is a valid method to estimate visceral fat in epidemiological studies of older men and women when MRI and computed tomography are not feasible.
PubMed Accession Number :: 19779473.

Arsenault, B. J.; Rana, J. S.; Lemieux, I.; Despres, J. P.; Wareham, N. J.; Kastelein, J. J.; Boekholdt, S. M.; Khaw, K. T. (2010) Physical activity, the Framingham risk score and risk of coronary heart disease in men and women of the EPIC-Norfolk study Atherosclerosis, 209 ,261-265 [Journal Article] Online
Abstract: OBJECTIVE: Test the hypothesis that considering leisure-time and work-related physical activity habits in addition to the Framingham risk score (FRS) would result into better classification of coronary heart disease (CHD) risk than FRS alone. METHODS: Prospective, population-based study of 9564 men and 12165 women aged 45-79 years followed for an average of 11.4 years. A modified FRS which takes into account physical activity (evaluated using a validated lifestyle questionnaire taking into account leisure-time and work-related physical activity) was computed. RESULTS: During follow-up, 2191 CHD events occurred. Among 3369 men who were classified as intermediate risk (event rate of 12.4%) according to the FRS, 413 were reclassified into the low-risk category and 279 were reclassified into the high-risk category after modification of the FRS. After reclassification of these men, CHD event rate was of 5.3% and 18.6%, respectively for men classified at low and high CHD risk. Among 4766 women initially classified as intermediate risk (event rate of 8.4%), 1282 were reclassified into the low-risk category whereas 1071 women were reclassified into the high-risk category. After reclassification of these women, CHD event rate was of 6.8% and 12.2%, respectively for women classified at low and high CHD risk. CONCLUSIONS: Results of the present study suggest that asking simple questions about leisure-time and work-related physical activity which can be rapidly obtained by any physician at no cost could be helpful in the estimation of patients' CHD risk.
PubMed Accession Number :: 19772963.

Brandys, M. K.; van Elburg, A. A.; Loos, R. J.; Bauer, F.; Hendriks, J.; van der Schouw, Y. T.; Adan, R. A. (2010) Are recently identified genetic variants regulating BMI in the general population associated with anorexia nervosa? Am J Med Genet B Neuropsychiatr Genet, 153B (2),695-699 [Journal Article] Online
Abstract: The influence of body mass index (BMI) on susceptibility to anorexia nervosa (AN) is not clear. Recently published genome-wide association (GWA) studies of the general population identified several variants influencing BMI. We genotyped these variants in an AN sample to test for association and to investigate a combined effect of BMI-increasing alleles (as determined in the original GWA studies) on the risk of developing the disease. Individual single nucleotide polymorphisms (SNPs) were tested for association with AN in a sample of 267 AN patients and 1,636 population controls. A logistic regression for the combined effect of BMI-increasing alleles included 225 cases and 1,351 controls. We found no significant association between individual SNPs and AN. The analysis of a combined effect of BMI-increasing alleles showed absence of association with the investigated condition. The percentages of BMI-increasing alleles were equal between cases and controls. This study found no evidence that genetic variants regulating BMI in the general population are significantly associated with susceptibility to AN. (c) 2009 Wiley-Liss, Inc.
PubMed Accession Number :: 19746409.

Myint, P. K.; Smith, R. D.; Luben, R. N.; Surtees, P. G.; Wainwright, N. W.; Wareham, N. J.; Bingham, S. A.; Khaw, K. T. (2010) The Short-Form Six-Dimension utility index predicted mortality in the European Prospective Investigation into Cancer-Norfolk prospective population-based study J Clin Epidemiol, 63 (2),192-198 [Journal Article] Online
Abstract: OBJECTIVE: To examine the relationship between the Short-Form Six-Dimension (SF-6D) and mortality. STUDY DESIGN AND SETTING: Participants were 17,736 men and women aged 40-79 years at baseline who lived in Norfolk, UK, and had no known cardiovascular disease or cancer, and completed the anglicized Short-Form 36 (SF-36)-item during 1996-2000 in the European Prospective Investigation into Cancer-Norfolk prospective population study. The SF-36 data were converted to SF-6D. The relationship between SF-6D and all-cause and cause-specific mortality were examined. RESULTS: One thousand and seventy deaths occurred during a total of 115,255 person years of follow-up (mean 6.5 years). Lower SF-6D was associated with increased risk of all-cause mortality in men and women. A decrease of 1 standard deviation (0.12 point) in SF-6D was associated with a 35% increase in all-cause mortality (hazards ratio=1.35; 95% CI: 1.26, 1.45) after controlling for age, gender, body mass index, systolic blood pressure, cholesterol, diabetes, smoking, and social class. Similar results were observed for cardiovascular, cancer, and other causes of deaths. CONCLUSION: Poor health utility measured by the SF-6D predicted increased risk of all-cause and cause-specific mortality in men and women. The present study provides the first evidence of the sensitivity of the SF-6D in predicting mortality in an apparently healthy population.
PubMed Accession Number :: 19682855.

Holleboom, A. G.; Kuivenhoven, J. A.; Vergeer, M.; Hovingh, G. K.; van Miert, J. N.; Wareham, N. J.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2010) Plasma levels of lecithin:cholesterol acyltransferase and risk of future coronary artery disease in apparently healthy men and women - a prospective case-control analysis nested in the EPIC-Norfolk population study J Lipid Res, 51 (2),416-21 [Journal Article] Online
Abstract: Lecithin:cholesterol acyltransferase (LCAT) plays a key role in the maturation of high-density lipoprotein (HDL) as evidenced by low HDL-cholesterol levels in carriers of deleterious mutations in LCAT. These carriers present with increased carotid intima media thickness, but in the general population, the role of LCAT in atherosclerosis is unclear. We set out to study this in a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition Norfolk population study. LCAT plasma levels, which strongly correlate with LCAT activity levels, were measured in baseline non-fasting plasma samples of 933 apparently healthy men and women who developed coronary artery disease (CAD) and 1,852 matched controls who remained free of CAD during 6-year follow-up. LCAT levels did not differ between cases and controls, but were significantly higher in women than in men. Stratification into LCAT quartiles revealed a positive association with plasma LDL-cholesterol and triglyceride levels, in the unexpected absence of an association with HDL-cholesterol. In mixed-gender analysis, the odds ratio for future CAD in the highest LCAT quartile versus the lowest was 1.00 (confidence interval: 0.76-1.29, P for linearity = 0.902), although opposite trends were observed in men and women. In fact, high LCAT levels were associated with an increased CAD risk in women (unadjusted odds ratio 1.45, confidence interval: 0.94-2.22, P for linearity: 0.036). In contrast to our studies in carriers of LCAT mutations, the current data show that low LCAT plasma levels are not associated with increased atherosclerosis in the general population.
PubMed Accession Number :: 19671930.

Williams, R. M.; Deeb, A.; Ong, K. K.; Bich, W.; Murgatroyd, P. R.; Hughes, I. A.; Acerini, C. L. (2010) Insulin sensitivity and body composition in children with classical and non-classical congenital adrenal hyperplasia Clin Endocrinol (Oxf), 72 ,155-160 [Journal Article] Online
Abstract: Summary Background: Reduced insulin sensitivity and increased fat mass have been reported in children and adults with congenital adrenal hyperplasia (CAH). To understand the potential mechanisms underlying these differences, we assessed insulin sensitivity and body composition in children with classical or non-classical (late-presenting) CAH compared to normal controls. Subjects and methods: 37 children with CAH (26 classical; 11 non-classical) median (range) age 9.4y (0.5 to 15.8) were compared to 41 healthy control children age 11.0y (3.2 to 17.1). All children had an overnight fasting blood sample and body composition assessed by DEXA. Pubertal children (14 CAH and 19 controls) also had an oral glucose tolerance test. Classical and non-classical CAH groups were each compared to controls, adjusting for age, sex and pubertal status. Results: Classical CAH children had more fat mass than controls (p=0.03), while non-classical CAH children had more lean mass (p=0.006) and higher systolic blood pressure (p=0.003) than control children. Among pubertal children, non-classical CAH children had higher mean insulin (0-120 min; p=0.04), stimulated insulin (0-30 min; p=0.02); 120 min insulin (p=0.004), and 120 min glucose levels (p=0.03) than controls, but no difference in disposition index. Discussion: Greater body fat in classical (early-presenting) CAH children could reflect the effects of lifetime glucocorticoid therapy. In contrast, the greater lean mass and parameters of insulin resistance in non-classical (late-presenting) CAH children likely indicate the adverse metabolic effects of prolonged postnatal androgen excess.
PubMed Accession Number :: 19508608.

Matthijs Boekholdt, S.; Titan, S. M.; Wiersinga, W. M.; Chatterjee, K.; Basart, D. C.; Luben, R.; Wareham, N. J.; Khaw, K. T. (2010) Initial thyroid status and cardiovascular risk factors: The EPIC-Norfolk prospective population study Clin Endocrinol (Oxf), 72 ,404-410 [Journal Article] Online
Abstract: Summary Context: Thyroid status affects several aspects of cardiovascular risk profile, including lipid levels and blood pressure. Whether thyroid status affects the risk of coronary heart disease (CHD) and all-cause mortality remains controversial. Design: The EPIC-Norfolk prospective population study. Mean follow-up was 10.6 years. Patients: Study participants were 11,554 men and women aged 45-79 years, who were living in Norfolk, United Kingdom. Measurements: Baseline cardiovascular risk factors were recorded and concentrations of thyroid stimulating hormone (TSH) and free thyroxine (FT4) were measured in baseline samples. Regression analyses were performed to assess the association between thyroid hormone levels and cardiovascular risk factors. A proportional hazards model was used to estimate the risk of CHD and all-cause mortality by baseline thyroid status. No information was available about thyroid treatment during follow-up. Results: Thyroid abnormalities were common, particularly among women. Thyroid abnormalities were associated with an altered cardiovascular risk profile. Even within the normal range, thyroid hormone levels were associated with lipid levels and blood pressure among both men and women, TSH more strongly than FT4. We did not observe a significant association between subclinical thyroid abnormalities and risk of CHD or all-cause mortality. Conclusions: Despite the association between thyroid hormone levels and cardiovascular risk factors, thyroid status was not statistically significantly associated with the risk of future CHD or all-cause mortality in this large cohort.
PubMed Accession Number :: 19486022.

Panter, J. R.; Jones, A. P.; van Sluijs, E. M.; Griffin, S. J. (2010) Attitudes, social support and environmental perceptions as predictors of active commuting behaviour in school children J Epidemiol Community Health, 64 ,41-48 [Journal Article] Online
Abstract: BACKGROUND: Environmental perceptions appear to play a role in determining behaviour in children, although their influence on active commuting remains unclear. This study examines whether attitudes, social support and environmental perceptions are associated with active commuting behaviour in school children and whether these associations are moderated by the distance to school. METHODS: Data were collected as part of the SPEEDY study (Sport, Physical activity and Eating behaviour: Environmental Determinants in Young people), a cross-sectional study of 2064 children from schools in Norfolk, England. Data regarding the usual mode of travel to school, attitudes towards and social support for active commuting, perceptions of the neighbourhood and route to school were assessed using questionnaires completed by 2012 children and their parents. Distance to school was estimated using a Geographic Information System and this was used to compare associations between personal and environmental factors and active travel, across different distance categories. RESULTS: 40% of children reported usually walking to school, with 9% cycling and the remainder using motorised travel. Parental attitudes and safety concerns, the presence of social support from parents and friends, and parent reported neighbourhood walkability were all found to be predictors of active commuting, with children receiving peer and family support and living in supportive environments being more likely to walk or cycle. There was some evidence of a moderating effect of distance whereby attitudes were more important for short distances and safety concerns long. CONCLUSION: Both attitudinal and environmental perceptions are associated with children's active commuting behaviours. Given the difficulty in modifying attitudes directly, the effect on them of interventions to provide more supportive environments should be evaluated.
PubMed Accession Number :: 19465403.

Wareham, N. J. (2009) Epidemiology of type 2 diabetes Endocrinol Nutr, 56S4 ,60-62 [Journal Article] Online
PubMed Accession Number :: 20542232.

Freitas, R. N.; Khaw, K. T.; Wu, K.; Bowman, R.; Jeffery, H.; Luben, R.; Wareham, N. J.; Bingham, S. A. (2009) A HMGCR polymorphism is associated with relations between blood pressure and urinary sodium and potassium ratio in the Epic-Norfolk Study J Am Soc Hypertens, 3 (4),238-44 [Journal Article] Online
Abstract: A polymorphism in the HMGCR gene (rs17238540) was related to a lower response to pravastatin treatment and we aimed to investigate whether an interaction is present for this polymorphism on blood pressure (BP) and salt intake. Cross-sectional urinary sodium and potassium concentration and the polymorphism were assessed in a large population study. Participants with the mutated allele (G) had significantly higher BP than homozygous TT. There were highly significant positive trends between BP and urinary sodium:potassium ratio across quartiles in men, with less effect in women, especially women carrying the mutated allele, G. Multivariate regression showed a significant positive association between BP and the urinary sodium: potassium ratio that differed in men and women according to genotype. In men carrying the G allele, the regression slopes for diastolic BP and systolic BP were higher than in men TT and the opposite was observed in women. Our results suggest that the SNP rs17238540 in the HMGCR is associated with the BP response to urinary sodium: potassium ratio, the magnitude of the association differing according to possession of the G allele.
PubMed Accession Number :: 20409966.

Arsenault, B. J.; Rana, J. S.; Stroes, E. S.; Despres, J. P.; Shah, P. K.; Kastelein, J. J.; Wareham, N. J.; Boekholdt, S. M.; Khaw, K. T. (2009) Beyond Low-Density Lipoprotein Cholesterol Respective Contributions of Non-High-Density Lipoprotein Cholesterol Levels, Triglycerides, and the Total Cholesterol/High-Density Lipoprotein Cholesterol Ratio to Coronary Heart Disease Risk in Apparently Healthy Men and Women J Am Coll Cardiol, 55 (1),35-41 [Journal Article] Online
Abstract: OBJECTIVES: This study was designed to test the hypothesis that at any low-density lipoprotein cholesterol (LDL-C) level, other lipid parameters such as non-high-density lipoprotein cholesterol (HDL-C) levels, triglyceride (TG) levels, and the total cholesterol (TC)/HDL-C are still associated with an increased coronary heart disease (CHD) risk. BACKGROUND: Although LDL-C is considered to be the primary target of lipid-lowering therapy, other parameters of the lipoprotein-lipid profile may more closely associated with CHD risk. METHODS: In the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk prospective population study, 21,448 participants without diabetes or CHD between age 45 and 79 years were followed for 11.0 years. A total of 2,086 participants developed CHD during follow-up. RESULTS: Among individuals with low LDL-C levels (<100 mg/dl), after adjustment for age, sex, smoking, systolic blood pressure, waist circumference, physical activity, and hormone replacement therapy (in women), those with non-HDL-C >130 mg/dl had a hazard ratio (HR) for future CHD of 1.84 (95% confidence interval [CI]: 1.12 to 3.04) when compared with those with non-HDL-C levels <130 mg/dl. In a similar model, individuals with TG levels >150 mg/dl had an HR of 1.63 (95% CI: 1.02 to 2.59) when compared with those with TG levels <150 mg/dl, and individuals with a TC/HDL-C ratio >5 had an HR of 2.19 (95% CI: 1.22 to 3.93) when compared with those with a TC/HDL-C ratio <5. CONCLUSIONS: In this prospective study, independently of their plasma LDL-C levels, participants with high non-HDL-C levels, high TG levels, or with an elevated TC/HDL-C ratio were at increased CHD risk. CHD risk assessment algorithms as well as lipid targets of lipid-lowering trials may also need to consider other easily available parameters such as non-HDL-C.
PubMed Accession Number :: 20117361.

Neovius, M.; Rossner, S. M.; Vagstrand, K.; von Hausswolff-Juhlin, Y. L.; Hoffstedt, J.; Ekelund, U. (2009) Adiposity Measures as Indicators of Metabolic Risk Factors in Adolescents Obes Facts, 2 (5),294-301 [Journal Article] Online
Abstract: Aim: To examine the relation between adiposity assessment methods (percentage body fat (%BF), BMI, and waist circumference (WC)) and individual metabolic risk factors (f-insulin, HDL cholesterol, triglycerides) and a combined measure of metabolic risk. Methods: Crosssectional study of 300 males (BMI 20.8 +/- 3.0 kg/m(2)) and females (BMI 21.3 +/- 2.9 kg/m(2)) 17 years of age. F-insulin and components of the metabolic syndrome defined by the International Diabetes Federation (IDF) were used as metabolic risk indicators, with samples stratified into BMI, %BF, and WC groups, respectively. Diagnostic accuracy was expressed as the area under the ROC curve (AUC). Results: In males, diagnostic accuracy for HDL and f-insulin was poor to fair for BMI (AUC 0.70, p = 0.001; 0.60, p = 0.22), WC (0.68, p = 0.003; 0.63, p = 0.11), and %BF (0.65, p = 0.009; 0.66, p = 0.04). The diagnostic accuracy for triglycerides was greater for all three measures (BMI 0.92, WC 0.95, %BF 0.87; all p < 0.001). For females, neither test performed better than chance for f-insulin and HDL, and only %BF performed better than chance for triglycerides (0.65, p = 0.08). All three measures exhibited higher accuracy for presence of >/=2 metabolic risk factors (AUCs 0.76-0.91, p < 0.001) in both sexes. Conclusion: %BF was not superior to BMI and WC for detecting metabolic risk in the general adolescent population.
PubMed Accession Number :: 20057196.

Thankamony, A.; Ong, K. K.; Dunger, D. B.; Acerini, C. L.; Hughes, I. A. (2009) Anogenital distance from birth to 2 years: a population study Environ Health Perspect, 117 (11),1786-90 [Journal Article] Online
Abstract: BACKGROUND: Anogenital distance (AGD) is sexually dimorphic in rodents and humans, being 2- to 2.5-fold greater in males. It is a reliable marker of androgen and antiandrogen effects in rodent reproductive toxicologic studies. Data on AGD in humans are sparse, with no longitudinal data collected during infancy. OBJECTIVE: This study was designed to determine AGD from birth to 2 years in males and females and relate this to other anthropometric measures. MATERIALS AND METHODS: Infants were recruited from the Cambridge Baby Growth Study. AGD was measured from the center of the anus to the base of the scrotum in males and to the posterior fourchette in females. Measurements were performed at birth and at 3, 12, 18, and 24 months of age. RESULTS: Data included 2,168 longitudinal AGD measurements from 463 male and 426 female full-term infants (median = 2 measurements per infant). Mean AGD (+/- SD) at birth was 19.8 +/- 6.1 mm in males and 9.1 +/- 2.8 mm in females (p < 0.0001). AGD increased up to 12 months in both sexes and in a sex-dimorphic pattern. AGD was positively correlated with penile length at birth (r = 0.18, p = 0.003) and the increase in AGD from birth to 3 months was correlated with penile growth (r = 0.20, p = 0.001). CONCLUSION: We report novel, longitudinal data for AGD during infancy in a large U.K. birth cohort. AGD was sex dimorphic at all ages studied. The availability of normative data provides a means of utilizing this biological marker of androgen action in population studies of the effects of environmental chemicals on genital development.
PubMed Accession Number :: 20049133.

Reuwer, A. Q.; Twickler, M. T.; Hutten, B. A.; Molema, F. W.; Wareham, N. J.; Dallinga-Thie, G. M.; Bogorad, R. L.; Goffin, V.; Smink-Bol, M.; Kastelein, J. J.; Boekholdt, S. M.; Khaw, K. T. (2009) Prolactin levels and the risk of future coronary artery disease in apparently healthy men and women Circ Cardiovasc Genet, 2 (4),389-95 [Journal Article] Online
Abstract: BACKGROUND: Prolactin is increasingly recognized to play a stimulatory role in the inflammatory response. Because inflammation is considered of crucial importance in the development of atherosclerosis, we aimed to evaluate whether prolactin levels are associated with the occurrence of coronary artery disease (CAD). METHODS AND RESULTS: We performed a nested case-control study in the prospective EPIC-Norfolk cohort. Cases were apparently healthy men and women, aged 45 to 79 years, who developed fatal or nonfatal CAD (n=882). Controls remained free of CAD (n=1490). Overall, systemic prolactin levels did not differ between cases and controls, and people in the highest prolactin tertile did not have a significantly increased risk of developing future CAD (in men, odds ratio, 1.21; 95% CI, 0.92 to 1.61; in women, odds ratio, 1.12; 95% CI, 0.76 to 1.64). However, in a separate immunohistochemical study, the presence of prolactin receptors could be demonstrated in postmortem human coronary artery plaques (preliminary data). CONCLUSIONS: Elevated systemic prolactin levels do not predict CAD in the general population. However, prolactin receptors were found in human coronary artery plaques. This observation may indicate a role of prolactin within atherosclerotic plaques. More studies are needed to define the possible role of prolactin in atherosclerotic plaque development.
PubMed Accession Number :: 20031611.

Luan, J.; Kerner, B.; Zhao, J. H.; Loos, R. J.; Sharp, S. J.; Muthen, B. O.; Wareham, N. J. (2009) A multilevel linear mixed model of the association between candidate genes and weight and body mass index using the Framingham longitudinal family data BMC Proc, 3 Suppl 7 ,S115 [Journal Article] Online
Abstract: ABSTRACT : Obesity has become an epidemic in many countries and is one of the major risk conditions for disease including type 2 diabetes, coronary heart disease, stroke, dyslipidemia, and hypertension. Recent genome-wide association studies have identified two genes (FTO and near MC4R) that were unequivocally associated with body mass index (BMI) and obesity. For the Genetic Analysis Workshop 16, data from the Framingham Heart Study were made available, including longitudinal anthropometric and metabolic traits for 7130 Caucasian individuals over three generations, each with follow-up data at up to four time points. We explored the associations between four single-nucleotide polymorphisms (SNPs) on FTO (rs1121980, rs9939609) or near MC4R (rs17782313, rs17700633) with weight and BMI under an additive model. We applied multilevel linear mixed model for continuous outcomes, using the Affymetrix 500k genome-wide genotype data for the four SNPs. The results of the multilevel modeling in the entire sample indicated that the minor alleles of the four SNPs were associated with higher weight and higher BMI. The most significant associations were between rs9939609 and weight (p = 4.7 x 10-6) and BMI (p = 8.9 x 10-8). The results also showed that, for SNPs at FTO, the homozygotes for the minor allele had the most pronounced increase in weight and BMI, while the common allele homozygotes gained less weight and BMI during the follow-up period. Linkage disequilibrium (LD) between the two FTO SNPs was strong (D' = 0.997, r2 = 0.875) but their haplotype was not significantly associated with either weight or BMI. The two SNPs near MC4R were in weak LD (D' = 0.487, r2 = 0.166).
PubMed Accession Number :: 20017980.

Kong, A.; Steinthorsdottir, V.; Masson, G.; Thorleifsson, G.; Sulem, P.; Besenbacher, S.; Jonasdottir, A.; Sigurdsson, A.; Kristinsson, K. T.; Jonasdottir, A.; Frigge, M. L.; Gylfason, A.; Olason, P. I.; Gudjonsson, S. A.; Sverrisson, S.; Stacey, S. N.; Sigurgeirsson, B.; Benediktsdottir, K. R.; Sigurdsson, H.; Jonsson, T.; Benediktsson, R.; Olafsson, J. H.; Johannsson, O. T.; Hreidarsson, A. B.; Sigurdsson, G.; Voight, B. F.; Scott, L. J.; Steinthorsdottir, V.; Dina, C.; Zeggini, E.; Huth, C.; Aulchenko, Y. S.; Welch, R. P.; Thorleifsson, G.; McCulloch, L. J.; Ferreira, T.; Grallert, H.; Amin, N.; Wu, G.; Willer, C. J.; Raychaudhuri, S.; Purcell, S.; McCarroll, S. A.; Langenberg, C.; Hoffmann, O. M.; Dupuis, J.; Qi, L.; Segre, A. V.; van Hoek, M.; Navarro, P.; Ardlie, K.; Balkau, B.; Benediktsson, R.; Bennett, A. J.; Blagieva, R.; Boerwinkle, E.; Bonnycastle, L. L.; Bostrom, K. B.; Bravenboer, B.; Bumpstead, S.; Burtt, N. P.; Charpentier, G.; Chines, P. S.; Cornelis, M.; Couper, D. J.; Crawford, G.; Doney, A. S.; Elliott, K. S.; Elliott, A. L.; Erdos, M. R.; Fox, C. S.; Franklin, C. S.; Ganser, M.; Gieger, C.; Grarup, N.; Green, T.; Griffin, S.; Groves, C. J.; Guiducci, C.; Hadjadj, S.; Hassanali, N.; Herder, C.; Isomaa, B.; Jackson, A. U.; Johnson, P. R.; Jorgensen, T.; Kao, W. H.; Klopp, N.; Kong, A.; Kraft, P.; Kuusisto, J.; Lauritzen, T.; Li, M.; Lieverse, A.; Lindgren, C. M.; Lyssenko, V.; Marre, M.; Meitinger, T.; Midthjell, K.; Morken, M. A.; Narisu, N.; Nilsson, P.; Owen, K. R.; Payne, F.; Perry, J. R.; Petersen, A. K.; Platou, C.; Proenca, C.; Prokopenko, I.; Rathmann, W.; William Rayner, N.; Robertson, N. R.; Rocheleau, G.; Roden, M.; Sampson, M. J.; Saxena, R.; Shields, B. M.; Shrader, P.; Sigurdsson, G.; Smith, N.; Sparso, T.; Strassburger, K.; Stringham, H. M.; Sun, Q.; Swift, A. J.; Thorand, B.; Tichet, J.; Tuomi, T.; van Dam, R.; van Herpt, T.; Walters, G. B.; Weedon, M. N.; Witteman, J.; Bergman, R. N.; Cauchi, S.; Collins, F. S.; Gloyn, A. L.; Gyllensten, U.; Hansen, T.; Hide, W. A.; Hitman, G. A.; Hofman, A.; Hunter, D.; Hveem, K.; Laakso, M.; Mohlke, K. L.; Morris, A. D.; Palmer, C. N.; Pramstaller, P. P.; Rudan, I.; Sijbrands, E.; Stein, L. D.; Tuomilehto, J.; Uitterlinden, A.; Walker, M.; Wareham, N. J.; Watanabe, R. M.; Abecasis, G. R.; Barroso, I.; Boehm, B. O.; Campbell, H.; Daly, M. J.; Florez, J. C.; Frayling, T. M.; Groop, L.; Hattersley, A. T.; Hu, F. B.; Meigs, J. B.; Morris, A. P.; Pankow, J. S.; Pedersen, O.; Sladek, R.; Thorsteinsdottir, U.; Wichmann, H. E.; Wilson, J. F.; Illig, T.; Froguel, P.; van Duijn, C. M.; Stefansson, K.; Altshuler, D.; Boehnke, M.; McCarthy, M. I.; Ferguson-Smith, A. C.; Gudbjartsson, D. F.; Thorsteinsdottir, U.; Stefansson, K. (2009) Parental origin of sequence variants associated with complex diseases Nature, 462 (7275),868-74 [Journal Article] Online
Abstract: Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
PubMed Accession Number :: 20016592.

Richards, J. B.; Waterworth, D.; O'Rahilly, S.; Hivert, M. F.; Loos, R. J.; Perry, J. R.; Tanaka, T.; Timpson, N. J.; Semple, R. K.; Soranzo, N.; Song, K.; Rocha, N.; Grundberg, E.; Dupuis, J.; Florez, J. C.; Langenberg, C.; Prokopenko, I.; Saxena, R.; Sladek, R.; Aulchenko, Y.; Evans, D.; Waeber, G.; Erdmann, J.; Burnett, M. S.; Sattar, N.; Devaney, J.; Willenborg, C.; Hingorani, A.; Witteman, J. C.; Vollenweider, P.; Glaser, B.; Hengstenberg, C.; Ferrucci, L.; Melzer, D.; Stark, K.; Deanfield, J.; Winogradow, J.; Grassl, M.; Hall, A. S.; Egan, J. M.; Thompson, J. R.; Ricketts, S. L.; Konig, I. R.; Reinhard, W.; Grundy, S.; Wichmann, H. E.; Barter, P.; Mahley, R.; Kesaniemi, Y. A.; Rader, D. J.; Reilly, M. P.; Epstein, S. E.; Stewart, A. F.; Van Duijn, C. M.; Schunkert, H.; Burling, K.; Deloukas, P.; Pastinen, T.; Samani, N. J.; McPherson, R.; Davey Smith, G.; Frayling, T. M.; Wareham, N. J.; Meigs, J. B.; Mooser, V.; Spector, T. D. (2009) A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels PLoS Genet, 5 (12),e1000768 [Journal Article] Online
Abstract: The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P</=5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P</=0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
PubMed Accession Number :: 20011104.

Goossens, V. J.; Dejager, S. A.; Grauls, G. E.; Gielen, M.; Vlietinck, R. F.; Derom, C. A.; Loos, R. J.; Rensen, S. S.; Buurman, W. A.; Greve, J. W.; van Baak, M. A.; Wolffs, P. F.; Bruggeman, C. A.; Hoebe, C. J. (2009) Lack of Evidence for the Role of Human Adenovirus-36 in Obesity in a European Cohort Obesity (Silver Spring), , [Journal Article] Online
Abstract: Adenovirus infection has been shown to increase adiposity in chickens, mice, and nonhuman primates. Adenovirus type 36 (Ad-36) DNA was detected in adipose tissues in these animal trials. In the United States, Ad-36 significantly correlates with obesity as illustrated by an Ad-36 seroprevalence of 30% in obese individuals and 11% in nonobese individuals. We investigated the possibility of a similar correlation of Ad-36 in Dutch and Belgian persons. In total, 509 serum samples were analyzed for Ad-36 antibodies using a serum neutralization assay. In addition, PCR was used to detect adenoviral DNA in visceral adipose tissue of 31 severely obese surgical patients. Our results indicated an overall Ad-36 seroprevalence of 5.5% increasing with age. BMI of Ad-36 seropositive humans was not significantly different from seronegative humans. No adenoviral DNA could be found using PCR on visceral adipose tissue. In conclusion, this first Ad-36 study in the Netherlands and in Belgium indicates that Ad-36 does not play a role as a direct cause of BMI increase and obesity in humans in Western Europe.
PubMed Accession Number :: 20010727.

Loos, R. J. (2009) Recent progress in the genetics of common obesity Br J Clin Pharmacol, 68 (6),811-29 [Journal Article] Online
Abstract: The genetic contribution to interindividual variation in common obesity has been estimated at 40-70%. Yet, despite a relatively high heritability, the search for obesity susceptibility genes has been an arduous task. This paper reviews recent progress made in the obesity genetics field with an emphasis on established obesity susceptibility loci identified through candidate gene as well as genome-wide studies. For the last 15 years, candidate gene and genome-wide linkage studies have been the two main genetic epidemiological approaches to identify genetic loci for common traits, yet progress has been slow and success limited. Only recently have candidate gene studies started to succeed; by means of large-scale studies and meta-analyses at least five variants in four candidate genes have been found to be robustly associated with obesity-related traits. Genome-wide linkage studies, however, have so far not been able to pinpoint genetic loci for common obesity. The genome-wide association approach, which has become available in recent years, has dramatically changed the pace of gene discoveries for common disease, including obesity. Three waves of large-scale high-density genome-wide association studies have already discovered at least 15 previously unanticipated genetic loci incontrovertibly associated with body mass index and extreme obesity risk. Although the combined contribution of these loci to the variation in obesity risk at the population level is small and their predictive value is typically low, these recently discovered loci are set to improve fundamentally our insights into the pathophysiology of obesity.
PubMed Accession Number :: 20002076.

Foster, C.; Hillsdon, M.; Jones, A.; Grundy, C.; Wilkinson, P.; White, M.; Sheehan, B.; Wareham, N.; Thorogood, M. (2009) Objective measures of the environment and physical activity--results of the environment and physical activity study in English adults J Phys Act Health, 6 Suppl 1 ,S70-80 [Journal Article] Online
Abstract: BACKGROUND: Physical activity has been positively associated with a range of objectively measured environmental variables. We explored the relationship of walking and other categories of physical activity with objectively measured activity specific environmental variables in a U.K. population. METHODS: We used a geographical information system (GIS) and gender specific multivariate models to relate 13,927 participants' reported levels of physical activity with a range of measures of the environment. RESULTS: Access to green space and area levels of crime were not associated with walking for recreation. Distance to facilities had either no or only a small effect on the uptake of different activities. Odds ratios of cycling for leisure dropped as local traffic density increased for both genders. Compared with the lowest quartile for traffic density the likelihood of reporting any cycling for leisure was OR 0.42, (95% CI 0.32 to 0.52, P < .001) for women and OR 0.41, (95% CI 0.33 to 0.50, P < .001) for men in the highest quartile. CONCLUSIONS: We were unable to reproduce results observed in previous studies. Future research should use large representative population samples from multiple areas to maximize environmental variability and if feasible use both objective and subjective measures of physical activity and the environment.
PubMed Accession Number :: 19998852.

McMinn, A. M.; van Sluijs, E. M.; Harvey, N. C.; Cooper, C.; Inskip, H. M.; Godfrey, K. M.; Griffin, S. J. (2009) Validation of a maternal questionnaire on correlates of physical activity in preschool children Int J Behav Nutr Phys Act, 6 (1),81 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Valid measures of physical activity correlates in preschool children are lacking. This study aimed to assess the validity, factor structure and internal consistency of a maternal questionnaire on potential correlates of four-year-old children's physical activity. METHODS: The questionnaire was designed to measure the following constructs: child personal factors; parental support and self-efficacy for providing support; parental rules and restrictions; maternal attitudes and perceptions; maternal behaviour; barriers to physical activity; and the home and local environments. Two separate studies were conducted. Study I included 24 mothers of four-year-old children who completed the questionnaire then participated in a telephone interview covering similar items to the questionnaire. To assess validity, the agreement between interview and questionnaire responses was assessed using Cohen's kappa and percentage agreement. Study II involved 398 mothers of four-year-old children participating in the Southampton Women's Survey. In this study, principal components analysis was used to explore the factor structure of the questionnaire to aid future analyses with these data. The internal consistency of the factors identified was assessed using Cronbach's alpha. RESULTS: Kappa scores showed 30% of items to have moderate agreement or above, 23% to have fair agreement and 47% to have slight or poor agreement. However, 89% of items had fair agreement as assessed by percentage agreement ([greater than or equal to]66%). Limited variation in responses to variables is likely to have contributed to some of the low kappa values. Six questions had a low kappa and low percentage agreement (defined as poor validity); these included questions from the child personal factors, maternal self-efficacy, rules and restrictions, and local environment domains. The principal components analysis identified eleven factors and found several variables to stand alone. Eight of the composite factors identified had acceptable internal consistency (alpha[greater than or equal to]0.60) and three fell just short of achieving this (0.60>alpha>0.50). CONCLUSIONS: Overall, this maternal questionnaire had reasonable validity and internal consistency for assessing potential correlates of physical activity in young children. With minor revision, this could be a useful tool for future research in this area. This, in turn, will aid the development of interventions to promote physical activity in this age group.
PubMed Accession Number :: 19954524.

Paddison, C. A.; Eborall, H. C.; Sutton, S.; French, D. P.; Vasconcelos, J.; Prevost, A. T.; Kinmonth, A. L.; Griffin, S. J. (2009) Are people with negative diabetes screening tests falsely reassured? Parallel group cohort study embedded in the ADDITION (Cambridge) randomised controlled trial Bmj, 339 ,b4535 [Journal Article] Online
Abstract: OBJECTIVE: To assess whether receiving a negative test result at primary care based stepwise diabetes screening results in false reassurance. DESIGN: Parallel group cohort study embedded in a randomised controlled trial. SETTING: 15 practices (10 screening, 5 control) in the ADDITION (Cambridge) trial. PARTICIPANTS: 5334 adults (aged 40-69) in the top quarter for risk of having undiagnosed type 2 diabetes (964 controls and 4370 screening attenders). MAIN OUTCOME MEASURES: Perceived personal and comparative risk of diabetes, intentions for behavioural change, and self rated health measured after an initial random blood glucose test and at 3-6 and 12-15 months later (equivalent time points for controls). RESULTS: A linear mixed effects model with control for clustering by practice found no significant differences between controls and people who screened negative for diabetes in perceived personal risk, behavioural intentions, or self rated health after the first appointment or at 3-6 months or 12-15 months later. After the initial test, people who screened negative reported significantly (but slightly) lower perceived comparative risk (mean difference -0.16, 95% confidence interval -0.30 to -0.02; P=0.04) than the control group at the equivalent time point; no differences were evident at 3-6 and 12-15 months. CONCLUSIONS: A negative test result at diabetes screening does not seem to promote false reassurance, whether this is expressed as lower perceived risk, lower intentions for health related behavioural change, or higher self rated health. Implementing a widespread programme of primary care based stepwise screening for type 2 diabetes is unlikely to cause an adverse shift in the population distribution of plasma glucose and cardiovascular risk resulting from an increase in unhealthy behaviours arising from false reassurance among people who screen negative. Trial registration Current controlled trials ISRCTN99175498.
PubMed Accession Number :: 19948642.

Wijndaele, K.; Lakshman, R.; Landsbaugh, J. R.; Ong, K. K.; Ogilvie, D. (2009) Determinants of Early Weaning and Use of Unmodified Cow's Milk in Infants: A Systematic Review J Am Diet Assoc, 109 (12),2017-2028 [Journal Article] Online
Abstract: Introduction of complementary foods (weaning) before 4 to 6 months of age and unmodified cow's milk before age 12 months are associated with several health risks. To develop effective interventions to discourage these practices, evidence of their determinants is needed. This systematic review identified documents from seven electronic databases (database inception 2008) and reference lists, and by contacting authors. Seventy-eight studies in developed countries, published between 1976 and 2008, quantifying the association between either feeding practice and its potential determinants were included. Study quality was systematically assessed in terms of representativeness, sample size, method of outcome ascertainment, and approach to statistical analysis. The distribution of evidence for each determinant was visualized in a harvest plot showing the strength and direction of associations found and the quality of relevant studies. The strength of evidence for each determinant was summarized as strong, moderate, limited, or inconclusive, using an algorithm based on the consistency of the results of studies of the highest available quality. Strong evidence denoted that the determinant was examined in three or more high-quality studies and >/=75% of results were consistent. Strong evidence was found for six determinants of early weaning (ie, young maternal age, low maternal education, low socioeconomic status, absence or short duration of breastfeeding, maternal smoking, and lack of information or advice from health care providers) and for two determinants of early introduction of unmodified cow's milk (ie, low maternal education and low socioeconomic status). Of these determinants, improving advice given by health care providers appears the most tractable area for intervention in the short term.
PubMed Accession Number :: 19942019.

Park, J. Y.; Mitrou, P. N.; Dahm, C. C.; Luben, R. N.; Wareham, N. J.; Khaw, K. T.; Rodwell, S. A. (2009) Baseline alcohol consumption, type of alcoholic beverage and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition-Norfolk study Cancer Epidemiol, 33 ,347-354 [Journal Article] Online
Abstract: Excessive alcohol consumption has been associated with increased risk of colorectal cancer (CRC). However, the effect of modest alcohol consumption or of particular types of beverages on CRC risk remains unclear. We examined whether consumption of total alcohol or specific types of alcoholic beverages relate to overall or site-specific CRC risk in a prospective population study of 24,244 participants and 407 incident CRC cases after 11 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Consumption of specific alcoholic beverages at baseline was collected using a detailed health and lifestyle questionnaire. Total alcohol consumption was not associated with CRC risk before or after adjustment for age, sex, weight, height, and smoking status (HR: 0.80, 95% CI: 0.51-1.26 for alcohol consumption of >/=21units/week compared with non-drinkers), and further adjustment for education level, exercise, family history of CRC, and dietary factors did not significantly alter the risk estimates (HR: 0.70, 95% CI: 0.44-1.13). No significant associations were observed between consumption of specific alcoholic beverages (beer, sherry, or spirits) and CRC risk when compared with non-drinkers after adjustment for lifestyle and dietary factors. Daily consumption of >/=1unit of wine appeared inversely related to CRC risk (HR: 0.61, 95% CI: 0.40-0.94). No evidence was found for sex-specific relationships, and further exclusion of cases incident within 3 years of baseline did not change the associations observed. In this population-based UK cohort, we did not find any significant adverse effect of alcohol over the moderate range of intake on colorectal cancer risk.
PubMed Accession Number :: 19932648.

Price, H. C.; Dudley, C.; Barrow, B.; Griffin, S. J.; Holman, R. R. (2009) Perceptions of heart attack risk amongst individuals with diabetes Prim Care Diabetes, 3 (4),239-244 [Journal Article] Online
Abstract: AIM: Individuals with diabetes are at increased risk of cardiovascular disease (CVD). There is good evidence that this risk can be reduced by pharmacotherapies and lifestyle modification. Despite this, knowledge of CVD risk amongst individuals with diabetes remains poor. We undertook a qualitative study to investigate lay perceptions of heart attack risk amongst individuals with diabetes in order to gather information about underlying perceptions concerning risk and risk reduction strategies. METHODS: We conducted three focus groups in Oxford using an open-ended question map. Content analysis was performed to identify recurring themes, similar patterns, distinctions and supportive quotations. RESULTS: Concern about having a heart attack varied widely. A commonly held view was that a 10-year heart attack risk of 10% or greater was high and being aware of one's risk was important so that lifestyle changes or other interventions could be implemented. Participants consistently viewed physical activity as potentially harmful. Almost all participants sought healthcare and lifestyle advice from their primary healthcare providers in the first instance, preferring this to information in the lay press or government campaigns. CONCLUSION: The focus groups have allowed us to better understand lay perceptions of, and underlying assumptions about, CVD risk. These findings may be of use when discussing CVD risk and risk reduction strategies in primary care.
PubMed Accession Number :: 19896425.

Lakshman, R.; Forouhi, N. G.; Sharp, S. J.; Luben, R.; Bingham, S. A.; Khaw, K. T.; Wareham, N. J.; Ong, K. K. (2009) Early Age at Menarche Associated with Cardiovascular Disease and Mortality J Clin Endocrinol Metab, 94 (12),4953-60 [Journal Article] Online
Abstract: Context: The relationship between age at menarche and cardiovascular disease remains unclear. Two recent studies found an inverse association between age at menarche and all-cause mortality. Objective: The aim of this study was to examine the relationship between age at menarche and cardiovascular disease risk factors, events, and mortality. Design, Setting, and Participants: A population-based prospective study involving 15,807 women, aged 40-79 yr in 1993-1997 and followed up to March 2007 for cardiovascular disease events (median follow-up 10.6 yr) and February 2008 for mortality (median follow-up 12.0 yr) was used. Main Outcome Measures: Odds ratios for cardiovascular disease risk factors and hazard ratios for incident cardiovascular disease and mortality were calculated. Results: There were 3888 incident cardiovascular disease events (1323 coronary heart disease, 602 stroke, and 1963 other) and 1903 deaths (640 cardiovascular disease, 782 cancer, and 481 other) during follow-up. Compared with other women, those who had early menarche (<12 yr) had higher risks of hypertension [1.13 (1.02-1.24)], incident cardiovascular disease [1.17 (1.07-1.27)], incident coronary heart disease [1.23 (1.06-1.43)], all-cause mortality [1.22 (1.07-1.39)], cardiovascular disease mortality [1.28 (1.02-1.62)], and cancer mortality [1.25 (1.03-1.51)], adjusted for age, physical activity, smoking, alcohol, educational level, occupational social class, oral contraceptive use, hormone replacement therapy, parity, body mass index, and waist circumference. Conclusions: Early age at menarche (before age 12 yr) was associated with increased risk of cardiovascular disease events, cardiovascular disease mortality, and overall mortality in women, and this association appeared to be only partly mediated by increased adiposity.
PubMed Accession Number :: 19880785.

Lee, A. S.; Griffin, S. J.; Simmons, R. K. (2009) An evaluation of the effectiveness of 'Active for Life': An exercise referral scheme in West Suffolk Public Health, 123 ,670-672 [Journal Article] Online
PubMed Accession Number :: 19854456.

Heid, I. M.; Huth, C.; Loos, R. J.; Kronenberg, F.; Adamkova, V.; Anand, S. S.; Ardlie, K.; Biebermann, H.; Bjerregaard, P.; Boeing, H.; Bouchard, C.; Ciullo, M.; Cooper, J. A.; Corella, D.; Dina, C.; Engert, J. C.; Fisher, E.; Frances, F.; Froguel, P.; Hebebrand, J.; Hegele, R. A.; Hinney, A.; Hoehe, M. R.; Hu, F. B.; Hubacek, J. A.; Humphries, S. E.; Hunt, S. C.; Illig, T.; Jarvelin, M. R.; Kaakinen, M.; Kollerits, B.; Krude, H.; Kumar, J.; Lange, L. A.; Langer, B.; Li, S.; Luchner, A.; Lyon, H. N.; Meyre, D.; Mohlke, K. L.; Mooser, V.; Nebel, A.; Nguyen, T. T.; Paulweber, B.; Perusse, L.; Qi, L.; Rankinen, T.; Rosskopf, D.; Schreiber, S.; Sengupta, S.; Sorice, R.; Suk, A.; Thorleifsson, G.; Thorsteinsdottir, U.; Volzke, H.; Vimaleswaran, K. S.; Wareham, N. J.; Waterworth, D.; Yusuf, S.; Lindgren, C.; McCarthy, M. I.; Lange, C.; Hirschhorn, J. N.; Laird, N.; Wichmann, H. E. (2009) Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design? PLoS Genet, 5 (10),e1000694 [Journal Article] Online
Abstract: The INSIG2 rs7566605 polymorphism was identified for obesity (BMI>/=30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI>/=32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.
PubMed Accession Number :: 19851442.

Forouhi, N. G.; Sharp, S. J.; Du, H.; van der, A. Dl; Halkjaer, J.; Schulze, M. B.; Tjonneland, A.; Overvad, K.; Jakobsen, M. U.; Boeing, H.; Buijsse, B.; Palli, D.; Masala, G.; Feskens, E. J.; Sorensen, T. I.; Wareham, N. J. (2009) Dietary fat intake and subsequent weight change in adults: results from the European Prospective Investigation into Cancer and Nutrition cohorts Am J Clin Nutr, 90 (6),1632-1641 [Journal Article] Online
Abstract: BACKGROUND: It is unclear from the inconsistent epidemiologic evidence whether dietary fat intake is associated with future weight change. OBJECTIVE: The objective was to assess the association between the amount and type of dietary fat and subsequent weight change (follow-up weight minus baseline weight divided by duration of follow-up). DESIGN: We analyzed data from 89,432 men and women from 6 cohorts of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. Using country-specific food-frequency questionnaires, we examined the association between baseline fat intake (amount and type of total, saturated, polyunsaturated, and monounsaturated fats) and annual weight change by using the residual, nutrient density, and energy-partition methods. We used random-effects meta-analyses to obtain pooled estimates across centers. RESULTS: Mean total fat intake as a percentage of energy intake ranged between 31.5% and 36.5% across the 6 cohorts (58% women; mean +/- SD age: 53.2 +/- 8.6 y). The mean (+/-SD) annual weight change was 109 +/- 817 g/y in men and 119 +/- 823 g/y in women. In pooled analyses adjusted for anthropometric, dietary, and lifestyle factors and follow-up period, no significant association was observed between fat intake (amount or type) and weight change. The difference in mean annual weight change was 0.90 g/y (95% CI: -0.54, 2.34 g/y) for men and -1.30 g/y (95% CI: -3.70, 1.11 g/y) for women per 1 g/d energy-adjusted fat intake (residual method). CONCLUSIONS: We found no significant association between the amount or type of dietary fat and subsequent weight change in this large prospective study. These findings do not support the use of low-fat diets to prevent weight gain.
PubMed Accession Number :: 19828709.

Peters, T. M.; Moore, S. C.; Gierach, G. L.; Wareham, N. J.; Ekelund, U.; Hollenbeck, A. R.; Schatzkin, A.; Leitzmann, M. F. (2009) Intensity and timing of physical activity in relation to postmenopausal breast cancer risk: the prospective NIH-AARP Diet and Health Study BMC Cancer, 9 (1),349 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Despite strong evidence of an inverse association of physical activity with postmenopausal breast cancer risk, whether a certain intensity or time of life of physical activity is most effective for lowering breast cancer risk is not known. METHODS: In 118,899 postmenopausal women in the prospective NIH-AARP Diet and Health Study, we examined the relations of light and moderate-to-vigorous intensity physical activity during four periods of life ("historical": ages 15-18, 19-29, 35-39 years; "recent": past 10 years) to postmenopausal breast cancer risk. Physical activity was assessed by self-report at baseline, and 4287 incident breast cancers were identified over 6.6 years of follow-up. RESULTS: In age-adjusted and multivariate Cox regression models, >7 hours/week of moderate-to-vigorous activity during the past 10 years was associated with 16% reduced risk of postmenopausal breast cancer (RR:0.84; 95%CI:0.76,0.93) compared with inactivity. The association remained statistically significant after adjustment for BMI (RR:0.87; 95%CI:0.78,0.96). Neither moderate-to-vigorous intensity activity during other periods of life nor light intensity activity during any period of life was related to breast cancer risk, and associations did not vary by tumor characteristics. CONCLUSIONS: A high level of recent, but not historical, physical activity of moderate-to-vigorous intensity is associated with reduced postmenopausal breast cancer risk. More precise recall of recent physical activity than activity in the distant past is one possible explanation for our findings.
PubMed Accession Number :: 19796379.

Simmons, R. K.; Ogilvie, D.; Griffin, S. J.; Sargeant, L. A. (2009) Applied public health research - falling through the cracks? BMC Public Health, 9 (1),362 [Journal Article] Online
Abstract: ABSTRACT: Background There is a degree of dissonance between the types of evaluative research required by organisations providing or commissioning health care, those recommended by organisations developing evidence-based guidance, and those which research funding bodies are prepared to support. Methods We present a case study of efforts to establish a pragmatic but robust evaluation of local exercise referral schemes. We considered the epidemiological, ethical and practical advantages and disadvantages of a number of study designs and applied for research funding based on an uncontrolled design, outlining the difficulties of carrying out a randomised controlled trial to evaluate an existing service. Results Our proposal was praised for its relevance and clear patient outcomes, but the application was twice rejected because both funders and reviewers insisted on a randomised controlled trial design, which we had found to be impractical, unacceptable to service users and potentially unethical. Conclusions The case study highlights continuing challenges for applied public health research in the current funding climate.
PubMed Accession Number :: 19781062.

Steele, R. M.; van Sluijs, E. M.; Cassidy, A.; Griffin, S. J.; Ekelund, U. (2009) Targeting sedentary time or moderate- and vigorous-intensity activity: independent relations with adiposity in a population-based sample of 10-y-old British children Am J Clin Nutr, 90 (50),1185-1192 [Journal Article] Online
Abstract: BACKGROUND: It is unclear whether subcomponents of physical activity (PA) are associated with adiposity independent of time spent while sedentary. OBJECTIVE: The objective was to examine associations between objectively measured PA and its subcomponents [ie, time spent at light-intensity PA, moderate-intensity PA (MPA), vigorous-intensity PA (VPA), and moderate-plus-vigorous-intensity PA (MVPA)], independent of sedentary time, and self-reported leisure screen time (television and electronic game use) with indexes of adiposity in a population-based sample of British children. DESIGN: A cross-sectional study was conducted in 1862 UK children aged 9-10 y. PA and sedentary activity were measured by accelerometry, and indicators of adiposity were waist circumference, body mass index (BMI), and fat mass index calculated from bioimpedance measurements. Screen time was assessed by self-report. We examined the associations between PA subcomponents and adiposity by multilevel linear models adjusted for birth weight, maternal BMI, energy intake, and sleep duration. RESULTS: Objectively measured sedentary time was positively associated with waist circumference (P = 0.04) and fat mass index (P = 0.05), independent of age and sex. However, this association was attenuated after adjustment for MVPA and other covariates. VPA (all P < 0.0001), combined MVPA (all P < 0.01), and total activity (counts/min) (all P < 0.001) were all inversely associated with each of the adiposity indexes, independent of sedentary time and other important covariates. Associations were weaker for MPA: P = 0.05, 0.87, and 0.1 for waist circumference, BMI, and fat mass index, respectively. CONCLUSIONS: Time spent in VPA appears to be more strongly associated with adiposity than sedentary time. Interventions may therefore need to incorporate higher intensity-based activities to curb the growing obesity epidemic.
PubMed Accession Number :: 19776141.

Corder, K.; Ogilvie, D.; van Sluijs, E. M. (2009) Invited Commentary: Physical Activity Over the Life Course--Whose Behavior Changes, When, and Why? Am J Epidemiol, 170 (9),1078-81 [Journal Article] Online
Abstract: Physical activity tends to decline from childhood into adulthood. Maintaining high levels of physical activity throughout life is therefore an important public health objective. Relatively little is known about changes in physical activity behavior over the life course, the domains of physical activity in which they occur, the characteristics of those whose physical activity declines, and the factors associated with such changes. In the future, incorporating more accurate measures of physical activity in large population studies would help to establish more accurate estimates of associations in this area. Determinants of behavior change, including the effects of socioeconomic position and social mobility on physical activity and fitness, are likely to change constantly throughout life, but it is largely unknown which determinants are most important at each life stage, let alone whether and at what times those determinants change. Better evidence on determinants of behavior change throughout the life course would contribute greatly to understanding when and how to intervene to help create and sustain lifelong healthy behavior patterns in those who have the most to gain from adopting them.
PubMed Accession Number :: 19767350.

Finucane, F. M.; Luan, J.; Wareham, N. J.; Sharp, S. J.; O'Rahilly, S.; Balkau, B.; Flyvbjerg, A.; Walker, M.; Hojlund, K.; Nolan, J. J.; Savage, D. B. (2009) Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals Diabetologia, 52 (11),2345-2349 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Obesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults. METHODS: Leptin and adiponectin levels were measured in 2,097 non-diabetic individuals from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index (M/I) from hyperinsulinaemic-euglycaemic clamp studies in 1,226 EGIR RISC participants. RESULTS: The LAR was highly correlated with HOMA-S in men (r = -0.58, p = 4.5 x 10(-33) and r = -0.65, p = 1.1 x 10(-66) within the Ely and EGIR RISC study cohorts, respectively) and in women (r = -0.51, p = 2.8 x 10(-36) and r = -0.61, p = 2.5 x 10(-73)). The LAR was also strongly correlated with the clamp M/I value (r = -0.52, p = 4.5 x 10(-38) and r = -0.47, p = 6.6 x 10(-40) in men and women, respectively), similar to correlations between HOMA-S and the M/I value. CONCLUSIONS/INTERPRETATION: The leptin:adiponectin ratio is a useful measure of insulin resistance in non-diabetic white adults. These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance. Given that variations between fasting and postprandial leptin and adiponectin levels tend to be small, the leptin to adiponectin ratio might also have potential value in assessing insulin sensitivity in the non-fasted state.
PubMed Accession Number :: 19756488.

Kelliny, C.; Ekelund, U.; Bo Andersen, L.; Brage, S.; Loos, R. J.; Wareham, N. J.; Langenberg, C. (2009) Common Genetic Determinants of Glucose Homeostasis in Healthy Children: The European Youth Heart Study (EYHS) Diabetes, 58 ,2939-2945 [Journal Article] Online
Abstract: Objective. To investigate whether the effects of common genetic variants associated with fasting glucose in adults are detectable in healthy children. Methods. Single nucleotide polymorphisms in MTNR1B (rs10830963), G6PC2 (rs560887) and GCK (rs4607517) were genotyped in 2,025 healthy European children aged 9-11 and 14-16 years. Associations with fasting glucose (FG), insulin, HOMA-IR and HOMA-B were investigated along with those observed for type 2 diabetes (T2D) variants available in this study (CDKN2A/B, IGF2BP2, CDKAL1, SLC30A8, HHEX-IDE, Chr 11p12). Results Strongest associations were observed for G6PC2 and MTNR1B, with FG levels (95% CI) being 0.084 (0.06; 0.11) mmol/L, p=7.9x10(-11) and 0.069 (0.04; 0.09) mmol/L, p=1.9x10(-7) higher per risk allele copy. A similar, but weaker trend was observed for GCK (0.028 (-0.006; 0.06) mmol/L, p=0.11). All three variants were associated with lower beta-cell function (HOMA-B p=9.38x10(-5), 0.004 and 0.04, respectively). SLC30A8 (rs13266634) was the only T2D variant associated with higher FG (0.033 mmol/L (0.01; 0.06); p=0.01). Calculating a genetic predisposition score adding the number of risk alleles of G6PC2, MTNR1B, GCK and SLC30A8 showed that glucose levels were successively higher in children carrying a greater number of risk alleles (p=7.1x10(-17)), with mean levels of 5.34 versus 4.91 mmol/L comparing children with 7 alleles (0.6% of all children) to those with none (0.5%). No associations were found for fasting insulin or HOMA-IR with any of the variants. Conclusions. The effects of common polymorphisms influencing FG are apparent in healthy children, where the presence of multiple risk alleles amounts to a difference of more than a standard deviation of FG.
PubMed Accession Number :: 19741166.

Nilsson, A.; Andersen, L. B.; Ommundsen, Y.; Froberg, K.; Sardinha, L. B.; Piehl-Aulin, K.; Ekelund, U. (2009) Correlates of objectively assessed physical activity and sedentary time in children: a cross-sectional study (The European Youth Heart Study) BMC Public Health, 9 (1),322 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Identifying leisure time activities performed before and after school that influence time in physical activity (PA) and/or time spent sedentary can provide useful information when designing interventions aimed to promote an active lifestyle in young people. The purpose of this study was to examine associations between mode of transportation to school, outdoor play after school, participation in exercise in clubs, and TV viewing with objectively assessed PA and sedentary behaviour in children. METHODS: A total of 1327 nine- and 15-year-old children from three European countries (Norway, Estonia, Portugal) participated as part of the European Youth Heart Study. PA was measured during two weekdays and two weekend days using the MTI accelerometer, and average percent of time in moderate-to-vigorous PA (MVPA) and time spent sedentary were derived. Potential correlates were assessed by self-report. Independent associations between self-reported correlates with percent time in MVPA and percent time sedentary were analysed by general linear models, adjusted by age, gender, country, measurement period, monitored days and parental socio-economic status. RESULTS: In 9-year-olds, playing outdoors after school was associated with higher percent time in MVPA (P < 0.01), while participation in sport clubs was associated with higher percent time in MVPA (P < 0.01) in 15-year-olds. No associations with percent time sedentary were observed in either age group. CONCLUSIONS: Frequency of outdoor play after school is a significant correlate for daily time in MVPA in 9-year-olds, while this correlate is attenuated in favour of participation in sport and exercise in clubs in 15-year-olds. Targeting walking to school or reduced TV viewing time in order to increase time in daily MVPA in children is unlikely to be sufficient. Correlates related to time spent sedentary need further examination.
PubMed Accession Number :: 19735565.

Nyberg, G. A.; Nordenfelt, A. M.; Ekelund, U.; Marcus, C. (2009) Physical Activity Patterns Measured by Accelerometry in 6- to 10-yr-Old Children Med Sci Sports Exerc, 41 ,1842-1848 [Journal Article] Online
Abstract: PURPOSE:: To examine differences in patterns of objectively measured physical activity (PA) among weekdays and weekend days and across different time blocks during the day in relation to age and gender. This knowledge is important when planning preventive initiatives aimed at increasing levels of PA in children. METHODS:: This is a cross-sectional analysis in 653 girls and 640 boys (6-10 yr) measured during 1 wk with accelerometry. Periods of the day were divided into school time (8:00 a.m. to 1:30 p.m.), after school care time (1:30-4:00 p.m.), and evening time (4:00-9:00 p.m.). Multivariate ANOVA was used to analyze mean PA. RESULTS:: Mean daily PA differed significantly across age groups (6-10 yr) in both boys and girls (P < 0.001). Mean (SE) daily PA was significantly lower during weekends compared with weekdays in all age groups (girls 782 (6.7) vs 681 (7.7) counts per min (CPM), P < 0.001; boys 853 (7.1) vs 729 (8.0) CPM, P < 0.001). This decline was similar across low, medium, and highly active children. Mean PA was highest during after school care time on weekdays (girls 879 (9.8) and boys 990 (10.0) CPM) compared with all other periods. The difference in mean PA between boys and girls was highest during school time (P < 0.001) and after school care time (P < 0.001). CONCLUSIONS:: The decline in PA in children may start already at the age of 6 yr. The school setting may be an important arena for targeting activity levels in girls because the difference in PA levels between girls and boys is most pronounced during school time. In both girls and boys, PA levels are disproportionally low during weekends and might be important targets for interventions aimed to increase PA.
PubMed Accession Number :: 19727031.

Beardsall, K.; Ong, K. K.; Murphy, N.; Ahmed, M. L.; Zhao, J. H.; Peeters, M. W.; Dunger, D. B. (2009) Heritability of Childhood Weight Gain from Birth and Risk Markers for Adult Metabolic Disease in Prepubertal Twins J Clin Endocrinol Metab, 94 (10),3708-3713 [Journal Article] Online
Abstract: Objective: Associations between size at birth, postnatal weight gain, and potential risk for adult disease have been variably explained by in utero exposures or genetic risk that could affect both outcomes. We utilized a twin model to explore these hypotheses. Methods: One hundred pairs of healthy twins aged 8.9 yr (range, 7.2-10.9 yr) had fasting blood samples collected, blood pressure (BP) measured, and anthropometry assessed. All measurements were converted to SD scores (SDS) to adjust for age and sex. Results: Mean birth weights in both monozygotic and dizygotic twins were -0.90 SDS lower than the UK reference. In postnatal life, 58% of monozygotic twins and 59% of dizygotic twins showed rapid weight gain (a change of more than +0.67 in weight SDS) from birth. Postnatal weight gain was positively associated with sum of skinfolds (r = 0.51; P < 0.0005), fasting insulin levels (r = 0.35; P < 0.0005), systolic BP (r = 0.30; P < 0.0005), and diastolic BP (r = 0.15; P < 0.05) at follow-up. Heritability estimates (additive genetic components) were calculated using variance components models for: birth weight, 44%; postnatal weight gain, 80%; childhood height, 89%; body mass index, 72%; sum of skinfolds, 89%; waist circumference, 74%; fasting insulin, 65%; systolic BP, 33%; and diastolic BP, 29%. Conclusions: Postnatal weight gain from birth, rather than birth weight, was associated with childhood risk markers for adult metabolic disease. Childhood weight gain was highly heritable, and genetic factors associated with postnatal weight gain are likely to also contribute to risks for adult disease.
PubMed Accession Number :: 19723754.

Ridgway, C. L.; Ong, K. K.; Tammelin, T. H.; Sharp, S.; Ekelund, U.; Jarvelin, M. R. (2009) Infant motor development predicts sports participation at age 14 years: northern Finland birth cohort of 1966 PLoS One, 4 (8),e6837 [Journal Article] Online
Abstract: BACKGROUND: Motor proficiency is positively associated with physical activity levels. The aim of this study is to investigate associations between the timing of infant motor development and subsequent sports participation during adolescence. METHODS: Prospective observational study. The study population consisted of 9,009 individuals from the Northern Finland Birth Cohort 1966. Motor development was assessed by parental report at age 1 year, using age at walking with support and age at standing unaided. At follow up aged 14 years, data were collected on the school grade awarded for physical education (PE). Self report was used to collect information on the frequency of sports participation and number of different sports reported. PRINCIPAL FINDINGS: Earlier infant motor development was associated with improved school PE grade, for age at walking supported (p<0.001) and standing unaided (p = <0.001). Earlier infant motor development, in terms of age at walking supported, was positively associated with the number of different sports reported (p = 0.003) and with a greater frequency of sports participation (p = 0.043). These associations were independent of gestational age and birth weight, as well as father's social class and body mass index at age 14 years. CONCLUSIONS: Earlier infant motor development may predict higher levels of physical activity as indicated by higher school PE grade, participation in a greater number of different types of sports and increased frequency of sports participation. Identification of young children with slower motor development may allow early targeted interventions to improve motor skills and thereby increase physical activity in later life.
PubMed Accession Number :: 19718258.

Travier, N.; Agudo, A.; May, A. M.; Gonzalez, C.; Luan, J.; Besson, H.; Wareham, N. J.; Slimani, N.; Rinaldi, S.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Palli, D.; Agnoli, C.; Mattiello, A.; Tumino, R.; Vineis, P.; Rodriguez, L.; Sanchez, M. J.; Dorronsoro, M.; Barricarte, A.; Tormo, M. J.; Norat, T.; Mouw, T.; Key, T. J.; Spencer, E. A.; Bueno-de-Mesquita, B.; Vrieling, A.; Orfanos, P.; Naska, A.; Trichopoulou, A.; Rohrmann, S.; Kaaks, R.; Bergmann, M.; Boeing, H.; Hallmans, G.; Johansson, I.; Manjer, J.; Lindkvist, B.; Jakobsen, M. U.; Overvad, K.; Tjonneland, A.; Halkjaer, J.; Lund, E.; Braaten, T.; Odysseos, A.; Riboli, E.; Peeters, P. H. (2009) Smoking and body fatness measurements: A cross sectional analysis in the EPIC-PANACEA study Prev Med, 49 ,365-373 [Journal Article] Online
Abstract: Objective The present study investigates the cross-sectional relationship between tobacco smoking and body fatness. Methods This cross-sectional study consisted of 469,543 men and women who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1992 and 2000 providing anthropometric measurements and information on smoking. Adjusted multilevel mixed effects linear regression models were used to assess the association between smoking and body fat mass. Results The analyses showed that BMI and WC were positively associated with smoking intensity in current smokers but negatively associated with time since quitting in former smokers. When compared to never smokers, average current smokers (17 and 13 cig/day for men and women respectively) showed a lower BMI. When average former smokers (men and women who had respectively stopped smoking for 16 and 15 years) were compared to never smokers, higher BMI and WC were observed in men whereas no significant associations were observed in women. Conclusions This cross-sectional study suggests that smoking may be associated with body fatness and fat distribution. Although our findings cannot establish cause and effect, they suggest that providing information and support to those who want to stop, may help in preventing weight gain, and therefore weaken a barrier against stopping smoking.
PubMed Accession Number :: 19716380.

Birjmohun, R. S.; Vergeer, M.; Stroes, E. S.; Sandhu, M. S.; Ricketts, S. L.; Tanck, M. W.; Wareham, N. J.; Jukema, J. W.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2009) Both paraoxonase-1 genotype and activity do not predict the risk of future coronary artery disease; the EPIC-Norfolk Prospective Population Study PLoS One, 4 (8),e6809 [Journal Article] Online
Abstract: BACKGROUND: Paraoxonase-1 (PON1) is an antioxidant enzyme, that resides on high-density lipoprotein (HDL). PON1-activity, is heavily influenced by the PON1-Q192R polymorphism. PON1 is considered to protect against atherosclerosis, but it is unclear whether this relation is independent of its carrier, HDL. In order to evaluate the atheroprotective potential of PON1, we assessed the relationships among PON1-genotype, PON1-activity and risk of future coronary artery disease (CAD), in a large prospective case-control study. METHODOLOGY/PRINCIPAL FINDINGS: Cases (n = 1138) were apparently healthy men and women aged 45-79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n = 2237) were matched by age, sex and enrollment time. PON1-activity was similar in cases and controls (60.7+/-45.3 versus 62.6+/-45.8 U/L, p = 0.3) and correlated with HDL-cholesterol levels (r = 0.16, p<0.0001). The PON1-Q192R polymorphism had a profound impact on PON1-activity, but did not predict CAD risk (Odds Ratio [OR] per R allele 0.98[0.84-1.15], p = 0.8). Using conditional logistic regression, quartiles of PON1-activity showed a modest inverse relation with CAD risk (OR for the highest versus the lowest quartile 0.77[0.63-0.95], p = 0.01; p-trend = 0.06). PON1-activity adjusted for Q192R polymorphism correlated better with HDL-cholesterol (r = 0.26, p<0.0001) and more linearly predicted CAD risk (0.79[0.64-0.98], p = 0.03; p-trend = 0.008). However, these relationships were abolished after adjustment for HDL (particles-cholesterol-size) and apolipoproteinA-I (0.94[0.74-1.18], p-trend = 0.3). CONCLUSIONS/SIGNIFICANCE: This study, shows that PON1-activity inversely relates to CAD risk, but not independent of HDL, due to its close association with the HDL-particle. These data strongly suggest that a low PON1-activity is not a causal factor in atherogenesis.
PubMed Accession Number :: 19710913.

Du, H.; van der, A. Dl; van Bakel, M. M.; Slimani, N.; Forouhi, N. G.; Wareham, N. J.; Halkjaer, J.; Tjonneland, A.; Jakobsen, M. U.; Overvad, K.; Schulze, M. B.; Buijsse, B.; Boeing, H.; Palli, D.; Masala, G.; Sorensen, T. I.; Saris, W. H.; Feskens, E. J. (2009) Dietary glycaemic index, glycaemic load and subsequent changes of weight and waist circumference in European men and women Int J Obes (Lond), 33 ,1280-1288 [Journal Article] Online
Abstract: Objectives:To investigate whether dietary glycaemic index (GI) and glycaemic load (GL) were associated with subsequent weight and waist circumference change.Design:Population-based prospective cohort study.Setting:Five European countries, which are Denmark, Germany, Italy, The Netherlands and the United Kingdom.Participants:A total of 89 432 participants, aged 20-78 years (mean =53 years) at baseline and followed for 1.9-12.5 years (mean=6.5 years). All participants were free of self-reported cancer, cardiovascular diseases and diabetes at baseline.Methods:Glycaemic index and GL were calculated on the basis of dietary intake assessed by food frequency questionnaires and by using a GI table developed for this study with published GI values as the main sources. Anthropometric data were collected both at baseline and at the end of follow-up. Multiple linear regression analyses were conducted in each centre and random-effect meta-analyses were used to combine the effects. Adjustment was made for baseline anthropometrics, demographic and lifestyle factors, follow-up duration and other dietary factors.Results:Mean GI and GL were 57 and 134, respectively. Associations of GI and GL with subsequent changes of weight and waist circumference were heterogeneous across centres. Overall, with every 10-unit higher in GI, weight increased by 34 g per year (95% confidence interval (CI): -47, 115) and waist circumference increased by 0.19 cm per year (95% CI: 0.11, 0.27). With every 50-unit higher in GL, weight increased by 10 g per year (95% CI: -65, 85) and waist circumference increased by 0.06 cm per year (95% CI: -0.01, 0.13).Conclusions:Our findings do not support an effect of GI or GL on weight change. The positively significant association between GI, not GL, and subsequent gain in waist circumference may imply a beneficial role of lower GI diets in the prevention of abdominal obesity. However, further studies are needed to confirm this finding given the small effect observed in this study.International Journal of Obesity advance online publication, 25 August 2009; doi:10.1038/ijo.2009.163.
PubMed Accession Number :: 19704411.

Dendrou, C. A.; Plagnol, V.; Fung, E.; Yang, J. H.; Downes, K.; Cooper, J. D.; Nutland, S.; Coleman, G.; Himsworth, M.; Hardy, M.; Burren, O.; Healy, B.; Walker, N. M.; Koch, K.; Ouwehand, W. H.; Bradley, J. R.; Wareham, N. J.; Todd, J. A.; Wicker, L. S. (2009) Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource Nat Genet, 41 (9),1011-5 [Journal Article] Online
Abstract: Genome-wide association studies (GWAS) have identified over 300 regions associated with more than 70 common diseases. However, identifying causal genes within an associated region remains a major challenge. One approach to resolving causal genes is through the dissection of gene-phenotype correlations. Here we use polychromatic flow cytometry to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases, type 1 diabetes (T1D) and multiple sclerosis. We confirm our strongest gene-phenotype correlation at the RNA level by allele-specific expression (ASE). We also define key parameters for the design and implementation of post-GWAS gene-phenotype investigations and demonstrate the usefulness of a large bioresource of genotype-selectable normal donors from whom fresh, primary cells can be analyzed.
PubMed Accession Number :: 19701192.

Bauer, F.; Elbers, C. C.; Adan, R. A.; Loos, R. J.; Onland-Moret, N. C.; Grobbee, D. E.; van Vliet-Ostaptchouk, J. V.; Wijmenga, C.; van der Schouw, Y. T. (2009) Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference Am J Clin Nutr, 90 (4),951-9 [Journal Article] Online
Abstract: BACKGROUND: New genetic loci, most of which are expressed in the brain, have recently been reported to contribute to the development of obesity. The brain, especially the hypothalamus, is strongly involved in regulating weight and food intake. OBJECTIVES: We investigated whether the recently reported obesity loci are associated with measures of abdominal adiposity and whether these variants affect dietary energy or macronutrient intake. DESIGN: We studied 1700 female Dutch participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Their anthropometric measurements and intake of macronutrients were available. Genotyping was performed by using KASPar chemistry. A linear regression model, assuming an additive effect, was used to analyze the association between genotypes of 12 single nucleotide polymorphisms (SNPs) and adiposity measures and dietary intake. RESULTS: Seven SNPs were associated (P < 0.05) with weight, body mass index (BMI), and waist circumference (unadjusted for BMI). They were in or near to 6 loci: FTO, MC4R, KCTD15, MTCH2, NEGR1, and BDNF. Five SNPs were associated with dietary intake (P < 0.05), which were in or near 5 loci: SH2B1 (particularly with increased fat), KCTD15 (particularly with carbohydrate intake), MTCH2, NEGR1, and BDNF. CONCLUSIONS: We confirmed some of the findings for the newly identified obesity loci that are associated with general adiposity in a healthy Dutch female population. Our results suggest that these loci are not specifically associated with abdominal adiposity but more generally with obesity. We also found that some of the SNPs were associated with macronutrient-specific food intake.
PubMed Accession Number :: 19692490.

Ward, H.; Mitrou, P. N.; Bowman, R.; Luben, R.; Wareham, N. J.; Khaw, K. T.; Bingham, S. (2009) APOE genotype, lipids, and coronary heart disease risk: a prospective population study Arch Intern Med, 169 (15),1424-9 [Journal Article] Online
Abstract: BACKGROUND: The risk of coronary heart disease (CHD) may be related to genetic mutations in the production of apolipoprotein E via alterations to the metabolism of CHD-related blood lipids such as low-density lipoprotein cholesterol and triglycerides. METHODS: The relationship between APOE genotype (*E3/*E3, *E3/*E4, *E2/*E3, *E4/*E4, *E2/*E4, and *E2/*E2) and fatal and nonfatal CHD was examined among 10 035 men and 12 134 women, aged 440 to 79 years, from the Norfolk, England, arm of the European Prospective Into Nutrition and Cancer Study (1993-2007). During an average of 11 years of follow-up, 2712 CHD events were documented. RESULTS: The hazard ratio for CHD was 0.88 (95% confidence interval, 0.77-0.99) for *E2 carriers (*E2/*E2 and *E2/*E3) and 1.09 (1.00-1.19) for *E4 carriers (*E3/*E4 and *E4/*E4) compared with homozygous *E3/*E3 individuals after age and sex adjustment. Similar values were obtained when systolic blood pressure, body mass index, diabetes mellitus, alcohol intake, physical activity, and smoking were added to the model. After additional adjustment for baseline levels of the ratio of low- to high-density lipoprotein cholesterol, the hazard ratios (and 95% confidence intervals) for *E2 and *E4 carriers were 0.97 (0.85-1.10) and 1.06 (0.97-1.15), respectively, when compared with *E3 homozygotes. No interactions by sex, smoking status, or age groups were observed. CONCLUSION: In the largest prospective cohort study to date, CHD risk was not associated with APOE genotype after controlling for a variety of cardiovascular risk factors, particularly the ratio of low- to high-density lipoprotein cholesterol.
PubMed Accession Number :: 19667307.

Chamnan, P.; Simmons, R. K.; Sharp, S. J.; Griffin, S. J.; Wareham, N. J. (2009) Cardiovascular risk assessment scores for people with diabetes: a systematic review Diabetologia, 52 (10),2001-14 [Journal Article] Online
Abstract: People with type 2 diabetes have an increased risk of cardiovascular disease (CVD). Multivariate cardiovascular risk scores have been used in many countries to identify individuals who are at high risk of CVD. These risk scores include those originally developed in individuals with diabetes and those developed in a general population. This article reviews the published evidence for the performance of CVD risk scores in diabetic patients by: (1) examining the overall rationale for using risk scores; (2) systematically reviewing the literature on available scores; and (3) exploring methodological issues surrounding the development, validation and comparison of risk scores. The predictive performance of cardiovascular risk scores varies substantially between different populations. There is little evidence to suggest that risk scores developed in individuals with diabetes estimate cardiovascular risk more accurately than those developed in the general population. The inconsistency in the methods used in evaluation studies makes it difficult to compare and summarise the predictive ability of risk scores. Overall, CVD risk scores rank individuals reasonably accurately and are therefore useful in the management of diabetes with regard to targeting therapy to patients at highest risk. However, due to the uncertainty in estimation of true risk, care is needed when using scores to communicate absolute CVD risk to individuals.
PubMed Accession Number :: 19629430.

van Hees, V. T.; Ekelund, U. (2009) Novel daily energy expenditure estimation by using objective activity type classification: Where do we go from here? J Appl Physiol, 107 (3),639-40 [Journal Article] Online
Abstract: N/a.
PubMed Accession Number :: 19628722.

Jones, A. P.; Coombes, E. G.; Griffin, S. J.; van Sluijs, E. M. (2009) Environmental supportiveness for physical activity in English schoolchildren: a study using Global Positioning Systems Int J Behav Nutr Phys Act, 6 (1),42 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: There is increasing evidence that the environment plays a role in influencing physical activity in children and adults. As children have less autonomy in their behavioural choices, neighbourhood environment supportiveness may be an important determinant of their ability to be active. Yet we know rather little about the types of environment that children use for bouts of physical activity. This study uses accelerometery and global positioning system technologies to identify the characteristics of environments being used for bouts of continuous moderate to vigorous physical activity (MVPA) in a sample of English schoolchildren. METHODS: The sample was 100 children from SPEEDY (Sport, Physical activity and Eating behaviour: Environmental Determinants in Young people), a cohort of 2064 9-10 year-olds from Norfolk, England, recruited in 2007. Children wore an ActiGraph GT1M accelerometer and a Garmin Forerunner 205 GPS unit over four consecutive days. Accelerometery data points were matched to GPS locations and bouts (5 minutes or more) of MVPA were identified. Bout locations were overlaid with a detailed landcover dataset developed in a GIS to identify the types of environment associated with MVPA. Findings are presented using descriptive statistics. RESULTS: Boys were more active than girls, spending an average of 20 (SD 23) versus 11 (SD 15) minutes per day in MVPA bouts. Children who spent more time outside the home were more active (p=0.002), especially girls and children living in rural locations (both p<0.05). Children tended to be active close to home, with 62.5% of all recorded bouts occurring inside neighbourhoods, although boys (p=0.05) and rural children (p=0.01) were more likely to roam outside their neighbourhood. Amongst urban children, gardens (28% of bout time) and the street environment (20%) were the most commonly used environments for MVPA bouts. Amongst rural children farmland (22%) and grassland (17%) were most frequently used. CONCLUSIONS: The study has developed a new method for the identification of environments in which bouts of continuous physical activity are undertaken. The results highlight the importance of the provision of urban gardens and green spaces, and the maintenance of safe street environments as places for children to be active.
PubMed Accession Number :: 19615073.

Salanti, G.; Southam, L.; Altshuler, D.; Ardlie, K.; Barroso, I.; Boehnke, M.; Cornelis, M. C.; Frayling, T. M.; Grallert, H.; Grarup, N.; Groop, L.; Hansen, T.; Hattersley, A. T.; Hu, F. B.; Hveem, K.; Illig, T.; Kuusisto, J.; Laakso, M.; Langenberg, C.; Lyssenko, V.; McCarthy, M. I.; Morris, A.; Morris, A. D.; Palmer, C. N.; Payne, F.; Platou, C. G.; Scott, L. J.; Voight, B. F.; Wareham, N. J.; Zeggini, E.; Ioannidis, J. P. (2009) Underlying Genetic Models of Inheritance in Established Type 2 Diabetes Associations Am J Epidemiol, 170 ,537-545 [Journal Article] Online
Abstract: For most associations of common single nucleotide polymorphisms (SNPs) with common diseases, the genetic model of inheritance is unknown. The authors extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations with type 2 diabetes. For 13 SNPs, the data fitted very well to an additive model of inheritance for the diabetes risk allele; for 4 SNPs, the data were consistent with either an additive model or a dominant model; and for 2 SNPs, the data were consistent with an additive or recessive model. Results were robust to the use of different priors and after exclusion of data for which index SNPs had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that were very similar to those previously reported based on fixed- or random-effects models, but uncertainty about several of the effects was substantially larger. The authors also examined the extent of between-study heterogeneity in the genetic model and found generally small between-study deviation values for the genetic model parameter. Heterosis could not be excluded for 4 SNPs. Information on the genetic model of robustly replicated association signals derived from genome-wide association studies may be useful for predictive modeling and for designing biologic and functional experiments.
PubMed Accession Number :: 19602701.

Lakshman, R.; Ogilvie, D.; Ong, K. (2009) Mothers' experiences of bottle feeding: a systematic review of qualitative and quantitative studies Arch Dis Child, 94 (8),596-601 [Journal Article] Online
Abstract: OBJECTIVE: Most babies receive at least some formula milk. Variations in formula-feeding practices can have both short- and long-term health consequences. We systematically reviewed the literature on parents' experiences of bottle feeding to understand how formula-feeding decisions are made. METHODS: We systematically searched for and appraised relevant English-language papers identified by searching 12 electronic databases, reference lists and related articles and by contacting first authors of included papers. We analysed and synthesised the included studies using a combination of narrative and thematic approaches. Consensus on the final inclusion, interpretation and synthesis of studies was reached across the research team. RESULTS: Six qualitative studies and 17 quantitative studies (involving 13,263 participants) were included. Despite wide differences in study design, context, focus and quality, several consistent themes emerged. Mothers who bottle-fed their babies experienced negative emotions such as guilt, anger, worry, uncertainty and a sense of failure. Mothers reported receiving little information on bottle feeding and did not feel empowered to make decisions. Mistakes in preparation of bottle feeds were common. No studies examined how mothers made decisions about the frequency or quantity of bottle feeds. CONCLUSIONS: Inadequate information and support for mothers who decide to bottle feed may put the health of their babies at risk. While it is important to promote breastfeeding, it is also necessary to ensure that the needs of bottle-feeding mothers are met.
PubMed Accession Number :: 19602520.

Patel, P. S.; Sharp, S. J.; Luben, R. N.; Khaw, K. T.; Bingham, S. A.; Wareham, N. J.; Forouhi, N. G. (2009) The association between type of dietary fish and seafood intake and the risk of incident type 2 diabetes: The EPIC-Norfolk cohort study Diabetes Care, 32 ,1857-1863 [Journal Article] Online
Abstract: Objective: To investigate the association between fish and seafood intake and new-onset type 2 diabetes. Research Design and Methods: Population-based prospective cohort (EPIC-Norfolk) study of men and women aged 40-79 years at baseline (1993-1997). Habitual fish and seafood intake (white fish, oily fish, fried fish, shellfish) was assessed using a semi-quantitative food frequency questionnaire and categorised as <1 or >/=1 portions/week. During a median (IQR) follow-up of 10.2 (9.1-11.2) years, there were 725 incident diabetes cases among 21,984 eligible participants. Results: Higher total fish intake (>/=1 vs. <1 portions/week) was associated with a significantly lower risk of diabetes [odds ratio (OR) 0.75 (95% CI 0.58-0.96)], in analyses adjusted for age, sex, family history of diabetes, education, smoking, physical activity, dietary factors (total energy intake, alcohol intake, plasma vitamin C) and obesity (BMI, waist circumference). White fish and oily fish intake were similarly inversely associated with diabetes risk, but the associations were not significant after adjustment for dietary factors (oily fish) or obesity (white fish). Fried fish was not significantly associated with diabetes risk. Consuming >/=1 portions/week of shellfish was associated with an increased risk of diabetes [OR 1.36 (95% CI 1.02 - 1.81)] in adjusted analyses. Conclusion: Total, white, and oily fish consumption may be beneficial for reducing risk of diabetes, reinforcing the public health message to consume fish regularly. Greater shellfish intake appears to be associated with an increased risk of diabetes, warranting further investigation into cooking methods and mechanisms.
PubMed Accession Number :: 19592633.

Rana, J. S.; Cote, M.; Despres, J. P.; Sandhu, M. S.; Talmud, P. J.; Ninio, E.; Wareham, N. J.; Kastelein, J. J.; Zwinderman, A. H.; Khaw, K. T.; Boekholdt, S. M. (2009) Inflammatory biomarkers and the prediction of coronary events among people at intermediate risk; the EPIC-Norfolk prospective population study Heart, 95 (20),1682-1687 [Journal Article] Online
Abstract: OBJECTIVE: To evaluate the role of the inflammatory biomarkers C-reactive protein, (CRP), myeloperoxidase, paraoxonase, secretory phospholipase A2 group IIA (sPLA2), lipoprotein-associated phospholipase A2, fibrinogen, macrophage chemoattractant protein-1, and adiponectin, in predicting the risk of coronary heart disease (CHD) among individuals estimated to be at intermediate risk according to Framingham Risk Score (FRS). DESIGN: Prospective case-control study nested in EPIC-Norfolk cohort. SETTING: Norfolk, United Kingdom. PATIENTS: Apparently healthy men and women aged 45-79 years. MAIN OUTCOME MEASURES: Risk of future coronary artery disease. RESULTS: For participants predicted to be at intermediate risk by the FRS, the highest c statistics were observed for FRS plus CRP (0.61, 95%CI 0.57 to 0.65) and for FRS plus sPLA2 (0.56, 95%CI 0.52 to 0.6). Net correct reclassification of cases and controls for each marker was assessed for people across the entire risk spectrum and again for people at intermediate risk only. The largest differences were observed for CRP, 12.0% net reclassification improvement in the entire risk spectrum and 28.4% net reclassification improvement in the intermediate risk group and for sPLA2, the net net reclassification improvement was 6.4% in the entire risk spectrum and 16.3% in the intermediate risk group. CONCLUSIONS: The discriminatory potential of inflammatory biomarkers was substantially different when analyzed across the entire risk spectrum compared to the subgroup of people at intermediate risk.
PubMed Accession Number :: 19587389.

Romaguera, D.; Norat, T.; Mouw, T.; May, A. M.; Bamia, C.; Slimani, N.; Travier, N.; Besson, H.; Luan, J.; Wareham, N.; Rinaldi, S.; Couto, E.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Cottet, V.; Palli, D.; Agnoli, C.; Panico, S.; Tumino, R.; Vineis, P.; Agudo, A.; Rodriguez, L.; Sanchez, M. J.; Amiano, P.; Barricarte, A.; Huerta, J. M.; Key, T. J.; Spencer, E. A.; Bueno-de-Mesquita, H. B.; Buchner, F. L.; Orfanos, P.; Naska, A.; Trichopoulou, A.; Rohrmann, S.; Kaaks, R.; Bergmann, M.; Boeing, H.; Johansson, I.; Hellstrom, V.; Manjer, J.; Wirfalt, E.; Uhre Jacobsen, M.; Overvad, K.; Tjonneland, A.; Halkjaer, J.; Lund, E.; Braaten, T.; Engeset, D.; Odysseos, A.; Riboli, E.; Peeters, P. H. (2009) Adherence to the Mediterranean Diet Is Associated with Lower Abdominal Adiposity in European Men and Women J Nutr, 139 (9),1728-37 [Journal Article] Online
Abstract: Given the lack of consistent evidence of the relationship between Mediterranean dietary patterns and body fat, we assessed the cross-sectional association between adherence to a modified Mediterranean diet, BMI, and waist circumference (WC). A total of 497,308 individuals (70.7% women) aged 25-70 y from 10 European countries participated in this study. Diet was assessed at baseline using detailed validated country-specific questionnaires, and anthropometrical measurements were collected using standardized procedures. The association between the degree of adherence to the modified-Mediterranean Diet Score (mMDS) (including high consumption of vegetables, legumes, fruits and nuts, cereals, fish and seafood, and unsaturated:saturated fatty acids ratio; moderate alcohol intake; and low consumption of meat and meat products and dairy products) and BMI (kgm(-2)) or WC (cm) was modeled through mixed-effects linear regression, controlling for potential confounders. Overall, the mMDS was not significantly associated with BMI. Higher adherence to the Mediterranean diet was significantly associated with lower WC, for a given BMI, in both men (-0.09; 95% CI -0.14 to -0.04) and women (-0.06; 95% CI -0.10 to -0.01). The association was stronger in men (-0.20; 95% CI -0.23 to -0.17) and women (-0.17; 95% CI -0.21 to -0.13) from Northern European countries. Despite the observed heterogeneity among regions, results of this study suggest that adherence to a modified Mediterranean diet, high in foods of vegetable origin and unsaturated fatty acids, is associated with lower abdominal adiposity measured by WC in European men and women.
PubMed Accession Number :: 19571036.

Reichert, F. F.; Menezes, A. M.; Kingdom Wells, J. C.; Ekelund, E.; Rodrigues, F. M.; Hallal, P. C. (2009) A methodological model for collecting high-quality data on physical activity in developing settings-the experience of the 1993 Pelotas (Brazil) Birth Cohort study J Phys Act Health, 6 (3),360-6 [Journal Article] Online
Abstract: BACKGROUND: Prospective studies on physical activity (PA), diet, and body composition in adolescents are lacking, particularly outside high-income countries. GOALS: To describe the methods used to assess these variables in the 1993 Pelotas (Brazil) Birth Cohort and to discuss the fieldwork challenges faced and alternatives to overcome them. METHODS: In 2006-07 a subsample of the 1993 Pelotas cohort was revisited. PA was estimated using questionnaires, a combined heart-rate and motion sensor (Acti-Heart), and the ActiGraph GT1M accelerometer. Diet was investigated by questionnaire. Total body water was determined by stable isotopes. Thirty individuals had their total energy expenditure assessed by doubly labeled water. All data were collected at participants' home. RESULTS: The logistics of the fieldwork and the difficulties in undertaking the study and alternatives to overcome them are presented. Preliminary analyses show that 511 individuals were traced (response rate = 90.0%). Compliance of both adolescents and their families for the motion sensors and body-composition measurements was excellent. CONCLUSIONS: The authors conclude that it is feasible to carry out high-quality studies on PA in developing countries. They hope the article will be useful to other researchers interested in carrying out similar studies.
PubMed Accession Number :: 19564666.

Lindgren, C. M.; Heid, I. M.; Randall, J. C.; Lamina, C.; Steinthorsdottir, V.; Qi, L.; Speliotes, E. K.; Thorleifsson, G.; Willer, C. J.; Herrera, B. M.; Jackson, A. U.; Lim, N.; Scheet, P.; Soranzo, N.; Amin, N.; Aulchenko, Y. S.; Chambers, J. C.; Drong, A.; Luan, J.; Lyon, H. N.; Rivadeneira, F.; Sanna, S.; Timpson, N. J.; Zillikens, M. C.; Zhao, J. H.; Almgren, P.; Bandinelli, S.; Bennett, A. J.; Bergman, R. N.; Bonnycastle, L. L.; Bumpstead, S. J.; Chanock, S. J.; Cherkas, L.; Chines, P.; Coin, L.; Cooper, C.; Crawford, G.; Doering, A.; Dominiczak, A.; Doney, A. S.; Ebrahim, S.; Elliott, P.; Erdos, M. R.; Estrada, K.; Ferrucci, L.; Fischer, G.; Forouhi, N. G.; Gieger, C.; Grallert, H.; Groves, C. J.; Grundy, S.; Guiducci, C.; Hadley, D.; Hamsten, A.; Havulinna, A. S.; Hofman, A.; Holle, R.; Holloway, J. W.; Illig, T.; Isomaa, B.; Jacobs, L. C.; Jameson, K.; Jousilahti, P.; Karpe, F.; Kuusisto, J.; Laitinen, J.; Lathrop, G. M.; Lawlor, D. A.; Mangino, M.; McArdle, W. L.; Meitinger, T.; Morken, M. A.; Morris, A. P.; Munroe, P.; Narisu, N.; Nordstrom, A.; Nordstrom, P.; Oostra, B. A.; Palmer, C. N.; Payne, F.; Peden, J. F.; Prokopenko, I.; Renstrom, F.; Ruokonen, A.; Salomaa, V.; Sandhu, M. S.; Scott, L. J.; Scuteri, A.; Silander, K.; Song, K.; Yuan, X.; Stringham, H. M.; Swift, A. J.; Tuomi, T.; Uda, M.; Vollenweider, P.; Waeber, G.; Wallace, C.; Walters, G. B.; Weedon, M. N.; Witteman, J. C.; Zhang, C.; Zhang, W.; Caulfield, M. J.; Collins, F. S.; Davey Smith, G.; Day, I. N.; Franks, P. W.; Hattersley, A. T.; Hu, F. B.; Jarvelin, M. R.; Kong, A.; Kooner, J. S.; Laakso, M.; Lakatta, E.; Mooser, V.; Morris, A. D.; Peltonen, L.; Samani, N. J.; Spector, T. D.; Strachan, D. P.; Tanaka, T.; Tuomilehto, J.; Uitterlinden, A. G.; van Duijn, C. M.; Wareham, N. J.; Hugh, Watkins; Waterworth, D. M.; Boehnke, M.; Deloukas, P.; Groop, L.; Hunter, D. J.; Thorsteinsdottir, U.; Schlessinger, D.; Wichmann, H. E.; Frayling, T. M.; Abecasis, G. R.; Hirschhorn, J. N.; Loos, R. J.; Stefansson, K.; Mohlke, K. L.; Barroso, I.; McCarthy, M. I. (2009) Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution PLoS Genet, 5 (6),e1000508 [Journal Article] Online
Abstract: To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
PubMed Accession Number :: 19557161.

Qi, Q.; Li, H.; Loos, R. J.; Liu, C.; Wu, Y.; Hu, F. B.; Wu, H.; Lu, L.; Yu, Z.; Lin, X. (2009) Common variants in KCNQ1 are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population Hum Mol Genet, 18 (18),3508-15 [Journal Article] Online
Abstract: Common variants in KCNQ1 have recently been reported to be associated with type 2 diabetes in East Asians. We aimed to examine whether these common variants (rs2074196, rs2237892, rs2237895 and rs2237897) were also associated with type 2 diabetes in a population-based cohort of 3,210 Chinese Hans and to explore the underlying mechanisms. The SNPs rs2237892, rs2237895 and rs2237897 were significantly associated with type 2 diabetes (OR: 1.33-1.36, P</=0.0009), IFG (OR: 1.16-1.19, P</=0.0193) and combined IFG/type 2 diabetes (OR: 1.23-1.24, P</=0.0004), and the corresponding population attributable risks of type 2 diabetes for the three SNPs were 32.5%, 18.8% and 35.8%, respectively. However, rs2074196 showed a weak but significant associations with IFG (OR 1.18[1.04-1.33], P=0.009) and combined IFG/type 2 diabetes (OR 1.17[1.05-1.30], P=0.0053), as well as a trend toward association with type 2 diabetes (OR 1.15[0.98-1.35], P=0.0882), suggesting a different pattern of association compared to the other three SNPs. The four SNPs were all significantly associated with HOMA-B (P</=0.042) while rs2237895 and rs22378897 also showed significant association with fasting glucose (P</=0.012). Notably, the associations with type 2 diabetes were markedly attenuated after adjusting for HOMA-B (OR(rs2237892) 1.33[1.05-1.68], P=0.018; OR(rs2237895) 1.24[1.00-1.54], P=0.0524; OR(rs2237897) 1.22[0.98-1.53], P=0.09). Moreover, GCCC haplotype showed similar associations with type 2 diabetes (OR 1.48[1.17-1.85], P=0.0008), IFG (OR 1.32[1.10-1.57], P=0.0023), combined IFG/type 2 diabetes (OR 1.37[1.17-1.61], P=8.7x10(-5)), and lower HOMA-B values (beta=-4.41+/-1.62, P=0.006). These results suggest that KCNQ1 is a major type 2 diabetes gene in the Chinese Hans and it may confer type 2 diabetes risk by impaired beta-cell function.
PubMed Accession Number :: 19556355.

Vimaleswaran, K. S.; Li, S.; Zhao, J. H.; Luan, J.; Bingham, S. A.; Khaw, K. T.; Ekelund, U.; Wareham, N. J.; Loos, R. J. (2009) Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene Am J Clin Nutr, 90 ,425-8 [Journal Article] Online
Abstract: BACKGROUND: Intronic variation in the FTO (fat mass and obesity-associated) gene has been unequivocally associated with increased body mass index (BMI; in kg/m(2)) and the risk of obesity in populations of different ethnicity. OBJECTIVE: We examined whether this robust genetic predisposition to obesity can be attenuated by being more physically active. DESIGN: The FTO variant rs1121980 was genotyped in 20,374 participants (39-79 y of age) from the European Prospective Investigation into Cancer and Nutrition-Norfolk Study, an ethnically homogeneous population-based cohort. Physical activity (PA) was assessed with a validated self-reported questionnaire. The interaction between rs1121980 and PA on BMI and waist circumference (WC) was examined by including the interaction term in mixed-effect models. RESULTS: We confirmed that the risk (T) allele of rs1121980 was significantly associated with BMI (0.31-unit increase per allele; P < 0.001) and WC (0.77-cm increase per allele; P < 0.001). The PA level attenuated the effect of rs1121980 on BMI and WC; ie, whereas in active individuals the risk allele increased BMI by 0.25 per allele, the increase in BMI was significantly (P for interaction = 0.004) more pronounced (76%) in inactive individuals (0.44 per risk allele). We observed similar effects for WC (P for interaction = 0.02): the risk allele increased WC by 1.04 cm per allele in inactive individuals but by only 0.64 cm in active individuals. CONCLUSIONS: Our results showed that PA attenuates the effect of the FTO rs1121980 genotype on BMI and WC. This observation has important public health implications because we showed that a genetic susceptibility to obesity induced by FTO variation can be overcome, at least in part, by adopting a physically active lifestyle.
PubMed Accession Number :: 19553294.

Souren, N. Y.; Paulussen, A. D.; Steyls, A.; Loos, R. J.; Brandao, R. D.; Gielen, M.; Smeets, H. J.; Beunen, G.; Fagard, R.; Derom, C.; Vlietinck, R.; Geraedts, J. P.; Zeegers, M. P. (2009) Parent-of-origin specific linkage and association of the IGF2 gene region with birth weight and adult metabolic risk factors Int J Obes (Lond), 33 ,962-970 [Journal Article] Online
Abstract: Objective:The maternally imprinted insulin-like growth factor 2 (IGF2) gene is an important fetal growth factor and is also suggested to have postnatal metabolic effects. In this study, we examined whether common polymorphisms in IGF2 (6815_6819delAGGGC, 1156T>C and 820G>A (ApaI)) and a microsatellite marker in the close vicinity of IGF2 were linked to or associated with birth weight and adult metabolic risk factors.Design and participants:Polymorphisms were genotyped in 199 monozygotic complete twin pairs, 109 dizygotic complete twin pairs, 15 single twins, 231 mothers and 228 fathers recruited from the East Flanders Prospective Twin Survey. Conventional and parent-of-origin specific linkage and association analyses were carried out with birth weight, adult body height and parameters quantifying obesity, insulin sensitivity and dyslipidaemia measured at adult age (mean age 25 years).Results:In the parent-of-origin specific association analysis, in which only the paternally inherited allele was incorporated, the 1156T>C SNP (single nucleotide polymorphism) showed significant association with IGF-binding protein 1 (IGFBP1) levels (T and C (mean (95% CI)): 13.2 (12.1-14.3) and 16.2 (14.6-18.0) ng ml(-1), P=0.002). No linkage was observed in either the conventional or in the parent-of-origin specific linkage analysis.Conclusion:This study suggests that paternally inherited alleles of a common polymorphism in the IGF2 gene affect IGFBP1 levels.International Journal of Obesity advance online publication, 23 June 2009; doi:10.1038/ijo.2009.126.
PubMed Accession Number :: 19546867.

Price, H. C.; Dudley, C.; Barrow, B.; Kennedy, I.; Griffin, S. J.; Holman, R. R. (2009) Use of focus groups to develop methods to communicate cardiovascular disease risk and potential for risk reduction to people with type 2 diabetes Fam Pract, 26 (5),351-8 [Journal Article] Online
Abstract: BACKGROUND: People need to perceive a risk in order to build an intention-to-change behaviour yet our ability to interpret information about risk is highly variable. OBJECTIVES: We aimed to use a user-centred design process to develop an animated interface for the UK Prospective Diabetes Study (UKPDS) Risk Engine to illustrate cardiovascular disease (CVD) risk and the potential to reduce this risk. In addition, we sought to use the same approach to develop a brief lifestyle advice intervention. METHODS: Three focus groups were held. Participants were provided with examples of materials used to communicate CVD risk and a leaflet containing a draft brief lifestyle advice intervention and considered their potential to increase motivation-to-change behaviours including diet, physical activity, and smoking in order to reduce CVD risk. Discussions were tape-recorded, transcribed and coded and recurring themes sought. RESULTS: Sixty-two percent of participants were male, mean age was 66 years (range = 47-76 years) and median age at leaving full-time education was 18 years (range = 15-40 years). Sixteen had type 2 diabetes and none had a prior history of CVD. Recurring themes from focus group discussions included the following: being less numerate is common, CVD risk reduction is important and a clear visual representation aids comprehension. CONCLUSION: A simple animated interface of the UKPDS Risk Engine to illustrate CVD risk and the potential for reducing this risk has been developed for use as a motivational tool, along with a brief lifestyle advice intervention. Future work will investigate whether use of this interactive version of the UKPDS Risk Engine and brief lifestyle advice is associated with increased behavioural intentions and changes in health behaviours designed to reduce CVD risk.
PubMed Accession Number :: 19546119.

Finucane, F. M.; Horton, J.; Purslow, L. R.; Savage, D. B.; Brage, S.; Besson, H.; Horton, K.; De Lucia Rolfe, E.; Sleigh, A.; Sharp, S. J.; Martin, H.; Ahie Sayer, A.; Cooper, C.; Ekelund, U.; Griffin, S. J.; Wareham, N. J. (2009) Randomised controlled trial of the efficacy of aerobic exercise in reducing metabolic risk in healthy older people: The Hertfordshire Physical Activity Trial BMC Endocr Disord, 9 (1),15 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: While there are compelling observational data confirming that individuals who exercise are healthier, the efficacy of aerobic exercise interventions to reduce metabolic risk and improve insulin sensitivity in older people has not been fully elucidated. Furthermore, while low birth weight has been shown to predict adverse health outcomes later in life, its influence on the response to aerobic exercise is unknown. Our primary objective is to assess the efficacy of a fully supervised twelve week aerobic exercise intervention in reducing clustered metabolic risk in healthy older adults. A secondary objective is to determine the influence of low birth weight on the response to exercise in this group. Methods/ Design We aim to recruit 100 participants born between 1931-1939, from the Hertfordshire Cohort Study and randomly assign them to no intervention or to 36 fully supervised one hour sessions on a cycle ergometer, over twelve weeks. Each participant will undergo detailed anthropometric and metabolic assessment pre- and post-intervention, including muscle biopsy, magnetic resonance imaging and spectroscopy, objective measurement of physical activity and sub-maximal fitness testing. DISCUSSION: Given the extensive phenotypic characterization, this study will provide valuable insights into the mechanisms underlying the beneficial effects of aerobic exercise as well as the efficacy, feasibility and safety of such interventions in this age group.
PubMed Accession Number :: 19545359.

Acerini, C. L.; Miles, H. L.; Dunger, D. B.; Ong, K. K.; Hughes, I. A. (2009) The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort Arch Dis Child, 94 ,868-872 [Journal Article] Online
Abstract: Introduction: Recent studies in other European countries suggest that the prevalence of congenital cryptorchidism continues to increase. We aimed to explore the prevalence and prognosis of congenital cryptorchidism in a UK centre. METHODS: Between October 2001 to July 2008, 784 male infants were born in the prospective Cambridge Baby Growth Study. 742 infants were examined by trained research nurses at birth; testicular position was assessed using standard techniques. Follow-up assessments were completed at ages 3, 12, 18 and 24 months in N=615, 462, 393, and 326 infants respectively. RESULTS: The prevalence of cryptorchidism at birth was 5.9% (95% CI: 4.4-7.9%). Congenital cryptorchidism was associated with earlier gestational age (p<0.0001), lower birth weight (p<0.0001), birth length (p<0.0001), and shorter penile length at birth (p<0.0001) compared to other males, but normal size after age 3 months. The prevalence of cryptorchidism declined to 2.4% at 3 months, but unexpectedly rose again to 6.7% at 12 months due to new cases. The cumulative incidence of "acquired cryptorchidism" by age 24 months was 7.0% and these cases had shorter penile length during infancy than other infants (p=0.003). CONCLUSIONS: The prevalence of congenital cryptorchidism was higher than earlier estimates in UK populations. Furthermore our study for the first time describes acquired cryptorchidism or "ascending testis" as a common entity in male infants, which is possibly associated with reduced early postnatal androgen activity.
PubMed Accession Number :: 19542061.

Ahmed, M. L.; Ong, K. K.; Dunger, D. B. (2009) Childhood obesity and the timing of puberty Trends Endocrinol Metab, 20 (5),237-42 [Journal Article] Online
Abstract: The potential relationship between childhood obesity and earlier puberty onset has major public health implications. Earlier menarche in girls is associated with increased risk of adult obesity, type 2 diabetes and breast cancer. Current methods for assessing puberty are unreliable, with a lack of consensus regarding the impact of childhood obesity on breast development and/or age of menarche. Effects of obesity on early puberty in boys are more contentious, necessitating development of robust biomarkers. The possibility of the obesity epidemic lowering the age of puberty onset fuels concerns over the growing mismatch in age of sexual and social maturity. Here, we describe the biological basis linking childhood obesity to early puberty and consider evidence for a trend towards its earlier onset.
PubMed Accession Number :: 19541497.

Kilpelainen, T. O.; Bingham, S. A.; Khaw, K. T.; Wareham, N. J.; Loos, R. J. (2009) Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk Study Hum Mol Genet, 18 (18),3496-501 [Journal Article] Online
Abstract: Recently, the rs6232 (N221D) and rs6235 (S690T) SNPs in the PCSK1 gene were associated with obesity in a meta-analysis comprising more than 13,000 individuals of European ancestry. Each additional minor allele of rs6232 or rs6235 was associated with a 1.34- or 1.22-fold increase in the risk of obesity, respectively. So far, only one relatively small study has aimed to replicate these findings, but could not confirm the association of the rs6235 SNP, and did not study the rs6232 variant. In the present study, we examined the associations of the rs6232 and rs6235 SNPs with obesity in a population-based cohort consisting of 20,249 individuals of European descent from Norfolk, UK. Logistic regression and generalized linear models were used to test the associations of the risk alleles with obesity and related quantitative traits, respectively. Neither of the SNPs was significantly associated with obesity, BMI, or waist circumference under the additive genetic model (P >0.05). However, we observed an interaction between rs6232 and age on the level of BMI (P = 0.010) and risk of obesity (P = 0.020). The rs6232 SNP was associated with BMI (P = 0.021) and obesity (P = 0.022) in the younger individuals (< median age (59 years)), but not among the older age group (P = 0.81 and P = 0.68 for BMI and obesity, respectively). In conclusion, our data suggest that the PCSK1 rs6232 and rs6235 SNPs are not major contributors to common obesity in the general population. However, the effect of rs6232 may be age-dependent.
PubMed Accession Number :: 19528091.

Harris, T. J.; Owen, C. G.; Victor, C. R.; Adams, R.; Ekelund, U.; Cook, D. G. (2009) A Comparison of Questionnaire, Accelerometer, and Pedometer: MeasuresinOlder People Med Sci Sports Exerc, 41 (7),1392-1402 [Journal Article] Online
Abstract: PURPOSE:: To compare (i) the convergent validity of the self-report Zutphen Physical Activity Questionnaire with the 7-d objective physical activity (PA) measurement by accelerometers and pedometers and (ii) the construct validity of these measures by examining their associations with physical health and psychological and anthropometric variables. METHODS:: Five hundred and sixty community-dwelling people aged >/=65 yr were invited from a UK primary care practice and 238 (43%) participated (mean age = 74, 53% male). PA was assessed subjectively by the Zutphen questionnaire (modified to include housework questions) and objectively by the 7-d accelerometer monitoring: a random half also had a pedometer. A questionnaire assessed health, disability, and psychological factors, and anthropometric assessment was performed. RESULTS:: Mean daily PA levels were as follows: Zutphen = 9.1 kcal.kg.d (SD = 6.6 kcal.kg.d); accelerometer activity count = 226,648 (SD = 121,966); accelerometer step count = 6495 (SD = 3212); and pedometer step count = 6712 (SD = 3526). Zutphen score was moderately correlated with accelerometer activity count (R = 0.34, P < 0.001) and pedometer step count (R = 0.36, P < 0.001). Pedometer step count was highly correlated with accelerometer activity count (R = 0.82, P< 0.001) and accelerometer step count (R = 0.86, P < 0.001). Objective PA measures showed strong associations with health and anthropometric and psychological variables. Zutphen score was not significantly related to most health or anthropometric measures but was associated with psychological variables and provided information about activity type. CONCLUSIONS:: Convergent validity was strong between accelerometers and pedometers but weaker between these and self-report Zutphen. Pedometers may be preferred to accelerometers for simple studies due to their lower cost. Objective measures had better construct validity, being more strongly associated with established PA determinants, and thus offered better value to researchers than the questionnaire, but the latter provided useful detail on activity type, so a combined approach to PA assessment may be preferable.
PubMed Accession Number :: 19516162.

Nathan, D (2009) International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes Diabetes Care, 32 (7),1327-34 [Journal Article] Online
PubMed Accession Number :: 19502545.

Steele, R. M.; Mummery, W. K.; Dwyer, T. (2009) A Comparison of Face-to-Face or Internet-Delivered Physical Activity Intervention on Targeted Determinants Health Educ Behav, 36 ,1051-1064 [Journal Article] Online
Abstract: This article describes the equivalency testing results of a 12-week behavior change program on targeted determinates of physical activity (PA) and self-reported health status. Participants (n = 192) were randomized to face-to-face, combined Internet and face-to-face, and Internet-only groups. Equivalency testing was used to examine differences and statistical equivalency across groups for all outcome measures (social support, self-efficacy, perceived health status, and motivational readiness for PA). Participants were assessed at baseline, postintervention, and 2 and 5 months postintervention. Motivational readiness for PA increased across all groups. The face-to-face and combined groups showed changes in social support; however, they were not statistically different and were equivalent. There were no changes in self-efficacy or physical health status. Overall face-to-face and the Internet delivery modes show similar results. If Internet-based programs can be shown to be as effective as face-to-face, they may in turn be a more efficient and cost-effective delivery method.
PubMed Accession Number :: 19502534.

Finucane, F. M. (2009) Obesity in Irish youth: epidemiology and implications Ir J Med Sci, 178 (3),249-55 [Journal Article] Online
Abstract: The worldwide epidemic of type 2 diabetes has been paralleled by a marked increase in the prevalence of obesity, particularly in younger people. This will contribute significantly to the future burden of cardiovascular disease. Complex environmental and genetic factors contribute to obesity and related metabolic disorders. These disorders are now manifesting in younger age groups, including children. Recent studies have described the clinical and metabolic characteristics of these children. A solution to the obesity crisis will need to be co-ordinated, multi-faceted and well resourced.
PubMed Accession Number :: 19495834.

Waden, J.; Forsblom, C.; Thorn, L. M.; Saraheimo, M.; Rosengard-Barlund, M.; Heikkila, O.; Hietala, K.; Ong, K.; Wareham, N.; Groop, P. H. (2009) Adult stature and diabetic complications in patients with type 1 diabetes Diabetes, 58 ,1914-1920 [Journal Article] Online
Abstract: Objective. Short adult stature has previously been associated with cardiovascular disease but its relationship with the microvascular complications of diabetes is uncertain. Therefore, we evaluated the association between adult stature and prevalence and incidence of diabetic microvascular complications. Research design and methods. This cross-sectional and longitudinal study comprises 3968 adult patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and 1246 adult patients from the Diabetes Control and Complications Trial (DCCT). In FinnDiane, diabetic nephropathy was defined as urinary albumin excretion >/=300 mg/24h, dialysis, or renal transplantation. Retinopathy was divided into background and proliferative (laser-treated) retinopathy. In the DCCT, original nephropathy (class 1-6) and retinopathy (ETDRS) classifications were used. Results. In FinnDiane, patients in the lowest quartile of adult height had increased risks of prevalent diabetic nephropathy (odds ratio 1.71, 95% confidence interval 1.44-2.02) and prevalent laser-treated retinopathy (1.66, 1.43-1.93) compared to other patients. Similarly, in the DCCT, patients in the lowest quartile of adult height had increased risks of incident diabetic nephropathy class 4-6 (hazard ratio 2.70, 95% confidence interval 1.59-4.59), and incident proliferative retinopathy (2.06, 1.15-3.71). In FinnDiane, the associations were largely explained by childhood exposure to diabetes. However, in the DCCT, where a greater proportion of patients had diabetes onset >18 years, the association with nephropathy was independent of childhood diabetes exposure. Conclusions. Short adult stature is associated with microvascular complications in patients with type 1 diabetes. These findings are compatible with either childhood diabetes exposure or 'common soil' or both as potential explanations.
PubMed Accession Number :: 19491208.

Ong, K. K.; Langkamp, M.; Ranke, M. B.; Whitehead, K.; Hughes, I. A.; Acerini, C. L.; Dunger, D. B. (2009) Insulin-like growth factor I concentrations in infancy predict differential gains in body length and adiposity: the Cambridge Baby Growth Study Am J Clin Nutr, 90 ,156-161 [Journal Article] Online
Abstract: BACKGROUND: Formula milk-fed infants show faster rates of growth and weight gain than do breastfed infants, and they have higher concentrations of insulin-like growth factor I (IGF-I). OBJECTIVE: Our objective was to determine the influence of IGF-I concentrations on gains in weight, length, body mass index (BMI), and adiposity in the first year of life. DESIGN: IGF-I concentrations were measured in 953 capillary blood samples from 675 unselected infants at ages 3 and 12 mo. These infants were born between 2002 and 2008 in one center and were participating in a prospective longitudinal birth cohort. Weight, length, and 4 skinfold thicknesses as an indicator of adiposity were measured at ages 0, 3, and 12 mo. Analyses were adjusted for age and sex. RESULTS: Infants who were formula milk-fed had higher IGF-I concentrations at 3 mo, and they showed greater gains in weight, length, BMI, and adiposity between age 3 and 12 mo. IGF-I concentrations at 3 mo were unrelated to subsequent overall weight gain (P = 0.5). However, higher IGF-I concentrations at age 3 mo predicted greater subsequent gains in body length (P < 0.001 and P = 0.007 in formula milk-fed and breastfed infants, respectively) and slower gains in BMI (P < 0.001 and P = 0.004, respectively) and adiposity (P = 0.03 and P = 0.003, respectively). CONCLUSIONS: Our findings support a key role for IGF-I in the partitioning of overall infant weight gain into statural growth compared with adiposity. In formula milk-fed infants, higher IGF-I concentrations may lead to faster gains in length; however, other mechanisms likely explain their faster gains in weight, BMI, and adiposity.
PubMed Accession Number :: 19474142.

Helmerhorst, H. J.; Wijndaele, K.; Brage, S.; Wareham, N. J.; Ekelund, U. (2009) Objectively measured sedentary time may predict insulin resistance, independent of moderate and vigorous physical activity Diabetes, 58 ,1776-1779 [Journal Article] Online
Abstract: Objective: To examine the prospective association between objectively measured time spent sedentary and insulin resistance, and whether this association is independent of moderate and vigorous physical activity (MVPA) and other relevant confounders. Research Design and Methods: Population-based study (MRC Ely study) in 376 middle-aged adults (166 men, 210 women) over 5.6 years of follow-up. Physical activity and sedentary time were measured objectively by individually calibrated minute-by-minute heart rate (HR) monitoring at both baseline and follow-up. Sedentary time was calculated as the HR observations (minutes) below an individually predetermined threshold (flex HR), and expressed as a percentage of total monitored time during waking hours over 4 days. The percentage of time spent above 1.75 x resting HR represented MVPA. Fasting plasma insulin was used as a surrogate measure of insulin resistance. Results: Time spent sedentary at baseline was significantly and positively associated with log fasting insulin at follow-up (ss = 0.003, 95% CI: 0.0006 to 0.006, P = 0.015), independent of baseline age, sex, fat mass, fasting insulin, smoking status and follow-up time. After further adjustment for MVPA, this association was somewhat strengthened (ss = 0.004, 95% CI: 0.0009 to 0.006, P = 0.009). Conclusions: Time spent sedentary predicts higher levels of fasting insulin, independent of the amount of time spent at moderate and vigorous intensity activity levels. This highlights the importance of reducing sedentary time in order to improve metabolic health, possibly in addition to the benefits associated with a physically active lifestyle.
PubMed Accession Number :: 19470610.

Dash, S.; Sano, H.; Rochford, J. J.; Semple, R. K.; Yeo, G.; Hyden, C. S.; Soos, M. A.; Clark, J.; Rodin, A.; Langenberg, C.; Druet, C.; Fawcett, K. A.; Tung, Y. C.; Wareham, N. J.; Barroso, I.; Lienhard, G. E.; O'Rahilly, S.; Savage, D. B. (2009) A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia Proc Natl Acad Sci U S A, 106 (23),9350-5 [Journal Article] Online
Abstract: Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and myotubes. To determine whether loss-of-function mutations in TBC1D4 might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulin-resistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in TBC1D4. After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, we further characterized the biological effects of the truncated protein in 3T3L1 adipocytes. Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (P = 0.053) and significantly reduced insulin-stimulated GLUT4 cell membrane translocation (P < 0.05). When coexpressed with wild-type TBC1D4, the truncated protein dimerized with full-length TBC1D4, suggesting that the heterozygous truncated variant might interfere with its wild-type counterpart in a dominant negative fashion. Two overweight family members with the mutation also manifested normal fasting glucose and insulin levels but disproportionately elevated insulin levels following an oral glucose challenge. This family provides unique genetic evidence of TBC1D4 involvement in human insulin action.
PubMed Accession Number :: 19470471.

Ridgway, C. L.; Ong, K. K.; Tammelin, T.; Sharp, S. J.; Ekelund, U.; Jarvelin, M. R. (2009) Birth size, infant weight gain, and motor development influence adult physical performance Med Sci Sports Exerc, 41 (6),1212-21 [Journal Article] Online
Abstract: PURPOSE: Adult physical performance is recognized as a marker of both current physical capacity and future health. The aim of the study was to examine the independent influences of birth weight, infant weight gain, and infant motor development on a variety of adult physical performance outcomes, in terms of muscular strength, muscular endurance, and aerobic fitness. METHODS: The study population consisted of 4304 individuals from the Northern Finland Birth Cohort 1966 (NFBC 1966) with anthropometry measured at birth and at 1 yr. Infant motor development at age 1 yr was assessed by parentally reported age at first walking supported and standing unaided. At follow-up, aged 31 yr, muscle strength was measured using a handgrip dynamometer, muscle endurance was measured using a timed trunk extension test, and aerobic fitness was estimated from heart rate immediately after a standardized step test. RESULTS: Birth weight was positively associated with muscle strength and aerobic fitness at age 31 yr, and these associations were independent of adult body size (P < 0.001). Greater infant weight gain between 0 and 1 yr was associated with lower muscle endurance (P = 0.004) and poorer aerobic fitness (P = 0.002); these associations seemed to be mediated by adult body size. Independent of infant birth weight and adult body size (height and weight), earlier infant motor development was associated with greater adult muscle strength (P < or = 0.001), muscle endurance (P < 0.001), and aerobic fitness (P < 0.001). CONCLUSIONS: Higher birth weight, lower infant weight gain, and earlier infant motor development independently predict higher levels of adult physical performance for muscle strength, muscle endurance, and aerobic fitness at age 31 yr.
PubMed Accession Number :: 19461546.

Buijsse, B.; Feskens, E. J.; Schulze, M. B.; Forouhi, N. G.; Wareham, N. J.; Sharp, S.; Palli, D.; Tognon, G.; Halkjaer, J.; Tjonneland, A.; Jakobsen, M. U.; Overvad, K.; van der, A. Dl; Du, H.; Sorensen, T. I.; Boeing, H. (2009) Fruit and vegetable intakes and subsequent changes in body weight in European populations: results from the project on Diet, Obesity, and Genes (DiOGenes) Am J Clin Nutr, 90 (1),202-9 [Journal Article] Online
Abstract: BACKGROUND: High fruit and vegetable intakes may limit weight gain, particularly in susceptible persons, such as those who stop smoking. OBJECTIVE: The objective was to assess the association of fruit and vegetable intake with subsequent weight change in a large-scale prospective study. DESIGN: The data used were from 89,432 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). The association between fruit and vegetable intake and weight change after a mean follow-up of 6.5 y was assessed by linear regression. Polytomous logistic regression was used to evaluate whether fruit and vegetable intake relates to weight gain, weight loss, or both. RESULTS: Per 100-g intake of fruit and vegetables, weight change was - 14 g/y (95% CI: - 19, - 9 g/y). In those who stopped smoking during follow-up, this value was - 37 g/y (95% CI: - 58, - 15 g/y; P for interaction < 0.0001). When weight gain and loss were analyzed separately per 100-g intake of fruit and vegetables in a combined model, the odds ratios (95% CIs) were 0.97 (0.95, 0.98) for weight gain >/=0.5 and <1 kg/y, 0.94 (0.92, 0.96) for weight gain >/=1 kg/y, and 0.97 (0.95, 0.99) for weight loss >/=0.5 kg/y. In those who stopped smoking during follow-up, the odds ratios (95% CIs) were 0.93 (0.88, 0.99), 0.87 (0.81, 0.92), and 0.97 (0.88, 1.07), respectively (P for interaction </= 0.0001). CONCLUSIONS: Fruit and vegetable intake relates significantly, albeit weakly inversely, to weight change. For persons who stop smoking, high fruit and vegetable intakes may be recommended to reduce the risk of weight gain.
PubMed Accession Number :: 19458016.

Langenberg, C.; Pascoe, L.; Mari, A.; Tura, A.; Laakso, M.; Frayling, T. M.; Barroso, I.; Loos, R. J.; Wareham, N. J.; Walker, M. (2009) Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response Diabetologia, 52 (8),1537-1542 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: We investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity. METHODS: We studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre. RESULTS: The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d'Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 x 10(-5)), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (-0.19 [-0.28, -0.10], p = 1.7 x 10(-5)), as well as with decreased beta cell glucose sensitivity (-0.11 [-0.20, -0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all). CONCLUSIONS/INTERPRETATION: Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.
PubMed Accession Number :: 19455304.

Wijndaele, K.; Lynch, B. M.; Owen, N.; Dunstan, D. W.; Sharp, S.; Aitken, J. F. (2009) Television viewing time and weight gain in colorectal cancer survivors: a prospective population-based study Cancer Causes Control, 20 ,1355-1362 [Journal Article] Online
Abstract: OBJECTIVE: To investigate the prospective relationships between television viewing time and weight gain in the 3 years following colorectal cancer diagnosis for 1,867 colorectal cancer survivors (body mass index (BMI) >/= 18.5 kg/m(2)). METHODS: BMI, television viewing time, physical activity, and socio-demographic and clinical covariates were assessed at baseline (5 months), 24 months and 36 months post-diagnosis. Multiple linear regression was used to study independent associations between baseline television viewing time and BMI at 24 and 36 months post-diagnosis. RESULTS: At both follow-up time points, there was a significant increase in mean BMI for participants reporting >/=5 h/day of television viewing compared to those watching <3 h/day at baseline (24 months: 0.72 kg/m(2) (0.31, 1.12), p < 0.001; 36 months: 0.61 kg/m(2) (0.14, 1.07), p = 0.01), independent of baseline BMI, gender, age, education, marital status, smoking, cancer site, cancer disease stage, treatment mode and co-morbidities. Additional adjustment for baseline physical activity did not change results. CONCLUSIONS: These findings suggest that a greater emphasis on decreasing television viewing time could help reduce weight gain among colorectal cancer survivors. This, in turn, could contribute to a risk reduction for co-morbid conditions such as type 2 diabetes and cardiovascular disease.
PubMed Accession Number :: 19449106.

Ong, K. K.; Elks, C. E.; Li, S.; Zhao, J. H.; Luan, J.; Andersen, L. B.; Bingham, S. A.; Brage, S.; Smith, G. D.; Ekelund, U.; Gillson, C. J.; Glaser, B.; Golding, J.; Hardy, R.; Khaw, K. T.; Kuh, D.; Luben, R.; Marcus, M.; McGeehin, M. A.; Ness, A. R.; Northstone, K.; Ring, S. M.; Rubin, C.; Sims, M. A.; Song, K.; Strachan, D. P.; Vollenweider, P.; Waeber, G.; Waterworth, D. M.; Wong, A.; Deloukas, P.; Barroso, I.; Mooser, V.; Loos, R. J.; Wareham, N. J. (2009) Genetic variation in LIN28B is associated with the timing of puberty Nat Genet, 41 ,729-733 [Journal Article] Online
Abstract: The timing of puberty is highly variable. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 x 10(-8)). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 x 10(-10); combined P = 3.6 x 10(-16)). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 x 10(-7); N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing, as the first genetic determinant regulating the timing of human pubertal growth and development.
PubMed Accession Number :: 19448623.

Echouffo-Tcheugui, J. B.; Simmons, R. K.; Williams, K. M.; Barling, R. S.; Prevost, A. T.; Kinmonth, A. L.; Wareham, N. J.; Griffin, S. J. (2009) The ADDITION-Cambridge trial protocol - a cluster randomised controlled trial of screening for type 2 diabetes and intensive treatment for screen-detected patients BMC Public Health, 9 ,136 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: The increasing prevalence of type 2 diabetes poses a major public health challenge. Population-based screening and early treatment for type 2 diabetes could reduce this growing burden. However, the benefits of such a strategy remain uncertain. METHODS: The ADDITION-Cambridge study aims to evaluate the effectiveness and cost-effectiveness of (i) a stepwise screening strategy for type 2 diabetes; and (ii) intensive multifactorial treatment for people with screen-detected diabetes in primary care. 63 practices in the East Anglia region participated. Three undertook the pilot study, 33 were allocated to three groups: no screening (control), screening followed by intensive treatment (IT) and screening plus routine care (RC) in an unbalanced (1:3:3) randomisation. The remaining 27 practices were randomly allocated to IT and RC. A risk score incorporating routine practice data was used to identify people aged 40-69 years at high-risk of undiagnosed diabetes. In the screening practices, high-risk individuals were invited to take part in a stepwise screening programme. In the IT group, diabetes treatment is optimised through guidelines, target-led multifactorial treatment, audit, feedback, and academic detailing for practice teams, alongside provision of educational materials for newly diagnosed participants. Primary endpoints are modelled cardiovascular risk at one year, and cardiovascular mortality and morbidity at five years after diagnosis of diabetes. Secondary endpoints include all-cause mortality, development of renal and visual impairment, peripheral neuropathy, health service costs, self-reported quality of life, functional status and health utility. Impact of the screening programme at the population level is also assessed through measures of mortality, cardiovascular morbidity, health status and health service use among high-risk individuals. DISCUSSION: ADDITION-Cambridge is conducted in a defined high-risk group accessible through primary care. It addresses the feasibility of population-based screening for diabetes, as well as the benefits and costs of screening and intensive multifactorial treatment early in the disease trajectory. The intensive treatment algorithm is based on evidence from studies including individuals with clinically diagnosed diabetes and the education materials are informed by psychological theory. ADDITION-Cambridge will provide timely evidence concerning the benefits of early intensive treatment and will inform policy decisions concerning screening for type 2 diabetes. Trial registration: Current Controlled trials ISRCTN86769081.
PubMed Accession Number :: 19435491.

Petry, C. J.; Rayco-Solon, P.; Fulford, A. J.; Stead, J. D.; Wingate, D. L.; Ong, K. K.; Sirugo, G.; Prentice, A. M.; Dunger, D. B. (2009) Common polymorphic variation in the genetically diverse African insulin gene and its association with size at birth Hum Genet, 126 ,375-384 [Journal Article] Online
Abstract: The insulin variable number of tandem repeats (INS VNTR) has been variably associated with size at birth in non-African populations. Small size at birth is a major determinant of neonatal mortality, so the INS VNTR may influence survival. We tested the hypothesis, therefore, that genetic variation around the INS VNTR in a rural Gambian population, who experience seasonal variation in nutrition and subsequently birth weight, may be associated with foetal and early growth. Six polymorphisms flanking the INS VNTR were genotyped in over 2,500 people. Significant associations were detected between the maternally inherited SNP 27 (rs689) allele and birth length [effect size 17.5 (5.2-29.8) mm; P = 0.004; n = 361]. Significant associations were also found between the maternally inherited African-specific SNP 28 (rs5506) allele and post-natal weight gain [effect size 0.19 (0.05-0.32) z score points/year; P = 0.005; n = 728). These results suggest that in the Gambian population studied there are associations between polymorphic variation in the genetically diverse INS gene and foetal and early growth characteristics, which contribute to overall polygenic associations with these traits.
PubMed Accession Number :: 19434426.

Newton-Cheh, C.; Johnson, T.; Gateva, V.; Tobin, M. D.; Bochud, M.; Coin, L.; Najjar, S. S.; Zhao, J. H.; Heath, S. C.; Eyheramendy, S.; Papadakis, K.; Voight, B. F.; Scott, L. J.; Zhang, F.; Farrall, M.; Tanaka, T.; Wallace, C.; Chambers, J. C.; Khaw, K. T.; Nilsson, P.; van der Harst, P.; Polidoro, S.; Grobbee, D. E.; Onland-Moret, N. C.; Bots, M. L.; Wain, L. V.; Elliott, K. S.; Teumer, A.; Luan, J.; Lucas, G.; Kuusisto, J.; Burton, P. R.; Hadley, D.; McArdle, W. L.; Brown, M.; Dominiczak, A.; Newhouse, S. J.; Samani, N. J.; Webster, J.; Zeggini, E.; Beckmann, J. S.; Bergmann, S.; Lim, N.; Song, K.; Vollenweider, P.; Waeber, G.; Waterworth, D. M.; Yuan, X.; Groop, L.; Orho-Melander, M.; Allione, A.; Di Gregorio, A.; Guarrera, S.; Panico, S.; Ricceri, F.; Romanazzi, V.; Sacerdote, C.; Vineis, P.; Barroso, I.; Sandhu, M. S.; Luben, R. N.; Crawford, G. J.; Jousilahti, P.; Perola, M.; Boehnke, M.; Bonnycastle, L. L.; Collins, F. S.; Jackson, A. U.; Mohlke, K. L.; Stringham, H. M.; Valle, T. T.; Willer, C. J.; Bergman, R. N.; Morken, M. A.; Doring, A.; Gieger, C.; Illig, T.; Meitinger, T.; Org, E.; Pfeufer, A.; Wichmann, H. E.; Kathiresan, S.; Marrugat, J.; O'Donnell, C. J.; Schwartz, S. M.; Siscovick, D. S.; Subirana, I.; Freimer, N. B.; Hartikainen, A. L.; McCarthy, M. I.; O'Reilly, P. F.; Peltonen, L.; Pouta, A.; de Jong, P. E.; Snieder, H.; van Gilst, W. H.; Clarke, R.; Goel, A.; Hamsten, A.; Peden, J. F.; Seedorf, U.; Syvanen, A. C.; Tognoni, G.; Lakatta, E. G.; Sanna, S.; Scheet, P.; Schlessinger, D.; Scuteri, A.; Dorr, M.; Ernst, F.; Felix, S. B.; Homuth, G.; Lorbeer, R.; Reffelmann, T.; Rettig, R.; Volker, U.; Galan, P.; Gut, I. G.; Hercberg, S.; Lathrop, G. M.; Zelenika, D.; Deloukas, P.; Soranzo, N.; Williams, F. M.; Zhai, G.; Salomaa, V.; Laakso, M.; Elosua, R.; Forouhi, N. G.; Volzke, H.; Uiterwaal, C. S.; van der Schouw, Y. T.; Numans, M. E.; Matullo, G.; Navis, G.; Berglund, G.; Bingham, S. A.; Kooner, J. S.; Connell, J. M.; Bandinelli, S.; Ferrucci, L.; Watkins, H.; Spector, T. D.; Tuomilehto, J.; Altshuler, D.; Strachan, D. P.; Laan, M.; Meneton, P.; Wareham, N. J.; Uda, M.; Jarvelin, M. R.; Mooser, V.; Melander, O.; Loos, R. J.; Elliott, P.; Abecasis, G. R.; Caulfield, M.; Munroe, P. B. (2009) Genome-wide association study identifies eight loci associated with blood pressure Nat Genet, 41 ,666-676 [Journal Article] Online
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N </= 71,225 European ancestry, N </= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
PubMed Accession Number :: 19430483.

Moayyeri, A.; Kaptoge, S.; Dalzell, N.; Luben, R. N.; Wareham, N. J.; Bingham, S.; Reeve, J.; Khaw, K. T. (2009) The effect of including quantitative heel ultrasound in models for estimation of 10-year absolute risk of fracture Bone, 45 (2),180-4 [Journal Article] Online
Abstract: The role of quantitative ultrasound (QUS) in clinical practice is debatable. An unanswered question is that whether combining QUS and BMD measurements could improve the prediction of fracture risk. We examined this in a sample of men and women in the European Prospective Investigation into Cancer (EPIC)-Norfolk who had both heel QUS and hip DXA between 1995 and 1997 and were followed for any incident fracture up to 2007. From 1455 participants (703 men) aged 65-76 years at baseline, 79 developed a fracture over 10.3+/-1.4 years of follow-up. Two separate sex-stratified Cox proportional-hazard models were used including clinical risk factors and total hip BMD. Heel broadband ultrasound attenuation (BUA) was also included in the second model. Global measures of model fit, area under ROC curve, and the Hosmer-Lemeshow statistic showed relative superiority of the model including BUA. Using each model, we calculated 10-year absolute risk of fracture for all participants and categorized them in groups of <5%, 5% to <15%, and >/=15%. Comparison of groupings showed a total re-classification of 16.6% of participants after inclusion of BUA with the greatest re-classification (30.7%) among the group with intermediate risk. Adding a QUS measurement to models based on clinical risk factors and BMD improves the predictive power of models and suggests that further attention should be paid to QUS as a clinical tool for fracture risk assessment.
PubMed Accession Number :: 19427923.

Hemmingsson, E.; Udden, J.; Neovius, M.; Ekelund, U.; Rossner, S. (2009) Increased physical activity in abdominally obese women through support for changed commuting habits: a randomized clinical trial Int J Obes (Lond), 33 ,645-652 [Journal Article] Online
Abstract: Background:Abdominally obese women can reduce their health risk through regular physical activity. There is, however, little evidence on the effectiveness of interventions that promote physical activity long-term, such as cycling and walking to and from work.Methods:This intervention focused on physically active commuting (cycling and walking) in middle-aged (30-60 years), abdominally obese (waist circumference >/=88 cm) women (n=120), recruited by newspaper advertisement. The intervention group was a moderate-intensity programme with physician meetings, physical activity prescriptions, group counselling and bicycles. The control group was a low-intensity group support programme with pedometers. We used a randomized, controlled, 2-armed design with 18 months duration and intention-to-treat analysis (data collection 2005-2006). Treatment success was defined as bicycling >/=2 km/d (primary) or walking 10 000 steps per day (secondary).Results:At baseline, mean (s.d.) age was 48.2 years (7.4), waist circumference 103.8 cm (7.8), walking 8471 steps per day (2646), bicycling 0 km per day. Attrition at 18 months was 10% for the intervention group and 25% in the control group (P=0.03). The intervention group was more likely to achieve treatment success for cycling than controls: 38.7 vs 8.9% (odds ratio (OR)=7.8 (95% confidence interval=4.0 to 15.0, P<0.001)), but with no difference for compliance with the walking recommendation: 45.7 vs 39.3% (OR=1.2 (95% CI=0.7 to 2.0, P=0.50)). Commuting by car and public transport were reduced by 34% (P<0.01) and 37% (P<0.001), respectively, with no differences between groups. Both groups attained similar waist reductions (-2.1 and -2.6 cm, P=0.72).Conclusions:Abdominally obese women can increase PA long-term through moderate-intensity behavioural support aimed at changing commuting habits.International Journal of Obesity advance online publication, 5 May 2009; doi:10.1038/ijo.2009.77.
PubMed Accession Number :: 19417772.

Johnsen, N. F.; Tjonneland, A.; Thomsen, B. L.; Christensen, J.; Loft, S.; Friedenreich, C.; Key, T. J.; Allen, N. E.; Lahmann, P. H.; Mejlvig, L.; Overvad, K.; Kaaks, R.; Rohrmann, S.; Boing, H.; Misirli, G.; Trichopoulou, A.; Zylis, D.; Tumino, R.; Pala, V.; Bueno-de-Mesquita, H. B.; Kiemeney, L. A.; Suarez, L. R.; Gonzalez, C. A.; Sanchez, M. J.; Huerta, J. M.; Gurrea, A. B.; Manjer, J.; Wirfalt, E.; Khaw, K. T.; Wareham, N.; Boffetta, P.; Egevad, L.; Rinaldi, S.; Riboli, E. (2009) Physical activity and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort Int J Cancer, 125 (4),902-8 [Journal Article] Online
Abstract: The evidence concerning the possible association between physical activity and the risk of prostate cancer is inconsistent and additional data are needed. We examined the association between risk of prostate cancer and physical activity at work and in leisure time in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. In our study, including 127,923 men aged 20-97 years from 8 European countries, 2,458 cases of prostate cancer were identified during 8.5 years of followup. Using the Cox proportional hazards model, we investigated the associations between prostate cancer incidence rate and occupational activity and leisure time activity in terms of participation in sports, cycling, walking and gardening; a metabolic equivalent (MET) score based on weekly time spent on the 4 activities; and a physical activity index. MET hours per week of leisure time activity, higher score in the physical activity index, participation in any of the 4 leisure time activities, and the number of leisure time activities in which the participants were active were not associated with prostate cancer incidence. However, higher level of occupational physical activity was associated with lower risk of advanced stage prostate cancer (p(trend) = 0.024). In conclusion, our data support the hypothesis of an inverse association between advanced prostate cancer risk and occupational physical activity, but we found no support for an association between prostate cancer risk and leisure time physical activity. (c) 2009 UICC.
PubMed Accession Number :: 19415749.

Moayyeri, A.; Bingham, S. A.; Luben, R. N.; Wareham, N. J.; Khaw, K. T. (2009) Respiratory function as a marker of bone health and fracture risk in an older population J Bone Miner Res, 24 (5),956-63 [Journal Article] Online
Abstract: Identification of those at high risk of osteoporosis and fractures using clinically available tests beyond BMD measures is a major clinical challenge. We examined forced expiratory volume in 1 s (FEV1), an easily obtainable measure of respiratory function, as a clinical measure for fracture prediction. In the context of the European Prospective Investigation into Cancer-Norfolk Study, 8304 women and 6496 men 42-81 yr of age underwent a health check including spirometry and heel quantitative ultrasonography between 1997 and 2000 and were followed up for incident hip fractures until 2007. The main outcome measures were broadband ultrasound attenuation (BUA) of the heel (cross-sectional analysis) and hip fracture risk (prospective analysis). In multivariate regression models, a 1-liter increase in FEV1 was associated with a statistically significant 2.2-dB/MHz increase in BUA, independent of age, smoking, height, body mass index, history of fracture, and use of corticosteroids. Mean FEV1 was significantly lower among 84 women and 36 men with hip fracture compared with other participants. In multivariate proportional-hazard regression models, the relative risk (RR) of hip fracture associated with a 1-liter increase in FEV1 was 0.5 (95% CI, 0.3-0.9; p < 0.001) for both men and women. RR of hip fracture for a 1 SD increase in FEV1 was approximately equivalent to a 0.5 SD increase in BUA among women (1 SD among men) and an 5-yr decrease in age among both men and women. Middle-aged and older people with low respiratory function are at increased risk of osteoporosis and hip fracture. FEV1, an easy, low-cost, and feasible clinical measure, may help improve the identification of high-risk groups.
PubMed Accession Number :: 19402201.

Ogilvie, D.; Craig, P.; Griffin, S.; Macintyre, S.; Wareham, N. J. (2009) A translational framework for public health research BMC Public Health, 9 (1),116 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: The paradigm of translational medicine that underpins frameworks such as the Cooksey report on the funding of health research does not adequately reflect the complex reality of the public health environment. We therefore outline a translational framework for public health research. DISCUSSION: Our framework redefines the objective of translation from that of institutionalising effective interventions to that of improving population health by influencing both individual and collective determinants of health. It incorporates epidemiological perspectives with those of the social sciences, recognising that many types of research may contribute to the shaping of policy, practice and future research. It also identifies a pivotal role for evidence synthesis and the importance of non-linear and intersectoral interfaces with the public realm. SUMMARY: We propose a research agenda to advance the field and argue that resources for 'applied' or 'translational' public health research should be deployed across the framework, not reserved for 'dissemination' or 'implementation'.
PubMed Accession Number :: 19400941.

Du, H.; van der, A. Dl; Ginder, V.; Jebb, S. A.; Forouhi, N. G.; Wareham, N. J.; Halkjaer, J.; Tjonneland, A.; Overvad, K.; Jakobsen, M. U.; Buijsse, B.; Steffen, A.; Palli, D.; Masala, G.; Saris, W. H.; Sorensen, T. I.; Feskens, E. J. (2009) Dietary energy density in relation to subsequent changes of weight and waist circumference in European men and women PLoS ONE, 4 (4),e5339 [Journal Article] Online
Abstract: BACKGROUND: Experimental studies show that a reduction in dietary energy density (ED) is associated with reduced energy intake and body weight. However, few observational studies have investigated the role of ED on long-term weight and waist circumference change. METHODS AND PRINCIPAL FINDINGS: This population-based prospective cohort study included 89,432 participants from five European countries with mean age 53 years (range: 20-78 years) at baseline and were followed for an average of 6.5 years (range: 1.9-12.5 years). Participants were free of cancer, cardiovascular diseases and diabetes at baseline. ED was calculated as the energy intake (kcal) from foods divided by the weight (g) of foods. Multiple linear regression analyses were performed to investigate the associations of ED with annual weight and waist circumference change. Mean ED was 1.7 kcal/g and differed across study centers. After adjusting for baseline anthropometrics, demographic and lifestyle factors, follow-up duration and energy from beverages, ED was not associated with weight change, but significantly associated with waist circumference change overall. For 1 kcal/g ED, the annual weight change was -42 g/year [95% confidence interval (CI): -112, 28] and annual waist circumference change was 0.09 cm/year [95% CI: 0.01, 0.18]. In participants with baseline BMI<25 kg/m(2), 1 kcal/g ED was associated with a waist circumference change of 0.17 cm/year [95% CI: 0.09, 0.25]. CONCLUSION: Our results suggest that lower ED diets do not prevent weight gain but have a weak yet potentially beneficial effect on the prevention of abdominal obesity as measured by waist circumference.
PubMed Accession Number :: 19396357.

Rana, J. S.; Visser, M. E.; Arsenault, B. J.; Despres, J. P.; Stroes, E. S.; Kastelein, J. J.; Wareham, N. J.; Boekholdt, S. M.; Khaw, K. T. (2009) Metabolic dyslipidemia and risk of future coronary heart disease in apparently healthy men and women: The EPIC-Norfolk prospective population study Int J Cardiol, 143 ,309-404 [Journal Article] Online
Abstract: BACKGROUND: The association of metabolic syndrome and risk of CHD is now well established. The association between 'metabolic dyslipidemia' as defined by high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels and the risk of coronary heart disease (CHD) risk is not known. The aim of this study was to investigate the association between metabolic dyslipidemia, and risk of coronary heart disease (CHD) in apparently healthy men and women. METHODS: Metabolic dyslipidemia was defined by combination of increased triglyceride (TG) levels (>/=150 mg/dl) and low high-density lipoprotein cholesterol (HDL-C) levels (</=50 mg/dl for women and </=40 mg/dl for men). In the EPIC-Norfolk prospective population study, 21,340 participants without diabetes (9326 men and 12,014 women) were followed for a mean of 11.4 years during which 2075 CHD events occurred. Three multivariate models were used adjusting for other metabolic risk factors including low-density lipoprotein cholesterol (LDL-C). RESULTS: Compared to men with normal HDL and normal TG, men with metabolic dyslipidemia had an increased risk for CHD (HR 1.61, 95% CI 1.40-1.86). The increased risk remained significant after adjustment for LDL-C and other metabolic risk factors. Among women, metabolic dyslipidemia was associated with increased CHD risk (HR 1.78, 95% CI 1.47-2.15). This association was lost when the model was additionally adjusted for other metabolic syndrome risk factors. In men and women Kaplan-Meier survival curves according to HDL and TG levels revealed that participants with metabolic dyslipidemia had poorer survival compared to people without metabolic dyslipidemia (logrank p<0.001 for each). CONCLUSIONS: Metabolic dyslipidemia is associated with an increased risk of CHD. This relationship was independent from LDL-C and other risk factors of the metabolic syndrome in men, but not in women. A better management of this phenotype via lifestyle modification or pharmacotherapy may be warranted.
PubMed Accession Number :: 19394708.

Steele, R. M.; Finucane, F. M.; Simmons, R. K.; Griffin, S. J.; Wareham, N. J.; Ekelund, U. (2009) Altered respiratory function is associated with increased metabolic risk, independently of adiposity, fitness and physical activity Diabet Med, 26 (4),362-9 [Journal Article] Online
Abstract: AIMS: Reduced lung function is associated with an adverse metabolic risk profile, even after adjusting for body fatness. However, previous observations may have been confounded by aerobic fitness and physical activity. This study aimed to examine the association between lung function and both metabolic risk and insulin resistance in a cohort of White British adults with a family history of Type 2 diabetes, and to explore the extent to which these associations are independent of body fatness, aerobic fitness (VO(2max)) and objectively measured physical activity. METHODS: Adults (n = 320, mean age 40.4 +/- 6.0 years) underwent measurement of physical activity energy expenditure (PAEE), spirometry [forced expiratory volume in 1 s (FEV(1))] and forced vital capacity (FVC), aerobic fitness (predicted VO(2max)), and anthropometric and metabolic status at baseline and again after 1 year (n = 257) in the ProActive trial. Clustered metabolic risk was calculated by summing standardized values for triglycerides, fasting insulin, fasting glucose, blood pressure and the inverse of high-density lipoprotein-cholesterol. A cross-sectional analysis using linear regression with repeated measures was performed. RESULTS: Both FEV(1) and FVC were inversely and statistically significantly associated with metabolic risk and insulin resistance after adjusting for age, sex, smoking status, height, PAEE and fitness. The associations with metabolic risk remained significant after adjusting for measures of body fatness, but those with insulin resistance did not. CONCLUSIONS: Reduced lung function was associated with increased metabolic risk in this cohort of carefully characterized at-risk individuals. This association was independent of overall and central body fatness, objectively measured physical activity and aerobic fitness.
PubMed Accession Number :: 19388965.

Owen, C. G.; Nightingale, C. M.; Rudnicka, A. R.; Cook, D. G.; Ekelund, U.; Whincup, P. H. (2009) Ethnic and gender differences in physical activity levels among 9-10-year-old children of white European, South Asian and African-Caribbean origin: the Child Heart Health Study in England (CHASE Study) Int J Epidemiol, 38 (4),1082-93 [Journal Article] Online
Abstract: BACKGROUND: Ethnic differences in physical activity in children in the UK have not been accurately assessed. We made objective measurements of physical activity in 9-10-year-old British children of South Asian, black African-Caribbean and white European origin. METHODS: Cross-sectional study of urban primary school children (2006-07). Actigraph-GT1M activity monitors were worn by 2071 children during waking hours on at least 1 full day. Ethnic differences in mean daily activity [counts, counts per minute of registered time (CPM) and steps] were adjusted for age, gender, day of week and month. Multilevel modelling allowed for repeated days within individual and clustering within school. RESULTS: In white Europeans, mean daily counts, CPM and mean daily steps were 394 785, 498 and 10 220, respectively. South Asian and black Caribbean children recorded more registered time per day than white Europeans (34 and 36 min, respectively). Compared with white Europeans, South Asians recorded 18 789 fewer counts [95% confidence interval (CI) 6390-31 187], 41 fewer CPM 95% CI 26-57) and 905 fewer steps (95% CI 624-1187). Black African-Caribbeans recorded 25 359 more counts (95% CI 14 273-36 445), and similar CPM, but fewer steps than white Europeans. Girls recorded less activity than boys in all ethnic groups, with 74 782 fewer counts (95% CI 66 665-82 899), 84 fewer CPM (95% CI 74-95) and 1484 fewer steps (95% CI 1301-1668). CONCLUSION: British South Asian children have lower objectively measured physical activity levels than European whites and black African-Caribbeans.
PubMed Accession Number :: 19377098.

Myint, P. K.; Luben, R. N.; Surtees, P. G.; Wainwright, N. W.; Bingham, S. A.; Wareham, N. J.; Khaw, K. T. (2009) Effect of age and sex on the relationship between different socioeconomic indices and self-reported functional health in the EPIC-Norfolk population-based study Ann Epidemiol, 19 (5),289-97 [Journal Article] Online
Abstract: BACKGROUND: The relationship between different social-economic indices and physical and mental functional health of older people compared with younger people is unclear. OBJECTIVE: To examine the effect of age and sex on the relationship between various social-economic indices and self-reported functional health. METHODS: A population-based cross-sectional study was conducted in 19,088 participants of European Prospective Investigation into Cancer (EPIC)-Norfolk, UK, ages 40-79 years at baseline. The independent relationships between three different socioeconomic indices; occupational social class, education and residential area deprivation, and functional health measured by anglicized version of 36-item short form questionnaire (UK SF-36), were compared between older (>or=65 years) and younger (<65 years) men and women. RESULTS: Residential area deprivation was significantly associated with poor physical and mental functional health independent of social class and education, and consistent in both age groups in men and women. A low level of education in younger men and being in low social class in younger women were associated with poorer physical functional health compared with their respective older counterparts. Social class had a significantly greater effect in older women compared with younger women. CONCLUSION: Commonly used socioeconomic indices have differing associations with functional health depending the age and sex of an individual. Residential area deprivation predicts poor functional health in all age and sex groups. This may have implications for health policy.
PubMed Accession Number :: 19362274.

Moayyeri, A.; Kaptoge, S.; Luben, R. N.; Wareham, N. J.; Bingham, S.; Reeve, J.; Khaw, K. T. (2009) Estimation of absolute fracture risk among middle-aged and older men and women: the EPIC-Norfolk population cohort study Eur J Epidemiol, 24 (5),259-66 [Journal Article] Online
Abstract: While estimates of relative risks associated with risk factors such as age and bone mineral density (BMD) may be of interest for etiologic and comparative purposes, clinical questions such as who might benefit most from preventive interventions or BMD monitoring depend on estimates of absolute fracture risk. The European prospective investigation into cancer (EPIC)-Norfolk study included 25,311 participants (11,476 men) aged 4,079 years in 1993-1997. All participants were followed for osteoporotic fractures to March 2007. Ten-year absolute risk of fracture in men and women were calculated using the baseline survivor function in multivariable Cox proportional-hazards models adjusting for age, sex, history of fractures, body mass index, smoking, and alcohol intake. In comparison of those without history of fracture versus those with history of fracture, the 10-year absolute risk of any fracture in men ranged from 1.0 vs. 1.2% at age 40 years to 3.0 vs. 4.4% at age 75 years. The respective estimates in women ranged from 0.7 vs. 1.0% at age 40 years to 9.3 vs. 17.2% at age 75 years. Statistically significant interaction between age and sex was found (P < 0.001), which contributed to the differences in predicted absolute fracture risks for men and women at different ages. Our study shows the need for population-specific data to develop efficient well calibrated algorithms for assessment of fracture risk. The interaction observed between sex and age points to the need for further prospective studies among men.
PubMed Accession Number :: 19350399.

Soranzo, N.; Rivadeneira, F.; Chinappen-Horsley, U.; Malkina, I.; Richards, J. B.; Hammond, N.; Stolk, L.; Nica, A.; Inouye, M.; Hofman, A.; Stephens, J.; Wheeler, E.; Arp, P.; Gwilliam, R.; Jhamai, P. M.; Potter, S.; Chaney, A.; Ghori, M. J.; Ravindrarajah, R.; Ermakov, S.; Estrada, K.; Pols, H. A.; Williams, F. M.; McArdle, W. L.; van Meurs, J. B.; Loos, R. J.; Dermitzakis, E. T.; Ahmadi, K. R.; Hart, D. J.; Ouwehand, W. H.; Wareham, N. J.; Barroso, I.; Sandhu, M. S.; Strachan, D. P.; Livshits, G.; Spector, T. D.; Uitterlinden, A. G.; Deloukas, P. (2009) Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size PLoS Genet, 5 (4),e1000445 [Journal Article] Online
Abstract: Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1x10(-8) and rs910316 in TMED10, P-value = 1.4x10(-7)) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3x10(-7) and rs849141 in JAZF1, P-value = 3.2x10(-11)). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4x10(-5) and rs6817306 in LCORL, P-value = 4x10(-4)), hip axis length (including rs6830062 at LCORL, P-value = 4.8x10(-4) and rs4911494 at UQCC, P-value = 1.9x10(-4)), and femur length (including rs710841 at PRKG2, P-value = 2.4x10(-5) and rs10946808 at HIST1H1D, P-value = 6.4x10(-6)). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.
PubMed Accession Number :: 19343178.

Brage, S.; van Hees, V. T.; Brage, N. (2009) Intergeneration accelerometer differences and correction for on-board frequency-based filtering J Appl Physiol, 106 (4),1473; author reply 1474 [Journal Article] Online
Keywords: Data Interpretation, Statistical Humans Models, Statistical Motor Activity/*physiology Physiology/*instrumentation Reproducibility of Results Software Young Adult
PubMed Accession Number :: 19336683.

Lee, C. C.; Adler, A. I.; Sandhu, M. S.; Sharp, S. J.; Forouhi, N. G.; Erqou, S.; Luben, R.; Bingham, S.; Khaw, K. T.; Wareham, N. J. (2009) Association of C-reactive protein with type 2 diabetes: prospective analysis and meta-analysis Diabetologia, 52 (6),1040-7 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: We examined the association between serum C-reactive protein (CRP) and incident diabetes in a prospective study, and added these data to a literature-based meta-analysis to explore potential sources of heterogeneity between studies. METHODS: We analysed a case-control study nested within the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort, including 293 incident diabetes cases and 708 controls. We combined 16 published studies on CRP and incident diabetes in a random-effect meta-analysis. RESULTS: In the EPIC-Norfolk cohort, serum CRP was associated with a higher risk of diabetes after adjusting for age, sex, BMI, family history of diabetes, smoking and physical activity (OR 1.49, comparing the extreme thirds of CRP distribution [95% CI 1.03-2.15], p = 0.03). However, the association was completely attenuated after further adjustment for WHR, serum gamma-glutamyltransferase and serum adiponectin (OR 1.00; 95% CI 0.66-1.51, p = 1.0). In a meta-analysis of 16 published studies with 3,920 incident diabetes cases and 24,914 controls, the RR was 1.72 (95% CI 1.54-1.92), comparing the extreme thirds of CRP distribution, with substantial heterogeneity between studies (I (2) = 52.8%, p = 0.007). CONCLUSIONS/INTERPRETATION: Initial evidence of association between CRP and incident diabetes was confounded by central adiposity, markers of liver dysfunction and adiponectin in the primary analysis. Despite an overall positive association in the meta-analysis, considerable heterogeneity existed between studies. The degree of adjustment for central adiposity and baseline glycaemia explained some of this heterogeneity and suggests that CRP may not be an independent risk factor for type 2 diabetes.
PubMed Accession Number :: 19326095.

Semb, A. G.; Ueland, T.; Aukrust, P.; Kuivenhoven, J. A.; Wareham, N. J.; Luben, R.; Gullestad, L.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, M. (2009) Osteoprotegerin and Soluble Receptor Activator of Nuclear Factor-{kappa}B Ligand and Risk for Coronary Events. A Nested Case-Control Approach in the Prospective EPIC-Norfolk Population Study 1993-2003 Arterioscler Thromb Vasc Biol, 29 ,975-980 [Journal Article] Online
Abstract: OBJECTIVE: The purpose of this study was to examine the association between serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) and future coronary artery disease (CAD) in apparently healthy individuals. The identification of OPG as a novel cardiovascular risk marker suggests an association between mediators of bone homeostasis and cardiovascular disease. METHODS AND RESULTS: Serum levels of OPG and RANKL were analyzed in a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study, a cohort study of 25 663 men and women, where 951 apparently healthy individuals who developed a coronary event during 6 years' follow-up were matched by sex and age with 1705 healthy controls. Baseline OPG, but not RANKL, was higher in cases than in controls, and OPG was higher in women than in men. Both men and women in the highest OPG quartile had a higher risk for future CAD. These associations were independent of established cardiovascular risk factors, and when using OPG as a continuous variable, also after adjustment for CRP. In contrast, RANKL showed no association with coronary events. CONCLUSIONS: OPG is associated with the risk of future CAD in apparently healthy men and women, independent of established cardiovascular risk factors.
PubMed Accession Number :: 19325145.

Loos, R. J.; Savage, D. B. (2009) Inherited susceptibility to non-alcoholic fatty liver disease Diabetologia, 52 (6),1000-2 [Journal Article] Online
PubMed Accession Number :: 19319505.

Zhang, L.; Qiao, Q.; Tuomilehto, J.; Hammar, N.; Ruotolo, G.; Stehouwer, C. D.; Heine, R. J.; Eliasson, M.; Zethelius, B. (2009) The impact of dyslipidaemia on cardiovascular mortality in individuals without a prior history of diabetes in the DECODE Study Atherosclerosis, 206 (1),298-302 [Journal Article] Online
Abstract: OBJECTIVE: To evaluate the impact of dyslipidaemia on cardiovascular disease (CVD) mortality in relation to fasting (FPG) and 2-h (2hPG) plasma glucose levels in individuals without a prior history of diabetes. METHODS: Data from 14 European population-based prospective studies of 9132 men and 8631 women aged 25-89 years were jointly analysed. A total of 871 CVD deaths occurred during the average 10 years of follow-up. Subjects were classified into normoglycaemia, isolated fasting hyperglycaemia (IFH, FPG> or =6.10 mmol/l and 2hPG<7.80 mmol/l), isolated post-load hyperglycaemia (IPH, FPG<6.10 mmol/l and 2hPG> or =7.80 mmol/l) and combined fasting and post-load hyperglycaemia (CH, FPG> or =6.10 mmol/l and 2hPG> or =7.80 mmol/l). Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD mortality were estimated using Cox proportional hazard analysis. RESULTS: Multivariate-adjusted HRs (95% CIs) for high-density lipoprotein cholesterol (HDL-C) were 0.84 (0.75-0.94), 0.66 (0.48-0.92), 1.03 (0.84-1.27) and 0.67 (0.51-0.89) in individuals with normoglycaemia, IFH, IPH and CH, respectively. For total cholesterol (TC) to HDL-C ratio they were 1.14 (1.03-1.27), 1.44 (1.13-1.84), 0.94 (0.77-1.15) and 1.26 (1.05-1.50), respectively. HRs for TC and triglycerides (TG) were not significant in most of the glucose categories except for TG in those with CH [HR 1.12 (1.00-1.27)]. CONCLUSIONS: Low HDL-C and high TC/HDL-C increase CVD mortality in either diabetic or non-diabetic individuals defined based on the fasting glucose criteria, but not the 2-h criteria. TG is a significant CVD risk predictor only in the presence of combined hyperglycaemia or diabetes. The difference between fasting and post-load hyperglycaemia with regard to the lipid-CVD relation may suggest a different pathophysiology underlying these two prediabetic states.
PubMed Accession Number :: 19303072.

Marcus, C.; Nyberg, G.; Nordenfelt, A.; Karpmyr, M.; Kowalski, J.; Ekelund, U. (2009) A 4-year, cluster-randomized, controlled childhood obesity prevention study: STOPP Int J Obes (Lond), 33 ,408-417 [Journal Article] Online
Abstract: Objective:To assess the efficacy of a school-based intervention programme to reduce the prevalence of overweight in 6 to 10-year-old children.Design:Cluster-randomized, controlled study.Subjects:A total of 3135 boys and girls in grades 1-4 were included in the study.Methods:Ten schools were selected in Stockholm county area and randomized to intervention (n=5) and control (n=5) schools. Low-fat dairy products and whole-grain bread were promoted and all sweets and sweetened drinks were eliminated in intervention schools. Physical activity (PA) was aimed to increase by 30 min day(-1) during school time and sedentary behaviour restricted during after school care time. PA was measured by accelerometry. Eating habits at home were assessed by parental report. Eating disorders were evaluated by self-report.Results:The prevalence of overweight and obesity decreased by 3.2% (from 20.3 to 17.1) in intervention schools compared with an increase of 2.8% (from 16.1 to 18.9) in control schools (P<0.05). The results showed no difference between intervention and controls, after cluster adjustment, in the longitudinal analysis of BMIsds changes. However, a larger proportion of the children who were initially overweight reached normal weight in the intervention group (14%) compared with the control group (7.5%), P=0.017. PA did not differ between intervention and control schools after cluster adjustment. Eating habits at home were found to be healthier among families with children in intervention schools at the end of the intervention. There was no difference between children in intervention and control schools in self-reported eating disorders.Conclusions:A school-based intervention can reduce the prevalence of overweight and obesity in 6 to 10-year-old children and may affect eating habits at home. The effect of the intervention was possibly due to its effect on healthy eating habits at school and at home rather than on increased levels of PA.International Journal of Obesity advance online publication, 17 March 2009; doi:10.1038/ijo.2009.38.
PubMed Accession Number :: 19290010.

McFadden, E.; Luben, R.; Wareham, N.; Bingham, S.; Khaw, K. T. (2009) How far can we explain the social class differential in respiratory function? A cross-sectional population study of 21,991 men and women from EPIC-Norfolk Eur J Epidemiol, 24 (4),193-201 [Journal Article] Online
Abstract: The objective of this study is to investigate the association between occupational social class and respiratory function, as measured by forced expiratory volume in one-second (FEV(1)). We examined the cross sectional relationship between lung function and social class in a population study of 21,991 men and women aged 39-79 years living in the general community in Norfolk, United Kingdom, recruited using general practice age-sex registers in 1993-1997. There was a significant socioeconomic gradient in age adjusted lung function with a difference of 0.37 in mean FEV(1) in men and 0.20 in women, respectively between social class I and V. The age adjusted OR for having poor lung function was 4.13 (95% CI 2.66-6.42) in men and 2.64 (95% CI 1.74-3.99) in women for social class V compared to I. This difference was substantially attenuated after adjustment for height, weight, smoking status, respiratory illness, educational level, living in a deprived area, physical activity and plasma vitamin C levels. There was a strong socioeconomic gradient in respiratory function. In men the gradient appeared to be largely explained by smoking status and height; in women a large part of the gradient was explained by potentially modifiable factors. This suggests that socioeconomic inequalities in respiratory function may be preventable or modifiable and highlights factors for further exploration.
PubMed Accession Number :: 19288214.

Wu, Y.; Li, H.; Loos, R. J.; Qi, Q.; Hu, F. B.; Liu, Y.; Lin, X. (2009) Genetic variation in the RBP4 gene, plasma retinol binding protein-4 levels, and hypertriglyceridemia risk in a Chinese Han population J Lipid Res, 50 (7),1479-86 [Journal Article] Online
Abstract: We previously found that plasma RBP4 levels were strongly associated with metabolic syndrome components. This study aimed to determine whether RBP4 variants are associated with the metabolic syndrome components and plasma RBP4 levels, and to investigate whether the associations between plasma RBP4 and the metabolic syndrome components are causal. Five tagSNPs were tested for their associations with plasma RBP4 levels and metabolic syndrome components in a population-based sample of 3,210 Chinese Hans. A possible causal relationship between plasma RBP4 levels and hypertriglyceridemia was explored by Mendelian randomization. Plasma RBP4 levels were significantly associated with rs10882273 (betaz -0.10SD[-0.17~-0.03], P=0.0050), rs3758538 (betaz -0.12SD[-0.24~-0.01], P=0.0325) in all participants, and with rs17108993 in Shanghai participants (betaz -0.19SD[-0.32~-0.05], P=0.0061). The SNP rs3758538 was significantly associated with hypertriglyceridemia (OR 0.62[0.46-0.85], P=0.0029) and triglycerides (betaz -0.19SD[-0.30~-0.08], P=0.001) in all participants. In Mendelian randomization analysis, the observed effect size of association between rs3758538 and hypertriglyceridemia was different from the expected effect size (P=0.0213). In conclusion, this is the first study to show that the RBP4 variants are significantly associated with plasma RBP4 levels and hypertriglyceridemia risk in Chinese Hans. However, results of Mendelian randomization do not support the hypothesis that RBP4 levels are causally related to hypertriglyceridemia risk.
PubMed Accession Number :: 19287041.

van Sluijs, E. M.; Fearne, V. A.; Mattocks, C.; Riddoch, C.; Griffin, S. J.; Ness, A. (2009) The contribution of active travel to children's physical activity levels: cross-sectional results from the ALSPAC study Prev Med, 48 ,519-524 [Journal Article] Online
Abstract: OBJECTIVE: To assess the association between active travel to school and physical activity (PA) in a large population-based sample of 11-year old children. METHOD: Cross-sectional analyses using data from the Avon Longitudinal Study of Parents and Children (Bristol, UK), collected in 2002-2004. The analyses include all children providing valid data on objectively-measured PA (Actigraph accelerometer), and having parent-proxy reported data on travel mode (walk, cycle, public transport, car) and distance to school (N=4688). RESULTS: 43.5% of children regularly walked or cycled to school (i.e. on every or most days). Compared with car travelers, walking to school was associated with 5.98 (95%CI: 3.82-8.14) more minutes of moderate-to-vigorous PA (MVPA) on weekdays in those living 0.5-1 miles from school, and with 9.77 (95%CI: 7.47-12.06) more minutes in those living at 1-5 miles. This equates to 24.6 to 40.2% of the average daily minutes of MVPA. Only modest differences were observed in those living <0.5 mile from school. CONCLUSION: Children who regularly walk to school are more active during the week than those travelling by car, especially if the distance is >0.5 mile. Increasing participation in active travel might be a useful part of an overall strategy to increase population PA.
PubMed Accession Number :: 19272404.

Arsenault, B. J.; Lemieux, I.; Despres, J. P.; Gagnon, P.; Wareham, N. J.; Stroes, E. S.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2009) HDL particle size and the risk of coronary heart disease in apparently healthy men and women: The EPIC-Norfolk prospective population study Atherosclerosis, 206 (1),276-81 [Journal Article] Online
Abstract: OBJECTIVE: To evaluate the association between HDL particle size measured by gradient gel electrophoresis and risk of incident coronary heart disease (CHD) in apparently healthy men and women. METHODS: We performed a prospective case-control study nested in the EPIC-Norfolk cohort. Cases were apparently healthy men and women aged 45-79 years who developed fatal or nonfatal CHD (n=1035). They were matched to 1920 controls who remained free of CHD over the follow-up period of 6 years. RESULTS: Participants with the smallest HDL particles had the most unfavourable cardiometabolic risk profile whereas those with the largest HDL particles had the most favourable risk profile. Plasma HDL cholesterol levels were found to be the best correlate of HDL particle size (r=0.58 and r=0.62, respectively, for men and women, p<0.001). Men in the highest quartile of HDL particle size had an unadjusted odds ratio (OR) for future CHD of 0.75 (95% CI, 0.57-0.97) compared to those in the bottom quartile. For women, the equivalent OR was 0.50 (0.35-0.71). After additional adjustment for diabetes, body mass index, systolic blood pressure, LDL and HDL cholesterol levels, the ORs were 1.43 (1.01-2.03) in men and 0.84 (0.52-1.35) in women. CONCLUSIONS: A decreased HDL particle size is associated with an adverse cardiometabolic risk profile. Small HDL particle size was also associated with an increased CHD risk, but this association was largely explained by traditional risk factors.
PubMed Accession Number :: 19268944.

Bener, A.; Zirie, M.; Janahi, I. M.; Al-Hamaq, A. O.; Musallam, M.; Wareham, N. J. (2009) Prevalence of diagnosed and undiagnosed diabetes mellitus and its risk factors in a population-based study of Qatar Diabetes Res Clin Pract, 84 (1),99-106 [Journal Article] Online
Abstract: OBJECTIVE: The objective of the study was to determine the prevalence of diagnosed and undiagnosed diabetes, pre-diabetes and to identify the associated risk factors in the sample of adult Qatari population. DESIGN: This was a cross-sectional study. SETTING: The survey was carried out in urban and semi-urban primary health care centers. SUBJECTS AND METHODS: The survey was conducted from January 2007 to July 2008 among Qatari nationals above 20 years of age. Of the 1434 subjects who were approached to participate in the study, 1117 (77.9%) gave their consent. Face to face interviews were conducted using a structured questionnaire followed by laboratory tests. DM was defined according to the WHO expert group. Pre diabetes status was based on the presence of impaired fasting glucose or impaired glucose tolerance. RESULTS: The overall prevalence of diabetes mellitus among adult Qatari population was high (16.7%) with diagnosed DM (10.7%) and newly diagnosed DM (5.9%). The impaired glucose tolerance (IGT) was diagnosed in 12.5%, while impaired fasting glucose was in 1.3% with a total of (13.8%). The proportion of DM was higher in Qatari women (53.2%) than in Qatari men (46.8%) and it peaked in the age group 40-49 years (31.2%). The age-specific prevalence of total DM and IGT increased with age. Risk factors were significantly higher in diabetic adult Qatari population: central obesity (p<0.001), hypertension (p<0.001), triglyceride (p<0.001), HDL (p=0.003), metabolic syndrome (p<0.001), heart diseases (p<0.001). Smoking habits and family history of DM were the major contributors for diabetes disease. The central obesity was associated with higher prevalence of DM and IFG among Qatari men and women. CONCLUSION: The present study has found a moderately high prevalence of diabetes mellitus in the adult Qatari population. High proportion of pre-diabetes in Qatari adults will increase the prevalence of DM in the next few years. Smoking habits and family history of DM were the major contributors for DM. Early diagnosis of DM is of major importance to reduce the risk of these diabetes-related conditions.
PubMed Accession Number :: 19261345.

Moayyeri, A.; Kaptoge, S.; Dalzell, N.; Bingham, S.; Luben, R. N.; Wareham, N. J.; Reeve, J.; Khaw, K. T. (2009) Is QUS or DXA Better for Predicting The 10-year Absolute Risk of Fracture? J Bone Miner Res, 24 (7),1319-1325 [Journal Article] Online
Abstract: Abstract Although quantitative ultrasound (QUS) is known to be correlated with BMD and bone structure, its long-term predictive power for fractures in comparison to dual-energy X-ray absorptiometry (DXA) is unclear. We examined this in a sample of men and women in the European Prospective Investigation into Cancer (EPIC)-Norfolk who had both heel QUS and hip DXA between 1995 and 1997. From 1,455 participants (703 men) aged 65-76 years at baseline, 79 developed a fracture over 10.3+/-1.4 years of follow-up. In a sex-stratified Cox proportional-hazard model including age, height, body mass index, prior fracture, smoking, alcohol intake and total hip BMD, 1 SD decrease in BMD was associated with a hazard ratio (HR) for fracture of 2.26 (95% CI 1.74-2.95). In the multivariable model with heel broadband ultrasound attenuation (BUA) in place of BMD, HR for 1 SD decrease in BUA was 2.04 (95% CI 1.55-2.69). Global measures of model fit showed relative superiority of the BMD model whereas the area under the ROC curve was slightly higher for the BUA model. Using both Cox models with BMD and BUA measures, we calculated exact 10-year absolute risk of fracture for all participants and categorized them in groups of <5%, 5% to <15%, and >/=15%. Comparison of groupings based on two models showed a total re-classification of 28.8% of participants with the greatest re-classification (about 40%) among the intermediate- and high-risk groups. This study shows that the power of QUS for prediction of fractures among the elderly is at least comparable to that of DXA. Given the feasibility and lower cost of ultrasound measurement in primary care, further studies to develop and validate models for prediction of 10-year risk of fracture using clinical risk factors and QUS are recommended.
PubMed Accession Number :: 19257820.

Ekelund, U.; Brage, S.; Griffin, S. J.; Wareham, N. J. (2009) Objectively Measured Moderate and Vigorous Intensity Physical Activity but Not Sedentary Time Predicts Insulin Resistance in High Risk Individuals Diabetes Care, 32 (6),1081-6 [Journal Article] Online
Abstract: Objective - Low levels of physical activity (PA) appear to be associated with insulin resistance (IR). However, the detailed associations of these complex relationships remain elusive. We examined the prospective associations between self-reported TV-viewing time, objectively measured time spent sedentary, at light (LPA), and moderate and vigorous intensity physical activity (MVPA) with IR. Research design and methods - In 192 individuals (81 men, 111 women) with a family history of type 2 diabetes we measured PA, anthropometric and metabolic variables at baseline and after 1 year of follow-up in the ProActive UK trail. Physical activity was measured objectively by accelerometry. IR was expressed as fasting insulin and the homeostasis model assessment score (HOMA). Results - Baseline MVPA was a significant predictor of fasting insulin at follow-up (beta=-0.004, 95% CI;-0.007;-0.0001, P=0.022), and the association approached significance for HOMA-IR (beta=-0.003, 95% CI;-0.007; 0.000002, P=0.052), independent of time spent sedentary, at light intensity activity, sex, age, smoking status, waist circumference and self-reported TV viewing. Time spent sedentary and at LPA were not significantly associated with IR. Change in MVPA between baseline and follow-up was inversely related to fasting insulin (beta=-0.003, 95% CI;-0.007;-0.0003, P=0.032) and the HOMA score (beta=-0.004, 95% CI;-0.008;-0.001, P=0.015) at follow-up, after adjusting for baseline phenotype in addition to the same confounders as above. Conclusion - These results highlight the importance of promoting moderate intensity activity such as brisk walking for improving insulin sensitivity and possibly other metabolic risk factors to prevent type 2 diabetes.
PubMed Accession Number :: 19252168.

Assah, F. K.; Ekelund, U.; Brage, S.; Corder, K.; Wright, A.; Mbanya, J. C.; Wareham, N. J. (2009) Predicting Physical Activity Energy Expenditure Using Accelerometry in Adults From Sub-Sahara Africa Obesity (Silver Spring), 17 ,1588-1595 [Journal Article] Online
Abstract: Lack of physical activity may be an important etiological factor in the current epidemiological transition characterized by increasing prevalence of obesity and chronic diseases in sub-Sahara Africa. However, there is a dearth of data on objectively measured physical activity energy expenditure (PAEE) in this region. We sought to develop regression equations using body composition and accelerometer counts to predict PAEE. We conducted a cross-sectional study of 33 adult volunteers from an urban (n = 16) and a rural (n = 17) residential site in Cameroon. Energy expenditure was measured by doubly labeled water (DLW) over a period of seven consecutive days. Simultaneously, a hip-mounted Actigraph accelerometer recorded body movement. PAEE prediction equations were derived using accelerometer counts, age, sex, and body composition variables, and cross-validated by the jack-knife method. The Bland and Altman limits of agreement (LOAs) approach was used to assess agreement. Our results show that PAEE (kJ/kg/day) was significantly and positively correlated with activity counts from the accelerometer (r = 0.37, P = 0.03). The derived equations explained 14-40% of the variance in PAEE. Age, sex, and accelerometer counts together explained 34% of the variance in PAEE, with accelerometer counts alone explaining 14%. The LOAs between DLW and the derived equations were wide, with predicted PAEE being up to 60 kJ/kg/day below or above the measured value. In summary, the derived equations performed better than existing published equations in predicting PAEE from accelerometer counts in this population. Accelerometry could be used to predict PAEE in this population and, therefore, has important applications for monitoring population levels of total physical activity patterns.Obesity (2009) doi:10.1038/oby.2009.39.
PubMed Accession Number :: 19247268.

Qi, Q.; Wu, Y.; Li, H.; Loos, R. J.; Hu, F. B.; Sun, L.; Lu, L.; Pan, A.; Liu, C.; Wu, H.; Chen, L.; Yu, Z.; Lin, X. (2009) Association of GCKR rs780094, alone or in combination with GCK rs1799884, with type 2 diabetes and related traits in a Han Chinese population Diabetologia, 52 ,834-843 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The GCKR rs780094 and GCK rs1799884 polymorphisms have been reported to be associated with dyslipidaemia and type 2 diabetes in white Europeans. The aim of this study was to replicate these associations in Han Chinese individuals and to identify the potential mechanisms underlying these associations. METHODS: The single nucleotide polymorphisms rs780094 and rs1799884 were genotyped in a population-based sample of Han Chinese individuals (n = 3,210) and tested for association with risk of type 2 diabetes and related phenotypes. RESULTS: The GCKR rs780094 A allele was marginally associated with reduced risk of type 2 diabetes (OR 0.85, 95% CI 0.73-1.00, p value under an additive model [p ((add))] = 0.05) and significantly associated with reduced risk of impaired fasting glucose (IFG) or type 2 diabetes (OR 0.86, 95% CI 0.77-0.96, p ([add]) = 0.0032). It was also significantly associated with decreased fasting glucose and increased HOMA of beta cell function (HOMA-B) and fasting triacylglycerol levels (p ([add]) = 0.0169-5.3 x 10(-6)), but not with HOMA of insulin sensitivity (HOMA-S). The associations with type 2 diabetes and IFG remained significant after adjustment for BMI, while adjustment for HOMA-B abolished the associations. The GCKR rs780094 was also associated with obesity and BMI, independently of its association with type 2 diabetes. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B (p ([add]) = 0.0005), but not with type 2 diabetes or IFG. Individuals with increasing numbers of risk alleles for both variants had significantly lower HOMA-B (p ([add]) = 5.8 x 10(-5)) in the combined analysis. CONCLUSIONS/INTERPRETATION: Consistent with observations in white Europeans, the GCKR rs780094 polymorphism contributes to the risk of type 2 diabetes and dyslipidaemia in Han Chinese individuals. In addition, we showed that the effect on type 2 diabetes is probably mediated through impaired beta cell function rather than through obesity.
PubMed Accession Number :: 19241058.

Ong, K. K.; Emmett, P.; Northstone, K.; Golding, J.; Rogers, I.; Ness, A. R.; Wells, J. C.; Dunger, D. B. (2009) Infancy weight gain predicts childhood body fat and age at menarche in girls J Clin Endocrinol Metab, 94 (5),1527-32 [Journal Article] Online
Abstract: Context: Rapid postnatal weight gain has been associated with subsequent increased childhood adiposity. However, the contribution of rapid weight gain during specific infancy periods is not clear. Objective: We aimed to determine which periods of infancy weight gain are related to childhood adiposity and also to age at menarche in UK girls. Design, Setting and Participants: 2715 girls from a prospective UK birth cohort study Main outcome measures: Routinely measured weights and lengths at ages 2, 9 and 19 months were extracted from the local child health computer database. Body composition was assessed by DXA at age 10 years, and age at menarche by questionnaire (categorised into 3 groups: <12.0 years; 12.0-13.0; >13.0). Results: Faster early infancy weight gain between 0 to 2 months and also 2 to 9 months were associated with increased body fat mass relative to lean mass at age 10 years, and also with earlier age at menarche. Each +1 unit gain in weight SD score between 0 to 9 months was associated with an odds ratio (95% CI) = 1.48 (1.27-1.60) for overweight (BMI > 85(th) centile) at 10 years, and 1.34 (1.21-1.49) for menarche at <12 years. In contrast, subsequent weight gain between 9 to 19 months was not associated with later adiposity or age at menarche. Conclusions: In developed settings, rapid weight gain during the first 9 months of life is a risk factor for both increased childhood adiposity and early menarche in girls.
PubMed Accession Number :: 19240149.

Mann, E.; Prevost, A. T.; Griffin, S.; Kellar, I.; Sutton, S.; Parker, M.; Sanderson, S.; Kinmonth, A. L.; Marteau, T. M. (2009) Impact of an informed choice invitation on uptake of screening for diabetes in primary care (DICISION): trial protocol BMC Public Health, 9 (1),63 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Screening invitations have traditionally been brief, providing information only about population benefits. Presenting information about the limited individual benefits and potential harms of screening to inform choice may reduce attendance, particularly in the more socially deprived. At the same time, amongst those who attend, it might increase motivation to change behavior to reduce risks. This trial assesses the impact on attendance and motivation to change behavior of an invitation that facilitates informed choices about participating in diabetes screening in general practice. Three hypotheses are tested: 1. Attendance at screening for diabetes is lower following an informed choice compared with a standard invitation. 2. There is an interaction between the type of invitation and social deprivation: attendance following an informed choice compared with a standard invitation is lower in those who are more rather than less socially deprived. 3. Amongst those who attend for screening, intentions to change behavior to reduce risks of complications in those subsequently diagnosed with diabetes are stronger following an informed choice invitation compared with a standard invitation. METHODS: 1500 people aged 40-69 years without known diabetes but at high risk are identified from four general practice registers in the east of England. 1200 participants are randomized by households to receive one of two invitations to attend for diabetes screening at their general practices. The intervention invitation is designed to facilitate informed choices, and comprises detailed information and a decision aid. A comparison invitation is based on those currently in use. Screening involves a finger-prick blood glucose test. The primary outcome is attendance for diabetes screening. The secondary outcome is intention to change health related behaviors in those attenders diagnosed with diabetes. A sample size of 1200 ensures 90% power to detect a 10% difference in attendance between arms, and in an estimated 780 attenders, 80% power to detect a 0.2 sd difference in intention between arms. DISCUSSION: The DICISION trial is a rigorous pragmatic denominator based clinical trial of an informed choice invitation to diabetes screening, which addresses some key limitations of previous trials.
PubMed Accession Number :: 19232112.

McFadden, E.; Luben, R.; Wareham, N.; Bingham, S.; Khaw, K. T. (2009) Social Class, Risk Factors, and Stroke Incidence in Men and Women. A Prospective Study in the European Prospective Investigation Into Cancer in Norfolk Cohort Stroke, 40 (4),1070-7 [Journal Article] Online
Abstract: BACKGROUND AND PURPOSE: The purpose of this study was to investigate the association between occupational social class and stroke incidence and the extent to which classical, lifestyle, and psychosocial risk factors may explain such relationships. METHODS: A prospective population study was conducted of 22 488 men and women aged 39 to 79 years living in the general community in Norfolk, UK, recruited in 1993 to 1997 and followed up for stroke incidence to 2007. RESULTS: An inverse relationship was observed between social class and stroke incidence with an age- and sex-adjusted hazard ratio for social Class V compared with I of 2.62 (95% CI, 1.63 to 4.22; P=0.001). Adjusting for classical (systolic blood pressure, total blood cholesterol, smoking, history of diabetes, and body mass index), lifestyle (plasma vitamin C levels, alcohol intake, and physical activity), and psychosocial (5-item version of the Mental Health Inventory) risk factors had little effect, and a socioeconomic differential was still apparent: hazard ratio for social Class V compared with I of 2.55 (95% CI, 1.34 to 4.85, P=0.004 for comparison of V to I). CONCLUSIONS: Stroke incidence increased with lower social class in both men and women. Adjustment for a comprehensive range of classical, lifestyle, and psychosocial risk factors did not explain the socioeconomic differential in stroke incidence. If we are to reduce inequalities in health, further understanding of the mechanisms underlying the association is needed.
PubMed Accession Number :: 19228844.

Myint, P. K.; Luben, R. N.; Wareham, N. J.; Bingham, S. A.; Khaw, K. T. (2009) Combined effect of health behaviours and risk of first ever stroke in 20 040 men and women over 11 years' follow-up in Norfolk cohort of European Prospective Investigation of Cancer (EPIC Norfolk): prospective population study Bmj, 338 ,b349 [Journal Article] Online
Abstract: OBJECTIVE: To quantify the potential combined impact of four health behaviours on incidence of stroke in men and women living in the general community. DESIGN: Population based prospective study (EPIC-Norfolk). SETTING: Norfolk, United Kingdom. PARTICIPANTS: 20 040 men and women aged 40-79 with no known stroke or myocardial infarction at baseline survey in 1993-7, living in the general community, and followed up to 2007. MAIN OUTCOME MEASURE: Participants scored one point for each health behaviour: current non-smoking, physically not inactive, moderate alcohol intake (1-14 units a week), and plasma concentration of vitamin C >/=50 micromol/l, indicating fruit and vegetable intake of at least five servings a day, for a total score ranging from 0 to 4. RESULTS: There were 599 incident strokes over 229 993 person years of follow-up; the average follow-up was 11.5 years. After adjustment for age, sex, body mass index (BMI), systolic blood pressure, cholesterol concentration, history of diabetes and aspirin use, and social class, compared with people with the four health behaviours the relative risks for stroke for men and women were 1.15 (95% confidence interval 0.89 to 1.49) for three health behaviours, 1.58 (1.22 to 2.05) for two, 2.18 (1.63 to 2.92) for one, and 2.31 (1.33 to 4.02) for none (P<0.001 for trend). The relations were consistent in subgroups stratified by sex, age, body mass index, and social class, and after exclusion of deaths within two years. CONCLUSION: Four health behaviours combined predict more than a twofold difference in incidence of stroke in men and women.
PubMed Accession Number :: 19228771.

Rana, J. S.; Arsenault, B. J.; Despres, J. P.; Cote, M.; Talmud, P. J.; Ninio, E.; Jukema, J. W.; Wareham, N. J.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2009) Inflammatory biomarkers, physical activity, waist circumference, and risk of future coronary heart disease in healthy men and women Eur Heart J, , [Journal Article] Online
Abstract: Aims The aim of this study was to determine the contribution of physical activity and abdominal obesity to the variation in inflammatory biomarkers and incident coronary heart disease (CHD) in a European population. Methods and results In a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, we examined the associations between circulating levels or activity of C-reactive protein, myeloperoxidase (MPO), secretory phospholipase A2 (sPLA2), lipoprotein-associated phospholipase A2 (Lp-PLA2), fibrinogen, adiponectin, waist circumference, physical activity, and CHD risk over a 10-year period among healthy men and women (45-79 years of age). A total of 1002 cases who developed fatal or non-fatal CHD were matched to 1859 controls on the basis of age, sex, and enrolment period. Circulating levels of C-reactive protein, sPLA2 (women only), fibrinogen, and adiponectin were linearly associated with increasing waist circumference and decreasing physical activity levels. After adjusting for waist circumference, physical activity, smoking, diabetes, systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol levels, and further adjusted for hormone replacement therapy in women, C-reactive protein, MPO (men only), sPLA2, fibrinogen, but not Lp-PLA2 and adiponectin were associated with an increased CHD risk. Conclusion Inactive participants with an elevated waist circumference were characterized by deteriorated levels of inflammatory markers. However, several inflammatory markers were associated with an increased CHD risk, independent of underlying CHD risk factors such as waist circumference and physical activity levels.
PubMed Accession Number :: 19224930.

Besson, H.; Ekelund, U.; Luan, J.; May, A. M.; Sharp, S.; Travier, N.; Agudo, A.; Slimani, N.; Rinaldi, S.; Jenab, M.; Norat, T.; Mouw, T.; Rohrmann, S.; Kaaks, R.; Bergmann, M.; Boeing, H.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Overvad, K.; Andreasen, E. L.; Johnsen, N. F.; Halkjaer, J.; Gonzalez, C.; Rodriguez, L.; Sanchez, M. J.; Arriola, L.; Barricarte, A.; Navarro, C.; Key, T. J.; Spencer, E. A.; Orfanos, P.; Naska, A.; Trichopoulou, A.; Manjer, J.; Wirfalt, E.; Lund, E.; Palli, D.; Agnoli, C.; Vineis, P.; Panico, S.; Tumino, R.; Bueno-de-Mesquita, H. B.; van den Berg, S. W.; Odysseos, A. D.; Riboli, E.; Wareham, N. J.; Peeters, P. H. (2009) A cross-sectional analysis of physical activity and obesity indicators in European participants of the EPIC-PANACEA study Int J Obes (Lond), 33 (4),497-506 [Journal Article] Online
Abstract: Objectives:Cross-sectional data suggest a strong association between low levels of physical activity and obesity. The EPIC-PANACEA (European Prospective Investigation into Cancer-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating out of home And obesity) project was designed to investigate the associations between physical activity and body mass index (BMI) and waist circumference based on individual data collected across nine European countries.Methods:In the European Prospective Investigation into Cancer and Nutrition (EPIC), 519 931 volunteers were recruited between 1992 and 2000, of whom 405 819 had data on main variables of interest. Height, body weight and waist circumference were measured using standardized procedures. Physical activity was assessed using a validated four-category index reflecting a self-reported usual activity during work and leisure time. The associations between physical activity and BMI and waist circumference were estimated using multilevel mixed effects linear regression models, adjusted for age, total energy intake, smoking status, alcohol consumption and educational level.Results:A total of 125 629 men and 280 190 women with a mean age of 52.9 (s.d. 9.7) and 51.5 (s.d. 10.0) years, respectively were included. The mean BMI was 26.6 kg/m(2) (s.d. 3.6) in men and 25.0 kg/m(2) (s.d. 4.5) in women. Fifty percent of men and 30% of women were categorized as being active or moderately active. A one-category difference in the physical activity index was inversely associated with a difference of 0.18 kg/m(2) in the mean BMI (95% confidence interval, CI, 0.11, 0.24) and 1.04-cm (95% CI 0.82, 1.26) difference in waist circumference in men. The equivalent figures for women were 0.31 kg/m(2) (95% CI 0.23, 0.38) and 0.90 cm (95% CI 0.71, 1.08), respectively.Conclusions:Physical activity is inversely associated with both BMI and waist circumference across nine European countries. Although we cannot interpret the association causally, our results were observed in a large and diverse cohort independently from many potential confounders.International Journal of Obesity advance online publication, 17 February 2009; doi:10.1038/ijo.2009.25.
PubMed Accession Number :: 19223851.

Vimaleswaran, K. S.; Franks, P. W.; Brage, S.; Sardinha, L. B.; Andersen, L. B.; Wareham, N. J.; Ekelund, U.; Loos, R. J. (2009) Absence of Association Between the INSIG2 Gene Polymorphism (rs7566605) and Obesity in the European Youth Heart Study (EYHS) Obesity (Silver Spring), 17 ,1453-57 [Journal Article] Online
Abstract: The first genome-wide association study for BMI identified a polymorphism, rs7566605, 10 kb upstream of the insulin-induced gene 2 (INSIG2) transcription start site, as the most significantly associated variant in children and adults. Subsequent studies, however, showed inconsistent association of this polymorphism with obesity traits. This polymorphism has been hypothesized to alter INSIG2 expression leading to inhibition of fatty acid and cholesterol synthesis. Hence, we investigated the association of the INSIG2 rs7566605 polymorphism with obesity- and lipid-related traits in Danish and Estonian children (930 boys and 1,073 girls) from the European Youth Heart Study (EYHS), a school-based, cross-sectional study of pre- and early pubertal children. The association between the polymorphism and obesity traits was tested using additive and recessive models adjusted for age, age-group, gender, maturity and country. Interactions were tested by including the interaction terms in the model. Despite having sufficient power (98%) to detect the previously reported effect size for association with BMI, we did not find significant effects of rs7566605 on BMI (additive, P = 0.68; recessive, P = 0.24). Accordingly, the polymorphism was not associated with overweight (P = 0.87) or obesity (P = 0.34). We also did not find association with waist circumference (WC), sum of four skinfolds, or with total cholesterol, triglycerides, low-density lipoprotein, or high-density lipoprotein. There were no gender-specific (P = 0.55), age-group-specific (P = 0.63) or country-specific (P = 0.56) effects. There was also no evidence of interaction between genotype and physical activity (P = 0.95). Despite an adequately powered study, our findings suggest that rs7566605 is not associated with obesity-related traits and lipids in the EYHS.Obesity (2009) doi:10.1038/oby.2008.650.
PubMed Accession Number :: 19223851.

Steele, R. M.; Finucane, F. M.; Griffin, S. J.; Wareham, N. J.; Ekelund, U. (2009) Obesity Is Associated With Altered Lung Function Independently of Physical Activity and Fitness Obesity (Silver Spring), 17 (3),578-84 [Journal Article] Online
Abstract: Measures of obesity, especially central adiposity, have been associated with reduced lung function. However, previous studies may have been affected by confounding by physical activity and fitness. This study aimed to examine the relationship among body fatness, fat distribution, and lung function, adjusted for physical activity energy expenditure (PAEE) and aerobic fitness (VO(2)max), in a cohort of British white adults with a family history of type 2 diabetes. A total of 320 adults (mean age 40.4 +/- 6.0 years) attended for anthropometric and VO(2)max testing, and had ambulatory heart rate monitoring for 4 days to determine PAEE. Spirometry was used to measure forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC). The tests were repeated 12 months later, and a cross-sectional analysis using linear regression with repeated measures was performed. Measures of obesity (BMI, waist circumference (WC), fat mass (FM), body fat percentage (BF%)) were associated with lower lung function in men and women (P < 0.01), while waist-to-hip ratio (WHR) was associated with lower lung function in men only (P < 0.001). Associations remained after adjusting for age, smoking status, height, PAEE, and VO(2)max. The estimated difference in mean FEV(1) and FVC per unit increase in the exposure measures were consistently stronger in men compared to women (P for interaction <0.001). Obesity is inversely associated with lung function in adults, but central fat distribution appears to have a stronger relationship with respiratory mechanics in men than in women. These associations were independent of the degree of physical activity and aerobic fitness in this cohort.Obesity (2008) doi:10.1038/oby.2008.584.
PubMed Accession Number :: 19219060.

Brito, E. C.; Vimaleswaran, K. S.; Brage, S.; Andersen, L. B.; Sardinha, L. B.; Wareham, N. J.; Ekelund, U.; Loos, R. J.; Franks, P. W. (2009) PPARGC1A sequence variation and cardiovascular risk-factor levels: a study of the main genetic effects and gene x environment interactions in children from the European Youth Heart Study Diabetologia, 52 (4),609-13 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The PPARGC1A gene coactivates multiple nuclear transcription factors involved in cellular energy metabolism and vascular stasis. In the present study, we genotyped 35 tagging polymorphisms to capture all common PPARGC1A nucleotide sequence variations and tested for association with metabolic and cardiovascular traits in 2,101 Danish and Estonian boys and girls from the European Youth Heart Study, a multicentre school-based cross-sectional cohort study. METHODS: Fasting plasma glucose concentrations, anthropometric variables and blood pressure were measured. Habitual physical activity and aerobic fitness were objectively assessed using uniaxial accelerometry and a maximal aerobic exercise stress test on a bicycle ergometer, respectively. RESULTS: In adjusted models, nominally significant associations were observed for BMI (rs10018239, p = 0.039), waist circumference (rs7656250, p = 0.012; rs8192678 [Gly482Ser], p = 0.015; rs3755863, p = 0.02; rs10018239, beta = -0.01 cm per minor allele copy, p = 0.043), systolic blood pressure (rs2970869, p = 0.018) and fasting glucose concentrations (rs11724368, p = 0.045). Stronger associations were observed for aerobic fitness (rs7656250, p = 0.005; rs13117172, p = 0.008) and fasting glucose concentrations (rs7657071, p = 0.002). None remained significant after correcting for the number of statistical comparisons. We proceeded by testing for gene x physical activity interactions for the polymorphisms that showed nominal evidence of association in the main effect models. None of these tests was statistically significant. CONCLUSIONS/INTERPRETATION: Variants at PPARGC1A may influence several metabolic traits in this European paediatric cohort. However, variation at PPARGC1A is unlikely to have a major impact on cardiovascular or metabolic health in these children.
PubMed Accession Number :: 19183932.

Samani, N. J.; Deloukas, P.; Erdmann, J.; Hengstenberg, C.; Kuulasmaa, K.; McGinnis, R.; Schunkert, H.; Soranzo, N.; Thompson, J.; Tiret, L.; Ziegler, A. (2009) Large scale association analysis of novel genetic loci for coronary artery disease Arterioscler Thromb Vasc Biol, 29 (5),774-80 [Journal Article] Online
Abstract: BACKGROUND: Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. METHODS AND RESULTS: We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11,550 cases and 11,205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81 x 10(-21)). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44 x 10(-7)), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02 x 10(-3)), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34 x 10(-4)). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P=0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86 x 10(-5)) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. CONCLUSIONS: The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.
Keywords: Aged Case-Control Studies Coronary Artery Disease/*genetics European Continental Ancestry Group Female Genetic Predisposition to Disease/*genetics Genome-Wide Association Study Humans Male Middle Aged Odds Ratio Polymorphism, Single Nucleotide/*genetics Risk Sex Factors
PubMed Accession Number :: 19164808.

El Harchaoui, K.; Arsenault, B. J.; Franssen, R.; Despres, J. P.; Hovingh, G. K.; Stroes, E. S.; Otvos, J. D.; Wareham, N. J.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2009) High-Density Lipoprotein Particle Size and Concentration and Coronary Risk Ann Intern Med, 150 (2),84-93 [Journal Article] Online
Abstract: BACKGROUND: High-density lipoprotein (HDL) cholesterol levels are inversely related to risk for coronary artery disease (CAD). Because HDL particles are heterogeneous in size and composition, they may be differentially associated with other cardiovascular risk factors and with cardiovascular risk. OBJECTIVE: To study the independent relationships of HDL size and particle concentration to risk for future CAD. DESIGN: Nested case-control study within the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk cohort; baseline survey between 1993 and 1997, follow-up until November 2003. SETTING: Norfolk, United Kingdom. PARTICIPANTS: Case patients were 822 apparently healthy men and women who developed CAD during follow-up. Control participants were 1401 participants who remained without CAD and were matched to case patients by sex, age, and enrollment time. MEASUREMENTS: First CAD event leading to either hospitalization or death. RESULTS: Nuclear magnetic resonance spectroscopy-measured HDL particle concentration (mean, 33.9 mumol/L [SD, 5] vs. 32.9 mumol/L [SD, 6]; P < 0.001) and HDL size (mean, 8.9 nm [SD, 0.5] vs. 8.8 nm [SD, 0.5]; P < 0.001), as well as gradient gel electrophoresis-measured HDL size (mean, 8.9 nm [SD, 0.4] vs. 8.8 nm [SD, 0.4]; P = 0.005) were lower in case patients than in control participants. High-density lipoprotein size and HDL particle concentration were only weakly correlated (r = 0.08, for those measured with nuclear magnetic resonance spectroscopy; r = 0.10, for those measured with gradient gel electrophoresis). High-density lipoprotein size was strongly associated with risk factors characteristic of the metabolic syndrome, including waist-to-hip ratio, triglyceride level, and apolipoprotein B level, whereas HDL particle concentration was not. Both HDL size and HDL particle concentration were independently associated with CAD risk. The association between HDL size and CAD risk was abolished on adjustment for apolipoprotein B and triglyceride levels (adjusted odds ratio, 1.00 [95% CI, 0.71 to 1.39] for top vs. bottom quartile), whereas HDL particle concentration remained independently associated with CAD risk (adjusted odds ratio, 0.50 [CI, 0.37 to 0.66]). Limitation: Measurements were performed in nonfasting blood samples, and residual confounding cannot be excluded. CONCLUSION: Both HDL size and HDL particle concentration were independently associated with other cardiovascular risk factors and with the risk for CAD. The relationship between HDL size and CAD risk was explained by markers associated with the metabolic syndrome, indicating that part of the relationship between HDL cholesterol and CAD risk is merely a reflection of this metabolic risk. Funding: The Medical Research Council and Cancer Research UK, the European Union, Stroke Association, British Heart Foundation, United Kingdom Department of Health, Food Standards Agency, the Wellcome Trust, and the Future Forum.
PubMed Accession Number :: 19153411.

McFadden, E. C.; Luben, R. N.; Bingham, S. A.; Wareham, N. J.; Kinmonth, A. L.; Khaw, K. T. (2009) Self-rated health does not explain the socioeconomic differential in mortality: A prospective study in the European Prospective Investigation of Cancer and Nutrition in Norfolk (EPIC-Norfolk) cohort J Epidemiol Community Health, 63 (4),329-31 [Journal Article] Online
Abstract: BACKGROUND: Self-rated health (SRH), a subjective measure of health, is strongly predictive of mortality, independently of objective measures of health status and existing known disease. There is also a strong social gradient in SRH. We ask whether SRH can explain the well-known socioeconomic gradient in mortality. METHODS: We examine the effect of adjusting for SRH on the socioeconomic differential in mortality in a prospective study of 20,754 men and women aged 39-79 years, without prevalent disease, living in the general community in Norfolk, United Kingdom, recruited using general practice age-sex registers in 1993-1997 and followed up for an average of 10 years. RESULTS: Mortality risk increased with decreasing social class in men and women. There was some attenuation after adjustment for covariates age, BMI, smoking, history of diabetes, systolic blood pressure, cholesterol level, alcohol consumption, physical activity and educational level, but a gradient remained. Further adjustment for SRH attenuated the association slightly more, but there was still some evidence of a socioeconomic differential in mortality, particularly in class V compared to class I (age and sex adjusted hazard ratio=1.57 (95%CI 1.19, 2.06). CONCLUSIONS: SRH does not substantially explain the socioeconomic differential in mortality beyond that explained by health related covariates.
PubMed Accession Number :: 19147634.

Corder, K.; van Sluijs, E. M.; Wright, A.; Whincup, P.; Wareham, N. J.; Ekelund, U. (2009) Is it possible to assess free-living physical activity and energy expenditure in young people by self-report? Am J Clin Nutr, 89 (3),862-70 [Journal Article] Online
Abstract: BACKGROUND: It is unclear whether it is possible to accurately estimate physical activity energy expenditure (PAEE) by self-report in youth. OBJECTIVE: We assessed the validity and reliability of 4 self-reports to assess PAEE and time spent at moderate and vigorous intensity physical activity (MVPA) over the previous week in British young people between 4 and 17 y of age. DESIGN: PAEE and MVPA were derived from the Children's Physical Activity Questionnaire, Youth Physical Activity Questionnaire, and Swedish Adolescent Physical Activity Questionnaire; a lifestyle score indicative of habitual activity was derived from the Child Heart and Health Study in England Questionnaire. These data were compared with criterion methods, PAEE, and MVPA derived from simultaneous measurements by doubly labeled water and accelerometry in 3 age groups: 4-5 y (n = 27), 12-13 y (n = 25), and 16-17 y (n = 24). Validity was assessed by using Spearman correlations and the Bland-Altman method, and reliability was assessed by using intraclass correlation coefficients. RESULTS: The strength of association between questionnaire and criterion methods varied (r = 0.09 to r = 0.46). Some questionnaires were able to accurately assess group-level PAEE and MVPA for some age groups, but the error was large for individual-level estimates throughout. Reliability of the Youth Physical Activity Questionnaire and Child Heart and Health Study in England Questionnaire was good (intraclass correlation coefficient: 0.64-0.92). CONCLUSIONS: Absolute PAEE and MVPA estimated from these self-reports were not valid on an individual level in young people, although some questionnaires appeared to rank individuals accurately. Age (the outcome of interest) and whether individual or group-level estimates are necessary will influence the best choice of self-report method when assessing physical activity in youth.
PubMed Accession Number :: 19144732.

Surtees, P. G.; Wainwright, N. W.; Bowman, R.; Luben, R. N.; Wareham, N. J.; Khaw, K. T.; Bingham, S. A. (2009) No association between APOE and major depressive disorder in a community sample of 17,507 adults J Psychiatr Res, , [Journal Article] Online
Abstract: Mood-related phenotypes are commonly comorbid with, and have been implicated in the development of, neurological disorders. APOE is a major susceptibility gene for neurodegeneration. Recent evidence from case-control studies has suggested that the apoE 2 allele is associated with major depressive disorder (MDD). However, evidence from large-scale community-based studies is limited. APOE was genotyped for 17,507 men and women, aged 41-80 years, participating in the European Prospective Investigation into Cancer-Norfolk study, who had also completed a psychosocial assessment that included measures of emotional health status defined by MDD, psychological distress (as represented by the Mental Health Inventory, MHI-5), and by an assessment of neuroticism. No associations were found between APOE genotypes and measures either of past-year or lifetime MDD, or of emotional health defined according to the MHI-5 or by neuroticism. Data from this large-scale, community-based, study are not supportive of an association between either MDD or associated measures of emotional state and APOE genotype. These findings suggest that the association between APOE and MDD risk is more modest than has been previously reported.
PubMed Accession Number :: 19135213.

Liem, E. T.; De Lucia Rolfe, E.; L'Abee, C.; Sauer, P. J.; Ong, K. K.; Stolk, R. P. (2009) Measuring abdominal adiposity in 6 to 7-year-old children Eur J Clin Nutr, 63 (7),835-41 [Journal Article] Online
Abstract: Background/Objectives:Both intra-abdominal adipose tissue (IAAT) and subcutaneous abdominal adipose tissue (SAAT) are associated with cardiovascular risk factors, even in childhood. Currently, the gold standard in assessing IAAT and SAAT is computed tomography (CT), which is not widely applicable. The aim of this study was to estimate abdominal fat using anthropometry, dual-energy X-ray absorptiometry (DEXA) and ultrasound, and compare these estimates with the amounts of IAAT and SAAT determined by CT in 6 to 7-year-old children.Subjects/Methods:In 31 healthy children, weight, height, circumferences, skinfolds, DEXA, abdominal ultrasound and CT were performed. Measurements were compared by simple correlations and receiver operating characteristic analyses.Results:Total abdominal fat on CT did not differ between boys and girls (86.5 versus 89.8 cm(3), P=0.84). Boys had a higher IAAT to SAAT ratio than girls (0.56 versus 0.37, P=0.03). The sum of supra-iliac and abdominal skinfolds was most strongly correlated with SAAT on CT (r=0.93, P<0.001), and the abdominal skinfold with IAAT on CT (r=0.72, P<0.001). Diagnosis of subcutaneous abdominal and intra-abdominal adiposity can also be made using skinfolds. The associations with circumferences, body mass index and DEXA were less pronounced; however, these techniques can also be used to classify children according to SAAT and IAAT. Ultrasound can be used to diagnose subcutaneous adiposity, although it was not superior to skinfold measurements.Conclusion:Skinfold measurements are the best non-invasive technique in predicting subcutaneous as well as intra-abdominal fat in our population of 6 to 7-year-old children.European Journal of Clinical Nutrition advance online publication, 7 January 2009; doi:10.1038/ejcn.2008.57.
PubMed Accession Number :: 19127281.

Peters, T. M.; Schatzkin, A.; Gierach, G. L.; Moore, S. C.; Lacey, J. V., Jr.; Wareham, N. J.; Ekelund, U.; Hollenbeck, A. R.; Leitzmann, M. F. (2009) Physical Activity and Postmenopausal Breast Cancer Risk in the NIH-AARP Diet and Health Study Cancer Epidemiol Biomarkers Prev, 18 (1),289-96 [Journal Article] Online
Abstract: BACKGROUND: Although physical activity has been associated with reduced breast cancer risk, whether this association varies across breast cancer subtypes or is modified by reproductive and lifestyle factors is unclear. METHODS: We examined physical activity in relation to postmenopausal breast cancer risk in 182,862 U.S. women in the NIH-AARP Diet and Health Study. Physical activity was assessed by self-report at baseline (1995-1996), and 6,609 incident breast cancers were identified through December 31, 2003. Cox regression was used to estimate the relative risk (RR) and 95% confidence interval (95% CI) of postmenopausal breast cancer overall and by tumor characteristics. Effect modification by select reproductive and lifestyle factors was also explored. RESULTS: In multivariate models, the most active women experienced a 13% lower breast cancer risk versus inactive women (RR, 0.87; 95% CI, 0.81-0.95). This inverse relation was not modified by tumor stage or histology but was suggestively stronger for estrogen receptor (ER)-negative (RR, 0.75; 95% CI, 0.54-1.04) than ER-positive (RR, 0.97; 95% CI, 0.84-1.12) breast tumors and was suggestively stronger for overweight/obese (RR, 0.86; 95% CI, 0.77-0.96) than lean (RR, 0.95; 95% CI, 0.87-1.05) women. The inverse relation with physical activity was also more pronounced among women who had never used menopausal hormone therapy and those with a positive family history of breast cancer than their respective counterparts. CONCLUSIONS: Physical activity was associated with reduced postmenopausal breast cancer risk, particular to ER-negative tumors. These results, along with heterogeneity in the physical activity-breast cancer relation for subgroups of menopausal hormone therapy use and adiposity, indicate that physical activity likely influences breast cancer risk via both estrogenic and estrogen-independent mechanisms. (Cancer Epidemiol Biomarkers Prev 2009;18(1):289-96).
PubMed Accession Number :: 19124511.

Simmons, R. K.; Coleman, R. L.; Price, H. C.; Holman, R. R.; Khaw, K. T.; Wareham, N. J.; Griffin, S. J. (2009) Performance of the UKPDS Risk Engine and the Framingham risk equations in estimating cardiovascular disease in the EPIC-Norfolk cohort Diabetes Care, 32 ,708-713 [Journal Article] Online
Abstract: Objective: To examine the performance of the UKPDS Risk Engine (version 3) and the Framingham risk equations (2008) in estimating cardiovascular disease (CVD) incidence in three populations: (i) individuals with known diabetes (DM); (ii) individuals with non-diabetic hyperglycaemia, HbA(1c)>/=6.0% (HG); (iii) individuals with HbA(1c)<6.0% (normoglycaemia) (NG). Research Design and Methods: Population-based prospective cohort (EPIC-Norfolk). Participants aged 40-79 years recruited from UK general practices attended a health examination (1993-1998) and were followed for CVD events/death until April 2007. CVD risk estimates were calculated for 10,137 individuals. Results: Over 10.1 years there were 69 CVD events in the DM group (25.4%), 160 in the HG group (17.7%) and 732 in the NG group (8.2%). Estimated CVD 10-year risk in the DM group was 33% and 37% using the UKPDS and Framingham equations respectively. In the HG group, estimated CVD risk was 31% and 22% respectively, and for the NG group, 20% and 14% respectively. There were no significant differences in the ability of the risk equations to discriminate between individuals at different risk of CVD events in each sub-group; both equations over-estimated CVD risk. The Framingham equations performed better in HG and NG groups as they did not over-estimate risk as much as the UKPDS Risk Engine and they classified more participants correctly. Conclusions: Both the UKPDS and Framingham risk equations were moderately effective at ranking individuals and are therefore suitable for resource prioritisation. However, both over-estimated true risk which is important when using scores to communicate prognostic information to individuals.
PubMed Accession Number :: 19114615.

Braithwaite, D.; Moore, D. H.; Lustig, R. H.; Epel, E. S.; Ong, K. K.; Rehkopf, D. H.; Wang, M. C.; Miller, S. M.; Hiatt, R. A. (2009) Socioeconomic status in relation to early menarche among black and white girls Cancer Causes Control, 20 (5),713-20 [Journal Article] Online
Abstract: OBJECTIVE: Early menarche is a risk factor for breast cancer. We investigated the variation in age at menarche by socioeconomic status (SES) and race. METHODS: A cohort study was conducted on 1,091 black and 986 white girls from the three sites in the United States as part of the NHLBI Growth and Health Study (NGHS), who were aged 9-10 years at baseline and followed through adolescence over a 10-year period with annual exams. Using logistic regression models, we evaluated the nature and strength of associations between two socioeconomic indicators (household income and parental education) and early menarche (<12 years old) unadjusted and adjusted for anthropometry and maternal age at menarche. RESULTS: Proportionately, more black girls were menarcheal before 12 years of age compared to their white counterparts (46%, n = 468 vs. 26%, n = 240, respectively, p < 0.0001). Parental education was not a significant predictor of early menarche. The graded association between household income and age at menarche was strong and significant among black girls but less clear among white girls. Compared with those in the lowest quartile of household income, white girls in the highest quartile were at a significantly lower risk of early menarche [adjusted odds ratio (OR) = 0.37, 95% confidence intervals (CIs) 0.18-0.80]. The inverse was true for black girls: those in the highest quartile of household income were at an increased risk of early menarche (adjusted OR = 2.15, 95% CI 1.27-3.63) CONCLUSION: The SES factor selected (household income versus parental education) affected the findings regarding racial differences in the timing of menarche. It will be important for future studies to elucidate the link between household income and age at menarche in developed countries.
PubMed Accession Number :: 19107561.

Greenfield, J. R.; Miller, J. W.; Keogh, J. M.; Henning, E.; Satterwhite, J. H.; Cameron, G. S.; Astruc, B.; Mayer, J. P.; Brage, S.; See, T. C.; Lomas, D. J.; O'Rahilly, S.; Farooqi, I. S. (2009) Modulation of blood pressure by central melanocortinergic pathways N Engl J Med, 360 (1),44-52 [Journal Article] Online
Abstract: BACKGROUND: Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association with blood pressure in humans. METHODS: We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers. RESULTS: The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (+/-SE) systolic blood pressures of 123+/-14 mm Hg and 131+/-12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73+/-10 mm Hg and 79+/-7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3+/-1.9 mm Hg in systolic blood pressure and of 6.6+/-1.1 mm Hg in diastolic blood pressure (P<0.001 for both comparisons) at 24 hours, as compared with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events. CONCLUSIONS: Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.
Keywords: Adult Autonomic Nervous System/physiology Blood Pressure/drug effects/genetics/*physiology Catecholamines/urine Cross-Over Studies Dose-Response Relationship, Drug Double-Blind Method Female Genotype Heart Rate/genetics/physiology Heterozygote Humans Hypertension/complications/genetics/*metabolism Male *Mutation Obesity/complications/genetics/metabolism Overweight/complications/genetics/*metabolism Prevalence Receptor, Melanocortin, Type 4/agonists/deficiency/genetics/*metabolism *Signal Transduction Sleep/physiology
PubMed Accession Number :: 19092146.

Ruchat, S. M.; Elks, C. E.; Loos, R. J.; Vohl, M. C.; Weisnagel, S. J.; Rankinen, T.; Bouchard, C.; Perusse, L. (2009) Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies Acta Diabetol, 46 (3),217-26 [Journal Article] Online
Abstract: Several single nucleotide polymorphisms (SNPs) for type 2 diabetes mellitus (T2DM) risk have been identified by genome wide association studies (GWAS). The objective of the present study was to investigate the impact of these SNPs on T2DM intermediate phenotypes in order to clarify the physiological mechanisms through which they exert their effects on disease etiology. We analysed 23 SNPs in 9 T2DM genes (CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1) in a maximum of 712 men and women from the Quebec Family Study. The participants underwent a 75 g oral glucose tolerance test (OGTT) and were measured for glucose, insulin and C-peptide levels. Indices of insulin sensitivity and insulin secretion were derived from fasting and OGTT measurements. We confirmed the significant associations of variants in CDKAL1, CDKN2B, HHEX/IDE, KCNJ11 and TCF7L2 with insulin secretion and also found associations of some of these variants with insulin sensitivity and glucose tolerance. IGF2BP2 and SLC30A8 SNPs were not associated with insulin secretion but were with insulin sensitivity and glucose tolerance (0.002 </= P </= 0.02). To examine the joint effects of these variants and their contribution to T2DM endophenotypes variance, stepwise regression models were used and the model R (2) was computed. The variance in the phenotypes explained by combinations of variants ranged from 2.0 to 8.5%. Diabetes-associated variants in CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8 and TCF7L2 are associated with physiological alterations leading to T2DM, such as glucose intolerance, impaired insulin secretion or insulin resistance, supporting their role in the disease aetiology. These variants were found to account for 2.0-8.5% of the variance of T2DM-related traits.
PubMed Accession Number :: 19082521.

Willer, C. J.; Speliotes, E. K.; Loos, R. J.; Li, S.; Lindgren, C. M.; Heid, I. M.; Berndt, S. I.; Elliott, A. L.; Jackson, A. U.; Lamina, C.; Lettre, G.; Lim, N.; Lyon, H. N.; McCarroll, S. A.; Papadakis, K.; Qi, L.; Randall, J. C.; Roccasecca, R. M.; Sanna, S.; Scheet, P.; Weedon, M. N.; Wheeler, E.; Zhao, J. H.; Jacobs, L. C.; Prokopenko, I.; Soranzo, N.; Tanaka, T.; Timpson, N. J.; Almgren, P.; Bennett, A.; Bergman, R. N.; Bingham, S. A.; Bonnycastle, L. L.; Brown, M.; Burtt, N. P.; Chines, P.; Coin, L.; Collins, F. S.; Connell, J. M.; Cooper, C.; Smith, G. D.; Dennison, E. M.; Deodhar, P.; Elliott, P.; Erdos, M. R.; Estrada, K.; Evans, D. M.; Gianniny, L.; Gieger, C.; Gillson, C. J.; Guiducci, C.; Hackett, R.; Hadley, D.; Hall, A. S.; Havulinna, A. S.; Hebebrand, J.; Hofman, A.; Isomaa, B.; Jacobs, K. B.; Johnson, T.; Jousilahti, P.; Jovanovic, Z.; Khaw, K. T.; Kraft, P.; Kuokkanen, M.; Kuusisto, J.; Laitinen, J.; Lakatta, E. G.; Luan, J.; Luben, R. N.; Mangino, M.; McArdle, W. L.; Meitinger, T.; Mulas, A.; Munroe, P. B.; Narisu, N.; Ness, A. R.; Northstone, K.; O'Rahilly, S.; Purmann, C.; Rees, M. G.; Ridderstrale, M.; Ring, S. M.; Rivadeneira, F.; Ruokonen, A.; Sandhu, M. S.; Saramies, J.; Scott, L. J.; Scuteri, A.; Silander, K.; Sims, M. A.; Song, K.; Stephens, J.; Stevens, S.; Stringham, H. M.; Tung, Y. C.; Valle, T. T.; Van Duijn, C. M.; Vimaleswaran, K. S.; Vollenweider, P.; Waeber, G.; Wallace, C.; Watanabe, R. M.; Waterworth, D. M.; Watkins, N.; Witteman, J. C.; Zeggini, E.; Zhai, G.; Zillikens, M. C.; Altshuler, D.; Caulfield, M. J.; Chanock, S. J.; Farooqi, I. S.; Ferrucci, L.; Guralnik, J. M.; Hattersley, A. T.; Hu, F. B.; Jarvelin, M. R.; Laakso, M.; Mooser, V.; Ong, K. K.; Ouwehand, W. H.; Salomaa, V.; Samani, N. J.; Spector, T. D.; Tuomi, T.; Tuomilehto, J.; Uda, M.; Uitterlinden, A. G.; Wareham, N. J.; Deloukas, P.; Frayling, T. M.; Groop, L. C.; Hayes, R. B.; Hunter, D. J.; Mohlke, K. L.; Peltonen, L.; Schlessinger, D.; Strachan, D. P.; Wichmann, H. E.; McCarthy, M. I.; Boehnke, M.; Barroso, I.; Abecasis, G. R.; Hirschhorn, J. N. (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation Nat Genet, 41 (1),25-34 [Journal Article] Online
Abstract: Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
PubMed Accession Number :: 19079261.

Vistisen, D.; Colagiuri, S.; Borch-Johnsen, K. (2009) Bimodal distribution of glucose is not universally useful for diagnosing diabetes Diabetes Care, 32 (3),397-403 [Journal Article] Online
Abstract: OBJECTIVE: Bimodality in the distribution of glucose has been used to define the cut point for the diagnosis of diabetes. Previous studies on bimodality have primarily been in populations with a high prevalence of type 2 diabetes, including one study in a white Caucasian population. All studies included participants with known diabetes. The aim of this study was to assess whether a bimodal structure is a general phenomenon in fasting plasma glucose (FPG) and 2-h plasma glucose that is useful for deriving a common cut point for diabetes in populations of different origin, both including and excluding known diabetes. RESEARCH DESIGN AND METHODS: The Evaluation of Screening and Early Detection Strategies for Type 2 Diabetes and Impaired Glucose Tolerance (DETECT-2) project is an international collaboration pooling surveys from all continents. These studies include surveys in which plasma glucose was measured during an oral glucose tolerance test; in total, 43 studies (135,383 participants) from 27 countries were included. A mixture of two normal distributions was fitted to plasma glucose levels, and a cut point for normal glycemia was estimated as their intersection. In populations with a biologically meaningful cut point, bimodality was tested for significance. RESULTS: Distributions of FPG and 2-h plasma glucose did not, in general, produce bimodal structures useful for deriving cut points for diabetes. When present, the cut points produced were inconsistent over geographical regions. CONCLUSIONS: Deriving cut points for normal glycemia from distributions of FPG and 2-h plasma glucose does not appear to be suitable for defining diagnostic cut points for diabetes.
PubMed Accession Number :: 19074990.

Prokopenko, I.; Langenberg, C.; Florez, J. C.; Saxena, R.; Soranzo, N.; Thorleifsson, G.; Loos, R. J.; Manning, A. K.; Jackson, A. U.; Aulchenko, Y.; Potter, S. C.; Erdos, M. R.; Sanna, S.; Hottenga, J. J.; Wheeler, E.; Kaakinen, M.; Lyssenko, V.; Chen, W. M.; Ahmadi, K.; Beckmann, J. S.; Bergman, R. N.; Bochud, M.; Bonnycastle, L. L.; Buchanan, T. A.; Cao, A.; Cervino, A.; Coin, L.; Collins, F. S.; Crisponi, L.; de Geus, E. J.; Dehghan, A.; Deloukas, P.; Doney, A. S.; Elliott, P.; Freimer, N.; Gateva, V.; Herder, C.; Hofman, A.; Hughes, T. E.; Hunt, S.; Illig, T.; Inouye, M.; Isomaa, B.; Johnson, T.; Kong, A.; Krestyaninova, M.; Kuusisto, J.; Laakso, M.; Lim, N.; Lindblad, U.; Lindgren, C. M.; McCann, O. T.; Mohlke, K. L.; Morris, A. D.; Naitza, S.; Orru, M.; Palmer, C. N.; Pouta, A.; Randall, J.; Rathmann, W.; Saramies, J.; Scheet, P.; Scott, L. J.; Scuteri, A.; Sharp, S.; Sijbrands, E.; Smit, J. H.; Song, K.; Steinthorsdottir, V.; Stringham, H. M.; Tuomi, T.; Tuomilehto, J.; Uitterlinden, A. G.; Voight, B. F.; Waterworth, D.; Wichmann, H. E.; Willemsen, G.; Witteman, J. C.; Yuan, X.; Zhao, J. H.; Zeggini, E.; Schlessinger, D.; Sandhu, M.; Boomsma, D. I.; Uda, M.; Spector, T. D.; Penninx, B. W.; Altshuler, D.; Vollenweider, P.; Jarvelin, M. R.; Lakatta, E.; Waeber, G.; Fox, C. S.; Peltonen, L.; Groop, L. C.; Mooser, V.; Cupples, L. A.; Thorsteinsdottir, U.; Boehnke, M.; Barroso, I.; Van Duijn, C.; Dupuis, J.; Watanabe, R. M.; Stefansson, K.; McCarthy, M. I.; Wareham, N. J.; Meigs, J. B.; Abecasis, G. R. (2009) Variants in MTNR1B influence fasting glucose levels Nat Genet, 41 (1),77-81 [Journal Article] Online
Abstract: To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
PubMed Accession Number :: 19060907.

Ekelund, U.; Anderssen, S.; Andersen, L. B.; Riddoch, C. J.; Sardinha, L. B.; Luan, J.; Froberg, K.; Brage, S. (2009) Prevalence and correlates of the metabolic syndrome in a population-based sample of European youth Am J Clin Nutr, 89 ,90-6 [Journal Article] Online
Abstract: BACKGROUND: Until recently, there has been no unified definition of the metabolic syndrome (MetS) in the youth. Therefore, the prevalence of MetS and its association with potential correlates are largely unknown. OBJECTIVE: The objective was to quantify the prevalence, identify the correlates, and examine the independent associations between potential correlates with MetS. DESIGN: A population-based cohort study was conducted in 10- and 15-y-old youth from Estonia, Denmark, and Portugal (n = 3193). MetS was defined according to the International Diabetes Federation. Correlates included maternal socioeconomic status, body mass index (BMI), hypertension, and prevalent diabetes and maternally reported child's birth weight and duration of breastfeeding. Data on sexual maturity, objectively measured physical activity, cardiorespiratory fitness, self-reported sports participation, television viewing, and regular play were collected for the children. RESULTS: The prevalence of MetS was 0.2% and 1.4% in 10- and 15-y-olds, respectively. Cardiorespiratory fitness (standardized odds ratio: 0.33; 95% CI: 0.15, 0.75), physical activity (standardized odds ratio: 0.40; 95% CI: 0.18, 0.88), and maternal BMI (standardized odds ratio: 1.61; 95% CI: 1.11, 2.34) were all independently associated with MetS after adjustment for sex, age group, study location, birth weight, and sexual maturity. An increase in daily moderate-intensity physical activity by 10-20% was associated with a 33% lower risk of being categorized with MetS. CONCLUSIONS: High maternal BMI and low levels of cardiorespiratory fitness and physical activity independently contribute to the MetS and may be targets for future interventions. Relatively small increases in physical activity may significantly reduce the risk of MetS in healthy children.
PubMed Accession Number :: 19056570.

Sattar, N.; Murray, H. M.; Welsh, P.; Blauw, G. J.; Buckley, B. M.; de Craen, A. J.; Ford, I.; Forouhi, N. G.; Freeman, D. J.; Jukema, J. W.; Macfarlane, P. W.; Murphy, M. B.; Packard, C. J.; Stott, D. J.; Westendorp, R. G.; Shepherd, J. (2009) Are elevated circulating intercellular adhesion molecule 1 levels more strongly predictive of diabetes than vascular risk? Outcome of a prospective study in the elderly Diabetologia, 52 (2),235-239 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The aim of this prospective study was to determine whether circulating intercellular adhesion molecule (ICAM) 1, as a potential surrogate of 'endothelial activation', is more strongly associated with risk of vascular events than with incident diabetes. METHODS: We related baseline ICAM-1 levels to vascular events (866 CHD and stroke events in 5,685 participants) and incident diabetes (292 in 4,945 without baseline diabetes) in the elderly over 3.2 years of follow-up. RESULTS: ICAM-1 levels correlated positively with triacylglycerol but negatively with LDL- and HDL-cholesterol. ICAM-1 levels were higher in those who developed diabetes (388.6 +/- 1.42 vs 369.4 +/- 1.39 ng/ml [mean+/-SD], p = 0.011) and remained independently associated with new-onset diabetes (HR 1.84, 95% CI 1.26-2.69, p = 0.0015 per unit increase in log[ICAM-1] after adjusting for classical risk factors and C-reactive protein). By contrast, ICAM-1 levels were not significantly (p = 0.40) elevated in those who had an incident vascular event compared with those who remained event-free, and corresponding adjusted risk associations were null (HR 0.98, 95% CI 0.80-1.22, p = 0.89) in analyses adjusted for other risk factors. CONCLUSIONS/INTERPRETATION: We show that elevated ICAM-1 levels are associated with risk of incident diabetes in the elderly at risk, despite no association with incident cardiovascular disease risk. We suggest that perturbations in circulating ICAM-1 levels are aligned more towards diabetes risk.
PubMed Accession Number :: 19030842.

McFadden, E.; Luben, R.; Bingham, S.; Wareham, N.; Kinmonth, A. L.; Khaw, K. T. (2009) Does the association between self-rated health and mortality vary by social class? Soc Sci Med, 68 ,275-280 [Journal Article] Online
Abstract: Self-rated health (SRH) predicts future mortality. Individuals in different social classes with similar physical health status may have different reference levels and criteria against which they judge their health, therefore the SRH-mortality relationship may vary according to social class. We examine the relationship between SRH and mortality by occupational social class in a prospective study of 22,457 men and women aged 39-79 years, without prevalent disease, living in the general community in Norfolk, United Kingdom, recruited using general practice age-sex registers in 1993-1997 and followed up for an average of 10 years. As expected, SRH was related to subsequent mortality. The age and sex adjusted hazard ratio for mortality for those with poor compared to those with excellent SRH was 4.35 (95% confidence interval 3.38-5.59, P<0.001). The prevalence of poor or moderate SRH was higher in manual than in non-manual classes. However, SRH was similarly related to mortality in manual and non-manual classes: when non-manual classes are compared with manual classes for each category of SRH, the 95% confidence intervals for the mortality hazard ratios overlap. There was no evidence of an interaction between social class and SRH in either men or women. Thus in this population, SRH appears to predict mortality in a similar manner in non-manual and manual classes.
PubMed Accession Number :: 19028414.

Assah, F. K.; Ekelund, U.; Brage, S.; Mbanya, J. C.; Wareham, N. J. (2009) Free-living physical activity energy expenditure is strongly related to glucose intolerance in Cameroonian adults independently of obesity Diabetes Care, 32 (2),367-9 [Journal Article] Online
Abstract: Objective: We examined the cross-sectional association between objectively measured free-living physical activity energy expenditure (PAEE) and glucose tolerance in adult Cameroonians without known diabetes. Research design and methods: PAEE was measured in 34 volunteers using the doubly labelled water method and indirect calorimetry (resting). Fasting blood glucose (FBG) and 2 hours post-load blood glucose (2-h BG) were measured during a standard 75g OGTT. Results: There was a significant negative correlation between PAEE and 2 hour glucose (r=-0.43, p=0.01) but not with fasting glucose (r=0.1, p=0.57). The inverse association between PAEE and 2 hour glucose remained after adjustment for age, sex, smoking alcohol consumption and BMI (beta=-0.017, 95%CI: -0.033, -0.002) and was unchanged after further adjustment for waist circumference, body fat percentage or aerobic fitness. Conclusion: PAEE is inversely associated with 2 hour glucose independently of adiposity or fitness. Interventions aimed at increasing PAEE could play an important role in diabetes prevention in developing countries.
PubMed Accession Number :: 19017776.

Mallat, Z.; Simon, T.; Benessiano, J.; Clement, K.; Taleb, S.; Wareham, N. J.; Luben, R.; Khaw, K. T.; Tedgui, A.; Boekholdt, S. M. (2009) Retinol Binding Protein 4 and Prediction of Incident Coronary Events in Healthy Men and Women J Clin Endocrinol Metab, 94 (1),255-60 [Journal Article] Online
Abstract: Context. Recent studies reported that retinol binding protein 4 (RBP4) has a causal role in insulin resistance, and suggested that its circulating levels may predict cardiovascular disease. However, the latter assumption has not yet been tested. Objective. We assessed the value of RBP4 measurement in the prediction of incident coronary artery disease (CAD). Design. Nested case-control study of incident CAD (n=1036 cases vs. n=1889 controls) selected from among 25,336 participants of the EPIC-Norfolk study. Setting. Healthy men and women, aged between 45 and 79 years, recruited from age-sex registers of general practices in Norfolk. Patients and other participants. Participants completed a baseline questionnaire survey between 1993 and 1997, attended a clinic visit and were followed for an average of 6 years. Cases (n=1036) were participants who developed CAD during the follow-up. Controls (n=1889) matched by age, sex, and enrolment time remained free of any CAD during follow-up. Intervention(s). None. Main outcomes measure (s). Risk of incident fatal or non fatal CAD according to RBP4 quartiles. Results. RBP4 levels were higher in cases than in controls. RBP4 levels correlated weakly with body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, total and LDL- cholesterol, and were inversely associated with CRP concentrations. The strongest correlation was found with triglycerides. The risk of incident CAD was associated with increasing quartiles of RBP4 levels (P=0.03). However, adjustment for cardiovascular risk factors abolished this association. Conclusions. Measurement of serum RBP4 does not provide added value for predicting CAD risk beyond traditional risk factors.
PubMed Accession Number :: 18854400.

Patra, B.; Parsian, A. J.; Racette, B. A.; Zhao, J. H.; Perlmutter, J. S.; Parsian, A. (2009) LRRK2 gene G2019S mutation and SNPs [haplotypes] in subtypes of Parkinson's disease Parkinsonism Relat Disord, 15 (3),175-80 [Journal Article] Online
Abstract: Mutation within the leucine-rich repeat kinase 2 (LRRK2) gene has been identified as a cause of autosomal dominant Parkinson's disease (PD). The purpose of this study was to determine the frequency of G2019S mutation and whether the differences in the allele and genotype distribution of six SNPs within LRRK2 gene are associated with PD in an American non-Hispanic white population. The sample included 350 sporadic PD (SPD), 225 familial PD (FPD) patients and 186 controls of the same race and ethnicity. The frequency of LRRK2 G2019S mutation in our total sample of PD (FPD and SPD) was 1.56%. The frequency of this mutation was 3.5% in the FPD and 0.3% in the SPD groups, respectively. Allele and genotype frequencies of six SNPs were compared between PD and control samples. In addition, PD groups were categorized by sporadic PD (no family history), familial PD (first degree relative with PD) and age of onset (AON, </=50 or >/=51years). The haplotypes of the six SNPs were also constructed for association analysis. After correction for multiple comparisons, there was no association between any SNPs (allele or genotype) and PD groups. One of the haplotypes was modestly associated with the combined PD (SPD and FPD) sample. There was also no association with age at onset of PD. Our study suggests that the LRRK2 gene may be a risk factor or the cause for a very small fraction of PD in American white population.
PubMed Accession Number :: 18752982.

French, D. P.; Eborall, H.; Griffin, S.; Kinmonth, A. L.; Prevost, A. T.; Sutton, S. (2009) Completing a postal health questionnaire did not affect anxiety or related measures: randomized controlled trial J Clin Epidemiol, 62 ,74-80 [Journal Article] Online
Abstract: OBJECTIVE: There is evidence from laboratory studies that anxiety scores are elevated by completing questionnaires about health problems for the first time. This limits interpretation of the common finding that people receiving risk information from screening programs show elevated anxiety (as assessed by questionnaire) in the short-term, which subsides over time. We examine the extent to which postal questionnaire studies are affected by this potential measurement artifact. STUDY DESIGN AND SETTING: Participants were 964 patients at high risk of undiagnosed diabetes, registered at five general practices. A two-group randomized experimental design was used, with the experimental group (n=484) receiving an initial questionnaire concerning screening for diabetes, and the control group (n=480) not receiving this questionnaire. Outcomes were assessed by an identical questionnaire 3 months later. RESULTS: There were no significant differences in questionnaire scores at three months between the two groups on any of the outcome measures, including anxiety, symptoms, perceptions of diabetes severity, and perceived diabetes risk. CONCLUSION: These results suggest that the problems associated with the use of anxiety questionnaires that are found in laboratory studies do not occur in postal studies: the observed changes in anxiety after receiving screening results are therefore unlikely to be artifactual.
PubMed Accession Number :: 18632252.

Bowman, R.; Joosen, A. M.; Welch, A. A.; Luben, R. N.; Khaw, K. T.; Wareham, N. J.; Bingham, S. A. (2009) Factor VII, blood lipids and fat intake: gene-nutrient interaction and risk of coronary heart disease with the factor VII R353Q polymorphism Eur J Clin Nutr, 63 (6),771-7 [Journal Article] Online
Abstract: Background: The relation between dietary fat, blood lipids, plasma factor VII coagulant activity (FVIIc) and risk of coronary heart disease (CHD) according to the R353Q polymorphism in the factor VII gene was assessed.Methods: Cross-sectional study of 15 073 individuals participating in the European Prospective Investigation of Cancer (EPIC) Norfolk, 7433 of which had FVIIc available. Nested case-control study of 985 CHD cases and 2009 matched controls.Results: FVIIc was significantly associated with total fat intake in females, especially in the RR homozygotes (standardized beta=0.24; 95% confidence interval (95% CI) 0.08-0.40; P<0.01), but there were no associations with intakes of saturated, monounsaturated or polyunsaturated fatty acids according to genotype and no associations in males. FVIIc was significantly positively associated with total cholesterol (P<0.01) and with triacylglycerol (P<0.001) in both genders, with an interaction according to genotype for triacylglycerol in males: beta Q allele carriers 0.26 (95% CI 0.18-0.34), beta RR homozygotes 0.16 (95% CI 0.12-0.20) (Z interaction =-2.24; P<0.05). There was no effect of genotype on the odds ratio (OR) for incident CHD: OR 0.89 for Q allele carriers compared with RR homozygotes (95% CI 0.77-1.02) in 985 cases and 2009 matched controls.Conclusion: These results show a strong association between dietary fat intake and FVIIc in women, and between serum triacylglycerol and cholesterol and FVIIc levels in both genders. The R353Q genotype only marginally affected modulation of FVIIc by dietary fat. The association between triacylglycerol and FVIIc was significantly stronger in males carrying the Q allele than in those with the RR genotype.European Journal of Clinical Nutrition advance online publication, 9 April 2008; doi:10.1038/ejcn.2008.28.
PubMed Accession Number :: 18398422.

Nyberg, G.; Ekelund, U.; Marcus, C. (2009) Physical activity in children measured by accelerometry: stability over time Scand J Med Sci Sports, 19 (1),30-5 [Journal Article] Online
Abstract: The aim of this study was to examine the stability of objectively measured physical activity in Swedish children and to study variables that predicted physical activity and body mass index standard deviation score (BMI SDS) at follow-up. A total of 97 children provided valid repeated measurements of physical activity between 2002 and 2005. The children were on average 7.5 years at baseline (SD+/-0.92) and 9 years at follow-up (SD+/-0.92). The mean follow-up time was approximately 1.5 years (mean 558 days, SD+/-224). An accelerometer (Actiwatch((R)), Cambridge Neurotechnology Ltd., Cambridge, UK) was used to measure physical activity during 7 consecutive days. Yearly weight and height were examined and BMI SDS was calculated. Baseline physical activity was significantly correlated with physical activity at follow-up (r=0.59) with a stronger correlation for boys (r=0.72) than for girls (r=0.51). High physical activity levels were more stable (r=0.74) than low physical activity levels (r=0.55). Physical activity at follow-up was explained by physical activity at baseline and season (R(2)=0.46) whereas BMI SDS at follow-up was explained by BMI SDS at baseline and age (R(2)=0.90). The results of this study suggest that physical activity levels are fairly stable in 6-10-year-old children.
PubMed Accession Number :: 18248540.

Nilsson, A.; Anderssen, S. A.; Andersen, L. B.; Froberg, K.; Riddoch, C.; Sardinha, L. B.; Ekelund, U. (2009) Between- and within-day variability in physical activity and inactivity in 9- and 15-year-old European children Scand J Med Sci Sports, 19 (1),10-8 [Journal Article] Online
Abstract: To examine differences in levels of physical activity (PA), time spent at moderate-to-vigorous intensity PA (MVPA) and time spent sedentary between and within days in children from four European countries, 1954 9 - and 15-year-olds were included. PA was measured during 2 weekdays and 2 weekend days using the manufacturing technology-incorporated (MTI) accelerometer. Average count per minute, time spent sedentary, time spent at MVPA and the proportion of children accumulating >/=60 min of MVPA were calculated. Data were compared between weekdays and weekend days and between school time and leisure-time. Although not entirely consistent across countries, overall PA, time spent sedentary and the proportion of children accumulating >/=60 min of MVPA were higher during weekdays compared with weekend days. Differences in overall PA between school time and leisure-time were highly inconsistent between countries. Few children (4-31%) accumulated >/=60 min of MVPA either during school time or during leisure-time. Differences in activity patterns between weekdays and weekend days are explained by less accumulated time in MVPA during weekend days. Weekend days and leisure-time during weekdays seem appropriate targets when promoting PA in order to increase the proportion of children achieving current recommendations on health-enhancing PA.
PubMed Accession Number :: 18248534.

Purslow, L. R.; Hill, C.; Saxton, J.; Corder, K.; Wardle, J. (2008) Differences in physical activity and sedentary time in relation to weight in 8-9 year old children Int J Behav Nutr Phys Act, 5 ,67 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: The health benefits of physical activity for children are well established. Although objective measures of physical activity are increasingly used there is still a lack of adequate data on physical activity in children. Sex differences in physical activity have been consistently demonstrated and lower levels of physical activity in obese than non-obese children have been shown. However, differences across the whole weight spectrum have not been examined in detail. The aim of this study was to assess associations between physical activity and sedentary time across the weight spectrum in children, and to determine whether the associations differed by sex. METHODS: Participants in the current study were 176 boys and 169 girls aged 8-9 years old taking part in a longitudinal study of associations between eating behaviours, physical activity and weight gain during childhood. Height, weight and waist circumference were measured, and physical activity data were collected using an Actigraph model GT1M worn for 5 consecutive days. Associations between sex, weight and physical activity were analysed using linear regression models. RESULTS: Boys had higher total activity (mean difference = 119, p < 0.001) and more minutes of moderate and vigorous physical activity (MVPA) (mean difference = 25, p < 0.001) than girls. A higher percentage of boys (72%) than girls (30%) met current physical activity guidelines of 60 minutes MVPA per day. In boys, weight status significantly predicted total activity (p = 0.001) and MVPA (p = 0.001) but there were no significant associations in girls. There was no significant difference in time spent sedentary between boys and girls, and weight status did not predict sedentary time. CONCLUSION: In boys, physical activity was progressively lower across the weight spectrum, but in girls physical activity was consistently low across all weight categories. Intervention is required prior to 8 years old to prevent weight-related declines in physical activity in boys and further research is required to determine at what age, if ever, weight related differences in physical activity are apparent in girls.
PubMed Accession Number :: 19077283.

Echouffo-Tcheugui, J. B.; Sargeant, L. A.; Prevost, A. T.; Williams, K. M.; Barling, R. S.; Butler, R.; Fanshawe, T.; Kinmonth, A. L.; Wareham, N. J.; Griffin, S. J. (2008) How much might cardiovascular disease risk be reduced by intensive therapy in people with screen-detected diabetes? Diabet Med, 25 (12),1433-9 [Journal Article] Online
Abstract: Aims To assess the cardiovascular disease (CVD) risk of people with screen-detected Type 2 diabetes and to estimate the risk reduction achievable through early intensive pharmacological intervention. Methods In ADDITION-Cambridge, diabetic patients were identified among people aged 40-69 years through a stepwise screening procedure including a risk score, random and fasting capillary blood glucose, HbA(1c) and oral glucose tolerance test. In those without prior macrovascular disease, 10-year CVD risk was computed using UK Prospective Diabetes Study (UKPDS) and Framingham engines. The absolute risk reduction achievable and its plausible range were predicted using relative risk reductions for individual therapies from published trials and sensitivity analysis. Results Of the 867 individuals with undiagnosed diabetes, 19% had pre-existing CVD, 97% were overweight or obese, 86% had hypertension, 75% had dyslipidaemia, 20% had microalbuminuria and 18% were smokers. Of those with hypertension, 35% were not prescribed drugs and 42% were suboptimally treated. Of participants with dyslipidaemia, 68% were not prescribed medications and 22% were poorly controlled. Median 10-year CVD risk was 34.0%[interquartile range (IQR) 26.2-44.6] in men and 21.5% (IQR 15.7-28.7) in women using the UKPDS engine; 38.6% (IQR 27.8-53.0) in men and 24.6% (IQR 17.2-32.9) in women using Framingham equations. In the most conservative scenario (no additive effect of therapies), the absolute risk reduction achievable through multifactorial therapy ranged from 4.9 to 9.5% (UKPDS) and from 5.4 to 10.5% (Framingham). The corresponding ranges of numbers needed to treat were 11-20 and 10-19. Conclusions People with screen-detected diabetes have an adverse cardiovascular risk profile, which is potentially modifiable through application of existing treatment recommendations.
PubMed Accession Number :: 19046242.

Wareham, N. J.; Young, E. H.; Loos, R. J. (2008) Epidemiological study designs to investigate gene-behavior interactions in the context of human obesity Obesity (Silver Spring), 16 Suppl 3 ,S66-71 [Journal Article] Online
Abstract: The epidemiology of obesity suggests that, for the majority of individuals, the disorder arises from an interaction between genetic predisposition and lifestyle behaviors such as dietary intake and physical activity. Unravelling the molecular basis of such interactions is complex but is becoming a realistic proposition as evidence emerges from whole genome association studies of genetic variants that are definitively associated with obesity. A range of possible study designs is available for investigating gene-lifestyle interaction, and the strengths and weaknesses of each approach are discussed in this article. Given the likely small main effect of common genetic variants and the difficulties in demonstrating associations of lifestyle factors with future risk of obesity, we would favor an analytical approach based on the clear specification of prior probabilities to reduce the likelihood of false discovery. Mixed approaches combining data from large-scale observational studies with smaller intervention trials may be ideal. In designing new studies to investigate these issues, a key choice is how precisely to quantify the important, but difficult to measure lifestyle behaviors. It is clear from power calculations that an approach based on enhancing precision of measurement of diet and physical activity is critical.Obesity (2008) 16, S66-S71; doi:10.1038/oby.2008.521.
PubMed Accession Number :: 19037217.

van Sluijs, E. M.; Skidmore, P. M.; Mwanza, K.; Jones, A. P.; Callaghan, A. M.; Ekelund, U.; Harrison, F.; Harvey, I.; Panter, J.; Wareham, N. J.; Cassidy, A.; Griffin, S. J. (2008) Physical activity and dietary behaviour in a population-based sample of British 10-year old children: the SPEEDY study (Sport, Physical activity and Eating behaviour: Environmental Determinants in Young people) BMC Public Health, 8 (1),388 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: The SPEEDY study was set up to quantify levels of physical activity (PA) and dietary habits and the association with potential correlates in 9-10 year old British school children. We present here the analyses of the PA, dietary and anthropometry data. METHODS: In a cross-sectional study of 2064 children (926 boys, 1138 girls) in Norfolk, England, we collected anthropometry data at school using standardised procedures. Body mass index (BMI) was used to define obesity status. PA was assessed with the Actigraph accelerometer over 7 days. A cut-off of >=2000 activity counts was used to define minutes of moderate-to-vigorous PA (MVPA). Dietary habits were assessed using the Health Behaviour in School Children food questionnaire. Weight status was defined using published international cut-offs (Cole, 2000). Differences between groups were assessed using independent t-tests for continuous data and chi-squared tests for categorical data. RESULTS: Valid PA data (>500 minutes per day on [greater than or equal to]3 days) was available for 1888 children. Mean (+/-SD) activity counts per minute among boys and girls were 716.5+/-220.2 and 635.6+/-210.6, respectively (p<0.001). Boys spent an average of 84.1+/-25.9 minutes in MVPA per day compared to 66.1+/-20.8 among girls (p<0.001), with an average of 69.1% of children accumulating 60 minutes each day. The proportion of children classified as overweight and obese was 15.0% and 4.1% for boys and 19.3% and 6.6% for girls, respectively (p=0.001). Daily consumption of at least one portion of fruit and of vegetables was 56.8% and 49.9% respectively, with higher daily consumption in girls than boys and in children from higher socioeconomic backgrounds. CONCLUSIONS: Results indicate that almost 70% of children meet national PA guidelines, indicating that a prevention of decline, rather than increasing physical activity levels, might be an appropriate intervention target. Promotion of daily fruit and vegetable intake in this age group is also warranted, possibly focussing on children from lower socioeconomic backgrounds.
PubMed Accession Number :: 19014571.

Wareham, N. J.; Corder, K.; van Sluijs, E. M. (2008) Decrease in activity from childhood to adolescence: potential causes and consequences Am J Prev Med, 35 (6),604-5 [Journal Article] Online
Keywords: Adolescent Body Mass Index Child *Child Development Humans Motor Activity/*physiology Risk Factors Social Environment
PubMed Accession Number :: 19000850.

Talmud, P. J.; Smart, M.; Presswood, E.; Cooper, J. A.; Nicaud, V.; Drenos, F.; Palmen, J.; Marmot, M. G.; Boekholdt, S. M.; Wareham, N. J.; Khaw, K. T.; Kumari, M.; Humphries, S. E. (2008) ANGPTL4 E40K and T266M: Effects on Plasma Triglyceride and HDL Levels, Postprandial Responses, and CHD Risk Arterioscler Thromb Vasc Biol, 28 (12),2319-2325 [Journal Article] Online
Abstract: Background- Angiopoietin-like 4 is a dual-function protein: an inhibitor of LPL, influencing plasma triglycerides (TGs), with angiogenic properties. We examined the association of common ANGPTL4 variants with CHD traits and risk in 5 studies (13 527 individuals). METHODS AND RESULTS: The effects on plasma lipids of 6 tagging SNPs and the recently identified E40K were examined in a study of 2772 men. Only T266M (rs1044250, MAF=30%) and E40K (MAF=2%) were significantly associated with TG-lowering (-10.4%, P<0.004 and -20.4%, P<0.0001), respectively. T266M no longer showed significant associations when K40 carriers (K40+) were excluded (P=0.2). Combining data from 5 studies confirmed the TG-lowering effect of K40+ (weighted mean difference: -0.12 [95% CI -0.18, -0.05] mmol/L TG P=0.0001). Surprisingly, in the 3 prospective studies, the combined OR for CHD was 1.48 (1.11 to 1.96, P=0.007), independent of TG. In individuals with a paternal history of MI (n=332) T266M, but not E40K, showed effects on postprandial AUC TG and glucose (P=0.009 and P=0.017, respectively) compared to controls (n=370). CONCLUSIONS: Although associated with an atheroprotective lipid profile, E40K was associated with increased CHD risk, suggesting Angptl4 influences parameters beyond lipid levels. T266M showed effects only under conditions of postprandial stress. The functionality of these potential "loss-of-function" variants needs validation.
PubMed Accession Number :: 18974381.

Califf, R. M.; Boolell, M.; Haffner, S. M.; Bethel, M. A.; McMurray, J.; Duggal, A.; Holman, R. R. (2008) Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial Am Heart J, 156 (4),623-32 [Journal Article] Online
Abstract: Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 x 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged > or = 50 years with known CVD or aged > or = 55 years with > or = 1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: nateglinide with valsartan, nateglinide with valsartan-placebo, nateglinide-placebo with valsartan, or nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a "core" composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an "extended" composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT.
PubMed Accession Number :: 18946890.

Zhang, L.; Qiao, Q.; Tuomilehto, J.; Hammar, N.; Alberti, K. G.; Eliasson, M.; Heine, R. J.; Stehouwer, C. D.; Ruotolo, G. (2008) Blood lipid levels in relation to glucose status in European men and women without a prior history of diabetes: the DECODE Study Diabetes Res Clin Pract, 82 (3),364-77 [Journal Article] Online
Abstract: OBJECTIVE: Dyslipidaemia is present not only in diabetic but also in prediabetic subjects. The purpose of this study is to investigate the relationship between lipid and glucose levels in a large European population without a prior history of diabetes. RESEARCH DESIGN AND METHODS: Data from the population-based studies of 8960 men and 10,516 women aged 35-74 years representing 15 cohorts in 8 European countries were jointly analyzed. Multivariate adjusted linear regression analyses with standardized coefficients (beta) were performed to estimate the relationship between lipid and plasma glucose. RESULTS: In subjects without a prior history of diabetes, positive relationships were shown between fasting plasma glucose (FPG) and total cholesterol (TC) (beta=0.06 and 0.03, respectively for men and women, p<0.01), triglycerides (TG) (beta=0.14 and 0.12, p<0.001), non-high-density lipoprotein cholesterol (non-HDL-C) (beta=0.06 and 0.03, p<0.01) and TC to HDL ratio (beta=0.06 and 0.05, p<0.001) but a negative trend between FPG and HDL-C (beta=-0.02, p>0.05 in men and beta=-0.03, p<0.05 in women). The relationship between lipid and 2-h plasma glucose (2hPG) followed a similar pattern as that for FPG, except that TC was not increased and HDL-C was reduced in both sexes in subjects with impaired glucose tolerance (IGT). CONCLUSIONS: For cardiovascular prevention, the different lipid patterns between impaired fasting glucose (IFG) and IGT may deserve further attention to evaluate the combined risks of dyslipidaemia and elevated glucose levels below the diagnostic threshold of diabetes.
PubMed Accession Number :: 18922596.

Besson, H.; Ekelund, U.; Brage, S.; Luben, R.; Bingham, S.; Khaw, K. T.; Wareham, N. J. (2008) Relationship between Subdomains of Total Physical Activity and Mortality Med Sci Sports Exerc, 40 ,1909-15 [Journal Article] Online
Abstract: PURPOSE:: The purpose of this study was to describe the association of the overall and domain-specific physical activity on all-cause and cardiovascular mortality. A large body of epidemiological evidence suggests a strong and consistent inverse association between physical activity and mortality risk. However, it is unclear how this association varies according to the domain of life in which the activity takes place. METHODS:: In an English population-based cohort of 14,903 participants (mean age = 63 yr), total and domain-specific physical activity was assessed using a validated questionnaire (EPAQ2). After a median follow-up of 7 yr, there were 1128 deaths, with 370 from cardiovascular disease. RESULTS:: The relative risks (95% confidence interval) for all-cause mortality due to physical activity undertaken at home, during exercise, at work, for transport, and in total were 0.81 (0.66-0.99), 0.66 (0.54-0.80), 0.84 (0.55-1.30), 0.82 (0.67-1.00), and 0.77 (0.61-0.98), respectively, after adjustment for baseline age, sex, social class, alcohol consumption, smoking status, history of diabetes, history of cancer, and history of cardiovascular disease and stroke. Cardiovascular mortality was inversely associated with physical activity undertaken at home (P for trend = 0.03), during exercise (P for trend = 0.001), and in total (P for trend = 0.007). The results were unchanged after excluding individuals with a history of heart disease, stroke, and cancer at baseline and those who died within the first 2 yr of follow-up. CONCLUSIONS:: In this study, physical activities at home and during exercise are associated with lower risk of mortality, whereas occupational and transportation-related activities are not. Promoting the potential benefits of physical activity undertaken at home and during exercise may be an important public health message for aging populations.
PubMed Accession Number :: 18845964.

Park, P.; Simmons, R. K.; Prevost, A. T.; Griffin, S. J. (2008) Screening for type 2 diabetes is feasible, acceptable, but associated with increased short-term anxiety: a randomised controlled trial in British general practice BMC Public Health, 8 (1),350 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: To assess the feasibility and uptake of a diabetes screening programme; to examine the effects of invitation to diabetes screening on anxiety, self-rated health and illness perceptions. METHODS: Randomised controlled trial in two general practices in Cambridgeshire. Individuals aged 40-69 without known diabetes were identified as being at high risk of having undiagnosed type 2 diabetes using patient records and a validated risk score (n=1,280). 355 individuals were randomised in a 2 to 1 ratio into non-invited (n=238) and invited (n=116) groups. A stepwise screening programme confirmed the presence or absence of diabetes. Six weeks after the last contact (either test or invitation), a questionnaire was sent to all participants, including non-attenders and those who were not originally invited. Outcome measures included attendance, anxiety (short-form Spielberger State Anxiety Inventory -STAI), self-rated health and diabetes illness perceptions. RESULTS: 95 people (82% of those invited) attended for the initial capillary blood test. Six individuals were diagnosed with diabetes. Invited participants were more anxious than those not invited (37.6 vs. 34.1 STAI, p-value = 0.015), and those diagnosed with diabetes were considerably more anxious than those classified free of diabetes (46.7 vs. 37.0 STAI, p-value = 0.031). Non-attenders had a higher mean treatment control sub-scale (3.87 vs. 3.56, p-value = 0.016) and a lower mean emotional representation sub-scale (1.81 vs. 2.68, p-value = 0.001) than attenders. No differences in the other five illness perception sub-scales or self-rated health were found. CONCLUSIONS: Screening for type 2 diabetes in primary care is feasible but may be associated with higher levels of short-term anxiety among invited compared with non-invited participants.
PubMed Accession Number :: 18840266.

Britton, J. A.; Khan, A. E.; Rohrmann, S.; Becker, N.; Linseisen, J.; Nieters, A.; Kaaks, R.; Tjonneland, A.; Halkjaer, J.; Severinsen, M. T.; Overvad, K.; Pischon, T.; Boeing, H.; Trichopoulou, A.; Kalapothaki, V.; Trichopoulos, D.; Mattiello, A.; Tagliabue, G.; Sacerdote, C.; Peeters, P. H.; Bueno-de-Mesquita, H. B.; Ardanaz, E.; Navarro, C.; Jakszyn, P.; Altzibar, J. M.; Hallmans, G.; Malmer, B.; Berglund, G.; Manjer, J.; Allen, N.; Key, T.; Bingham, S.; Besson, H.; Ferrari, P.; Jenab, M.; Boffetta, P.; Vineis, P.; Riboli, E. (2008) Anthropometric characteristics and non-Hodgkin lymphoma and multiple myeloma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Haematologica, 93 (11),1666-77 [Journal Article] Online
Abstract: Background The incidence of non-Hodgkin lymphoma and multiple myeloma is increasing steadily. It has been hypothesized that this may be due, in part, to the parallel rising prevalence of obesity. It is biologically plausible that anthropometric characteristics can infuence the risk of non-Hodgkin lymphoma and multiple myeloma. DESIGN AND METHODS: In the contest of the European Prospective Investigation into Cancer and Nutrition (EPIC), anthropometric characteristics were assessed in 371,983 cancer-free individuals at baseline. During the 8.5 years of follow-up, 1,219 histologically confirmed incident cases of non-Hodgkin lymphoma and multiple myeloma occurred in 609 men and 610 women. Gender-specific proportional hazards models were used to estimate relative risks and 95% confidence intervals (95% CI) of development of non-Hodgkin lymphoma and multiple myeloma in relation to the anthropometric characteristics. RESULTS: Height was associated with overall non-Hodgkin lymphoma and multiple myeloma in women (RR 1.50, 95% CI 1.14-1.98) for highest versus lowest quartile; p-trend < 0.01) but not in men. Neither obesity (weight and body mass index) nor abdominal fat (waist-to-hip ratio, waist or hip circumference) measures were positively associated with overall non-Hodgkin lymphoma and multiple myeloma. Relative risks for highest versus lowest body mass index quartile were 1.09 (95% CI 0.85-1.38) and 0.92 (95% CI 0.71-1.19) for men and women, respectively. Women in the upper body mass index quartile were at greater risk of diffuse large B-cell lymphoma (RR 2.18, 95% CI 1.05-4.53) and taller women had an elevated risk of follicular lymphoma (RR 1.25, 95% CI 0.59-2.62). Among men, height and body mass index were non-significantly, positively related to follicular lymphoma. Multiple myeloma risk alone was elevated for taller women (RR 2.34, 95% CI 1.29-4.21) and heavier men (RR 1.77, 95% CI 1.02-3.05). Conclusions The EPIC analyses support an association between height and overall non-Hodgkin lymphoma and MM among women and suggest heterogeneous subtype associations. This is one of the first prospective studies focusing on central adiposity and non-Hodgkin lymphoma subtypes.
PubMed Accession Number :: 18835833.

Souren, N. Y.; Zeegers, M. P.; Janssen, R. G.; Steyls, A.; Gielen, M.; Loos, R. J.; Beunen, G.; Fagard, R.; Stassen, A. P.; Aerssens, J.; Derom, C.; Vlietinck, R.; Paulussen, A. D. (2008) Anthropometry, Carbohydrate and Lipid Metabolism in the East Flanders Prospective Twin Survey: Linkage of Candidate Genes Using Two Sib-Pair Based Variance Components Analyses Twin Res Hum Genet, 11 (5),505-516 [Journal Article] Online
Abstract: Abstract Insulin resistance and obesity are underlying causes of type 2 diabetes and therefore much interest is focused on the potential genes involved. A series of anthropometric and metabolic characteristic were measured in 240 MZ and 112 DZ twin pairs recruited from the East Flanders Prospective Twin Survey. Microsatellite markers located close to ABCC8, ADIPOQ, GCK, IGF1, IGFBP1, INSR, LEP, LEPR, PPARgamma and the RETN gene were genotyped. Univariate single point variance components linkage analyses were performed using two methods: (1) the standard method, only comprising the phenotypic and genotypic data of the DZ twin pairs and (2) the extended method, also incorporating the phenotypic data of the MZ twin pairs. Suggestive linkages (LOD > 1) were observed between the ABCC8 marker and waist-to-hip ratio and HDL-cholesterol levels. Both markers flanking ADIPOQ showed suggestive linkage with triglycerides levels, the upstream marker also with body mass and HDL-cholesterol levels. The IGFBP1 marker showed suggestive linkage with fat mass, fasting insulin and leptin levels and the LEP marker showed suggestive linkage with birth weight. This study suggests that DNA variants in ABCC8, ADIPOQ, IGFBP1 and LEP gene region may predispose to type 2 diabetes. In addition, the two methods used to perform linkage analyses yielded similar results. This was however not the case for birth weight where chorionicity seems to be an important confounder.
PubMed Accession Number :: 18828733.

Finucane, F. M.; Pittock, S.; Fallon, M.; Hatunic, M.; Ong, K.; Burns, N.; Costigan, C.; Murphy, N.; Nolan, J. J. (2008) Elevated blood pressure in overweight and obese Irish children Ir J Med Sci, 177 (4),379-81 [Journal Article] Online
Abstract: BACKGROUND: The Irish childhood obesity epidemic, one of the highest ranking internationally, represents a major threat to public health. We sought to perform a retrospective observational study of a clinic based cohort of obese Irish children. METHODS: Clinical data relating to gender, age, height, weight, body mass index and blood pressure were analysed, from 206 children referred to a paediatric endocrine referral centre over a 15-year period for assessment of obesity. RESULTS: Younger patients tended to have a higher standardised body mass index at initial presentation; 92% of boys and 96% of girls referred were obese (age-related BMI >/= 95th percentile). Boys (51%) and girls (49%) had initial blood pressure measurements in the hypertensive range. There was a correlation between the degree of obesity and systolic blood pressure, particularly in boys. CONCLUSIONS: Obese Irish children present with significant long-term health risks, including hypertension at baseline.
PubMed Accession Number :: 18825476.

van Sluijs, E. M.; Page, A.; Ommundsen, Y.; Griffin, S. J. (2008) Behavioural and social correlates of sedentary time in young people Br J Sports Med, , [Journal Article] Online
Abstract: OBJECTIVE: To identify behavioural and social correlates of objectively-measured sedentary time in young people. DESIGN: Cross-sectional analysis of data from the European Youth Heart Study (EYHS). SETTING: Schools in Denmark, Estonia, Portugal and Norway. PARTICIPANTS: Invited using a two-stage cluster sampling procedure. Analyses include 2107 children (9-10 years) and adolescents (14-15 years). Assessment of independent variables: Seven behavioral and 15 social variables assessed by parental and computerized child questionnaires. MAIN OUTCOME MEASURE: Sedentary activity as assessed by accelerometry (10-minute blocks at <200 counts/minute). Analyses were stratified by country and interactions with grade and gender were investigated. RESULTS: Adolescents were more sedentary than children (335.4 (SD: 90.4) vs. 217.2 (SD: 75.6) minutes/day, p<0.001). Patterns of associations differed across countries. High computer use and no television viewing before school in Norway, and being sedentary during school-breaks in Estonia were positively associated with sedentary time. No behavioural variables were associated with sedentary time in the Danish and Portuguese models. Socioeconomic position was positively associated with sedentary time in Portugal and Estonia, father inverted exclamation mark|s body mass index negatively in the Estonian model. Norwegian participants with a games console at home and Portuguese participants with a television in their bedroom were more sedentary. CONCLUSIONS: A single strategy aimed at reducing sedentary behaviour is unlikely to be effective across Europe as the target populations and behaviours of focus differ between countries. Targeting high socioeconomic groups in Portugal and Estonia or focusing on reducing computer use in Norway might be effective intervention strategies to reduce overall sedentary time.
PubMed Accession Number :: 18812418.

Myint, P. K.; Sinha, S.; Luben, R. N.; Bingham, S. A.; Wareham, N. J.; Khaw, K. T. (2008) Risk factors for first-ever stroke in the EPIC-Norfolk prospective population-based study Eur J Cardiovasc Prev Rehabil, 15 (6),663-669 [Journal Article] Online
Abstract: BACKGROUND: Many studies examining stroke risk factors have focused on men and younger age groups. We examined stroke risk factors over a wide age range including elderly and women in a British population. METHODS: We examined the prospective relationship between known risk factors for stroke and stroke incidence in 22 516 men and women aged 40-79 years without stroke at baseline in the years 1993-1997 participating in the European Prospective Investigation into Cancer-Norfolk. RESULTS: During a total of 214 542 person-years of follow-up, 507 incident strokes occurred (fatal=162). Stroke risk increased with increasing age [relative risk (RR) 1.65, 95% confidence interval: 1.54, 1.75 per increase in 5 years]. Our results confirm the importance of modifiable risk factors for stroke in men and women, in particular, blood pressure and smoking. Higher systolic blood pressure of 10 mmHg was associated with RR of 1.19 (1.13, 1.24) and current smokers had RR of 1.70 (1.29, 2.23) compared with never smokers independent of age, sex, body mass index, cholesterol, triglycerides and diabetes. Having a systolic blood pressure greater than 140 mmHg compared with less than 140 mmHg was equivalent to being 6 years older and current smoking compared with nonsmoking equivalent to being 5 years older and diabetes 5 years older in terms of stroke risk. CONCLUSION: Classical modifiable stroke risk factors, blood pressure and smoking, may have a substantial impact on the age-related increase in stroke risk in men and women.
PubMed Accession Number :: 18779737.

Ekelund, U.; Brage, S.; Besson, H.; Sharp, S.; Wareham, N. J. (2008) Time spent being sedentary and weight gain in healthy adults: reverse or bidirectional causality? Am J Clin Nutr, 88 (3),612-7 [Journal Article] Online
Abstract: BACKGROUND: Whether obesity is a cause or a consequence of a sedentary lifestyle has not yet been fully elucidated, which leaves uncertainty about the direction of causality. OBJECTIVE: We aimed to assess the longitudinal associations between objectively measured time spent being sedentary (sedentary time) and obesity indicators. DESIGN: The study was a prospective, population-based cohort study in 393 middle-aged healthy whites (n = 176 M, 217 F). Sedentary time (% of daytime hours) was measured by individually calibrated monitoring of the heart rate. Body weight (BW), body mass index (BMI), and waist circumference (WC) were assessed by standard clinical procedures. Fat mass (FM) was assessed with bioimpedance. All measurements were collected at baseline and at 5.6-y follow-up. RESULTS: At baseline, sedentary time was significantly correlated with FM (partial r = 0.10, P = 0.043) and WC (partial r = 0.11, P = 0.027) after adjustment for sex and age. At follow-up, sedentary time was significantly correlated with BW (partial r = 0.19, P < 0.0001), BMI (partial r = 0.20, P < 0.0001), WC (partial r = 0.15, P = 0.003), and FM (partial r = 0.19, P < 0.0001). Sedentary time did not predict any of the obesity indicators at follow-up. In contrast, BW (beta = 0.33; 95% CI: 0.15, 0.50), BMI (1.10; 0.58, 1.63), FM (0.59; 0.11, 0.40), and WC (0.44; 0.23, 0.66) predicted sedentary time at follow-up after adjustment for sex, baseline age, baseline sedentary time, baseline physical activity energy expenditure, and follow-up time. CONCLUSION: BMI, FM, and WC may predict sedentary time, but our results do not suggest that sedentary time predicts future obesity.
PubMed Accession Number :: 18779275.

Sardinha, L. B.; Baptista, F.; Ekelund, U. (2008) Objectively measured physical activity and bone strength in 9-year-old boys and girls Pediatrics, 122 (3),e728-36 [Journal Article] Online
Abstract: OBJECTIVE: The purpose of this work was to analyze the relationship between intensity and duration of physical activity and composite indices of femoral neck strength and bone-mineral content of the femoral neck, lumbar spine, and total body. METHODS: Physical activity was assessed by accelerometry in 143 girls and 150 boys (mean age: 9.7 years). Measurement of bone-mineral content, femoral neck bone-mineral density, femoral neck width, hip axis length, and total body fat-free mass was performed with dual-energy radiograph absorptiometry. Compressive [(bone-mineral density x femoral neck width/weight)] and bending strength [(bone-mineral density x femoral neck width(2))/(hip axis length x weight)] express the forces that the femoral neck has to withstand in weight bearing, whereas impact strength [(bone-mineral density x femoral neck width x hip axis length)/(height x weight)] expresses the energy that the femoral neck has to absorb in an impact from standing height. RESULTS: Analysis of covariance (fat-free mass and age adjusted) showed differences between boys and girls of approximately 9% for compressive, 10% for bending, and 9% for impact strength. Stepwise regression analysis using time spent at sedentary, light, moderate, and vigorous physical activity as predictors revealed that vigorous physical activity explained 5% to 9% of femoral neck strength variable variance in both genders, except for bending strength in boys, and approximately 1% to 3% of total body and femoral neck bone-mineral content variance. Vigorous physical activity was then used to categorize boys and girls into quartiles. Pairwise comparison indicated that boys in the third and fourth quartiles (accumulation of >26 minutes/day) demonstrated higher compressive (11%-12%), bending (10%), and impact (14%) strength than boys in the first quartile. In girls, comparison revealed a difference between the fourth (accumulation of >25 minutes/day) and first quartiles for bending strength (11%). We did not observe any relationship between physical activity and lumbar spine strength. CONCLUSIONS: Femoral neck strength is higher in boys than girls. Vigorous intensity emerged as the main physical activity predictor of femoral neck strength but did not explain gender differences. Daily vigorous physical activity for at least approximately 25 minutes seems to improve femoral neck bone health in children.
PubMed Accession Number :: 18762509.

Tan, Q.; Zhao, J. H.; Zhang, D.; Kruse, T. A.; Christensen, K. (2008) Power for Genetic Association Study of Human Longevity Using the Case-Control Design Am J Epidemiol, , [Journal Article] Online
Abstract: The efficiency of the popular case-control design in gene-longevity association studies needs to be verified because, different from a binary trait, longevity represents only the extreme end of the continuous life span distribution without a clear cutoff for defining the phenotype. In this paper, the authors use the current Danish life tables to simulate individual life span by using a variety of scenarios and assess the empirical power for different sample sizes when cases are defined as centenarians or as nonagenarians. Results show that, although using small samples of centenarians (several hundred) provides power to detect only common alleles with large effects (a >20% reduction in hazard rate), large samples of centenarians (>1,000) achieve power to capture genes responsible for minor effects (5%-10% hazard reduction depending on the mode of inheritance). Although the method provides good power for rare alleles with multiplicative or dominant effects, it performs poorly for rare recessive alleles. Power is drastically reduced when nonagenarians are considered cases, with a more than 5-fold difference in the size of the case sample required to achieve comparable power as that found with centenarians.
PubMed Accession Number :: 18756013.

Davies, C.; Mummery, W. K.; Steele, R. (2008) The Relationship between Personality, Theory of Planned Behaviour and Physical Activity in Individuals with Type II Diabetes Br J Sports Med, , [Journal Article] Online
Abstract: OBJECTIVE: The purpose of the present study was to conduct a process analysis of the effects of personality on physical activity intention and behaviour using the Theory of Planned Behaviour (TPB). DESIGN: Prospective study design with data collected by means of two questionnaires. METHODS: Data were obtained by means of two questionnaires, the initial questionnaire measured demographic characteristics, TPB constructs, physical activity intention and personality. The two week follow up questionnaire assessed self-report physical activity behaviour. A number of regression analysis were undertaken to identify the relationship between the variables and to determine mediation effects of the TPB constructs. PATIENTS: A random sample of individuals with Type II Diabetes was selected from the Diabetes Australia (Queensland) membership database. A total of 74 complete data sets were obtained. RESULTS: Intention explained 28 percent of the variance in physical activity behaviour. Attitude, subjective norm and PBC explained 73 percent of variance in physical activity intention. Attitude and PBC mediated the relationship between conscientiousness and physical activity intention. CONCLUSIONS: These results provide preliminary evidence that targeting constructs proximal to the behaviour (attitudes and PBC) may be effective in overcoming inherent qualities such as personality in order to produce physical activity behaviour change within this sample population.
PubMed Accession Number :: 18753158.

Ogilvie, D.; Mitchell, R.; Mutrie, N.; Petticrew, M.; Platt, S. (2008) Personal and environmental correlates of active travel and physical activity in a deprived urban population Int J Behav Nutr Phys Act, 5 (1),43 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Environmental characteristics may be associated with patterns of physical activity in general or with particular types of physical activity such as active travel (walking or cycling for transport). However, most studies in this field have been conducted in North America and Australia, and hypotheses about putative correlates should be tested in a wider range of sociospatial contexts. We therefore examined the contribution of putative personal and environmental correlates of active travel and overall physical activity in deprived urban neighbourhoods in Glasgow, Scotland as part of the baseline for a longitudinal study of the effects of opening a new urban motorway (freeway). METHODS: We conducted a postal survey of a random sample of residents (n=1322), collecting data on socioeconomic status, perceptions of the local environment, travel behaviour, physical activity and general health and wellbeing using the SF-8, the short form of the International Physical Activity Questionnaire (IPAQ), a travel diary and a new 14-item neighbourhood rating scale. We analysed the correlates of active travel and overall physical activity using multivariate logistic regression, first building models using personal (individual and household) explanatory variables and then adding environmental variables. RESULTS: Active travel was associated with being younger, living in owner-occupied accommodation, not having to travel a long distance to work and not having access to a car, whereas overall physical activity was associated with living in social rented accommodation and not being overweight. After adjusting for personal characteristics, neither perceptions of the local environment nor the objective proximity of respondents' homes to motorway or major road infrastructure explained much of the variance in active travel or overall physical activity, although we did identify a significant positive association between active travel and perceived proximity to shops. CONCLUSIONS: Apart from access to local amenities, environmental characteristics may have limited influence on active travel in deprived urban populations characterised by a low level of car ownership, in which people may have less capacity for making discretionary travel choices than the populations studied in most published research on the environmental correlates of physical activity.
PubMed Accession Number :: 18752663.

Barroso, I.; Luan, J.; Wheeler, E.; Whittaker, P.; Wasson, J.; Zeggini, E.; Weedon, M. N.; Hunt, S.; Venkatesh, R.; Frayling, T. M.; Delgado, M.; Neuman, R. J.; Zhao, J.; Sherva, R.; Glaser, B.; Walker, M.; Hitman, G.; McCarthy, M. I.; Hattersley, A. T.; Permutt, M. A.; Wareham, N. J.; Deloukas, P. (2008) Population-specific risk of type 2 diabetes (T2D) conferred by HNF4A P2 promoter variants: a lesson for replication studies Diabetes, 57 ,3161-3165 [Journal Article] Online
Abstract: Objective: SNPs in the P2 promoter region of HNF4A associated with T2D predisposition originally in Finnish and Ashkenazim and more recently in Scandinavian populations, but generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in UK populations, and whether these data would allow us to refine the association signal. Research Design and Methods: Using a dense linkage disequilibrium (LD) map of 20q we selected SNPs from a 10Mb interval centred on HNF4A. In a staged approach we first typed 4608 SNPs in case-control populations from four UK and an Ashkenazi population (N=2516). In phase 2, a subset of 763 SNPs were genotyped in 2513 additional samples from the same populations. Results: Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and T2D in the Ashkenazim (N=991, p<1.6x10(-6)). Importantly these associations are significant in a subset of Ashkenazi samples (N=531) not previously tested for association with P2 SNPs (OR approximately 1.7, p<0.002), thus providing replication within the Ashkenazim. In the UK populations this association was not significant (N=4022, p>0.5) and the estimate for the odds ratio was much smaller OR=1.04 (95%CI 0.91 - 1.19). Conclusions: These data indicate that the risk conferred by HNF4A P2 is significantly different between UK and Ashkenazi populations (p<0.00007) suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations.
PubMed Accession Number :: 18728231.

Surtees, P. G.; Wainwright, N. W.; Boekholdt, S. M.; Luben, R. N.; Wareham, N. J.; Khaw, K. T. (2008) Major Depression, C-Reactive Protein, and Incident Ischemic Heart Disease in Healthy Men and Women Psychosom Med, 70 ,850-855 [Journal Article] Online
Abstract: Objective: To investigate how C-reactive protein (CRP) and major depressive disorder (MDD) relate to each other and to incident ischemic heart disease (IHD). Studies have shown that both depression and raised CRP concentration predict IHD and that elevated CRP is linked with increased risk of depression. Methods: A prospective case-control study of healthy men and women, aged 45 to 79 years, was undertaken within the United Kingdom European Prospective Investigation into Cancer (EPIC)-Norfolk study. CRP concentration was measured for 726 (fatal or nonfatal) IHD cases and 1688 matched controls who completed a baseline MDD self-assessment, defined by restricted Diagnostic and Statistical Manual of Mental Disorders, 4th Edition diagnostic criteria. Results: Past-year MDD was associated with increased CRP concentration levels (4.31 mg/L for participants who reported episodes of MDD in the past year versus 3.65 mg/L for those who did not; p = .003), and the odds ratio for incident IHD associated with higher CRP concentration was 2.02 (comparing the top versus bottom quartile of CRP; 95% Confidence Interval (CI) = 1.52-2.68), adjusted for cigarette smoking, diabetes, systolic blood pressure, body mass index, and cholesterol. The association between past-year MDD and IHD was independent of CRP (odds ratio = 1.55; 95% CI = 1.01-2.37, with adjustments as above, and additionally for CRP). Conclusions: Evidence from this study is supportive of an association between MDD and CRP although it suggests that CRP does not account for the association between MDD and future IHD.
PubMed Accession Number :: 18725428.

McMinn, A. M.; van Sluijs, E. M.; Wedderkopp, N.; Frobert, K.; Griffin, S. J. (2008) Sociocultural correlates of physical activity in children and adolescents: findings from the danish arm of the European youth heart study Pediatr Exerc Sci, 20 (3),319-32 [Journal Article] Online
Abstract: Cross-sectional associations between sociocultural factors and objectively-measured physical activity in a sample of 397 children (aged 9) and 213 adolescents (aged 15) were investigated. Associations with children's physical activity were found for mothers' physical activity (Beta = 80, p < .01), parental participation (Beta = 67, p = .01), mother's age (Beta=-8, p < .01) and, in girls, fathers' physical activity (Beta=73, p = .045; R2 for final model: 10.6%). No sociocultural factors were significantly associated with adolescents' physical activity. Parental factors might be important targets for interventions to increase children's physical activity but other factors may have greater influence. For adolescents' physical activity, factors from other domains may be more important to target.
PubMed Accession Number :: 18714121.

Stegle, O.; Fallert, S. V.; Mackay, D. J.; Brage, S. (2008) Gaussian process robust regression for noisy heart rate data IEEE Trans Biomed Eng, 55 (9),2143-51 [Journal Article] Online
Abstract: Heart rate data collected during nonlaboratory conditions present several data-modeling challenges. First, the noise in such data is often poorly described by a simple Gaussian; it has outliers and errors come in bursts. Second, in large-scale studies the ECG waveform is usually not recorded in full, so one has to deal with missing information. In this paper, we propose a robust postprocessing model for such applications. Our model to infer the latent heart rate time series consists of two main components: unsupervised clustering followed by Bayesian regression. The clustering component uses auxiliary data to learn the structure of outliers and noise bursts. The subsequent Gaussian process regression model uses the cluster assignments as prior information and incorporates expert knowledge about the physiology of the heart. We apply the method to a wide range of heart rate data and obtain convincing predictions along with uncertainty estimates. In a quantitative comparison with existing postprocessing methodology, our model achieves a significant increase in performance.
PubMed Accession Number :: 18713683.

Ong, K. K.; Diderholm, B.; Salzano, G.; Wingate, D.; Hughes, I. A.; Macdougall, J.; Acerini, C. L.; Dunger, D. B. (2008) Pregnancy insulin, glucose and BMI contribute to birth outcomes in non-diabetic mothers Diabetes Care, 31 (11),2193-7 [Journal Article] Online
Abstract: Objective: We investigated the effects of normal variations in maternal glycaemia on birth size and other birth outcomes. Research design and methods: Two unselected birth cohorts, one retrospective (n=3,158) and one prospective (n=668), underwent an oral glucose challenge at 28 weeks gestation. In the retrospective study, glycaemia was linked to routine birth records. In the prospective study, offspring adiposity was assessed by skinfold thickness from birth to age 24 months. Results: In the retrospective study, within the non-diabetic range (2.1-7.8 mmol/L), each 1 mmol/L rise in mother's 60 min glucose level was associated with a: (mean+/-SE) 2.1+/-0.8% (P=0.006) rise in absolute risk of assisted vaginal delivery; 3.4+/-0.8% (P<0.0001) rise in emergency caesarean; 3.1+/-0.7% (P<0.0001) rise in elective caesarean; and 46+/-8 g (P<0.0001) increase in offspring birth weight. In the prospective study, fetal macrosomia (birth weight >90(th) centile) was independently related to mother's fasting glucose (OR=2.61 per +1 mmol/L, 95% CI: 1.15-5.93) and mother's pre-pregnancy BMI (1.10 per +1 kg/m(2), 1.04-1.18). Mother's higher fasting glycaemia (P=0.004), lower insulin sensitivity (P=0.01) and lower insulin secretion (P=0.02) were independently related to greater offspring adiposity at birth. During postnatal follow-up, the correlation between mother's glycaemia and offspring adiposity disappeared by 3 months, while mother's pre-pregnancy BMI was associated with offspring adiposity only apparent at 12 and 24 months (both P<0.05). Conclusions: Mother's pre-pregnancy BMI and pregnancy glycaemia, insulin sensitivity and insulin secretion all contribute offspring adiposity and macrosomia, and may be separate targets for intervention to optimize birth outcomes and later offspring health.
PubMed Accession Number :: 18697902.

Wang, J.; Luben, R.; Khaw, K. T.; Bingham, S.; Wareham, N. J.; Forouhi, N. G. (2008) Dietary energy density predicts the risk of clinically incident type 2 diabetes: The EPIC-Norfolk study Diabetes Care, 31 ,2120-2125 [Journal Article] Online
Abstract: Objective: Accumulating evidence suggests that energy dense foods predispose to obesity, and such foods may also be associated with increased risk of type 2 diabetes, but there is limited evidence. Our aim was to investigate whether there is an independent association between dietary energy density and incidence of diabetes. Research Design and Methods: Population-based prospective study, the EPIC (European Prospective Investigation of Cancer)-Norfolk Cohort Study of persons aged 40-79 years at baseline. We calculated energy density for overall diet (all solids and drinks) using food frequency questionnaire. During 12 years of follow-up, we documented 725 clinically incident cases of diabetes among 21,919 participants without diabetes, cancer or cardiovascular disease at baseline. Results: Baseline energy density (age, sex, baseline BMI adjusted) was higher in those who developed type 2 diabetes (Mean 3.08 kJ/g, 95% CI 3.03-3.13) than those who remained non-diabetic (3.01 kJ/g, 3.00-3.02) (P=0.012). Energy density was positively associated with incident diabetes (odds ratio, OR, 1.21 per unit increase, 95% CI 1.06-1.38) adjusted for known risk factors. There was a 60% higher risk of diabetes (OR 1.60, 95% CI 1.19-2.16) in the highest quintile of energy density (range 3.55-7.97 kJ/g) compared with the lowest quintile (range 1.04-2.43 kJ/g) in adjusted analysis. Conclusions: This is the first large population-based prospective study to report that an energy dense diet may be associated with increased risk of developing diabetes, independently of baseline obesity. The potential public health impact of a low energy dense diet on reducing the risk of diabetes deserves further study.
PubMed Accession Number :: 18689693.

Norat, T.; Bowman, R.; Luben, R.; Welch, A.; Khaw, K. T.; Wareham, N.; Bingham, S. (2008) Blood pressure and interactions between the angiotensin polymorphism AGT M235T and sodium intake: a cross-sectional population study Am J Clin Nutr, 88 (2),392-7 [Journal Article] Online
Abstract: BACKGROUND: Intervention studies have indicated an interaction between the blood pressure response to a low-sodium or a low-fat and high-fruit and -vegetable diet and the angiotensinogen gene (AGT) polymorphisms G-6A and M235T. OBJECTIVE: We investigated whether this interaction is also present in a large free-living population. DESIGN: Urinary sodium, potassium as biomarkers of intake, and blood pressure were measured in 11 384 men and women aged 45-79 y participating in the Norfolk arm of the European Prospective Investigation of Nutrition and Cancer (EPIC). The M235T polymorphism was assessed by pyrosequencing. RESULTS: Highly significant associations between sodium and blood pressure were shown for all genotypes (P < 0.001), but the regression coefficient for systolic blood pressure associated with each unit of sodium for each of the MT and TT genotypes was approximately double that for the MM homozygotes (P < 0.001 for heterogeneity between genotypes). Differences were evident at high exposures to sodium but not at low exposures. There were no significant associations between blood pressure and dietary or urinary potassium. CONCLUSIONS: This large cross-sectional study supports public health recommendations to reduce salt consumption in the population as a whole, and it confirms intervention trial data showing the greatest response to intervention in persons with the AA and TT genotype in the AGT G-6A and M235T polymorphisms. Genotype effects in populations at low exposure to sodium are not likely to be seen.
PubMed Accession Number :: 18689375.

van Sluijs, E. M.; McMinn, A. M.; Griffin, S. J. (2008) Effectiveness of interventions to promote physical activity in children and adolescents: systematic review of controlled trials Br J Sports Med, 42 (8),653-7 [Journal Article] Online
Abstract: OBJECTIVE: To review the published literature on the effectiveness of interventions to promote physical activity in children and adolescents. DESIGN: Systematic review. DATA SOURCES: Literature search using PubMed, SCOPUS, Psychlit, Ovid Medline, Sportdiscus, and Embase up to December 2006. REVIEW METHODS: Two independent reviewers assessed studies against the following inclusion criteria: controlled trial, comparison of intervention to promote physical activity with no intervention control condition, participants younger than 18 years, and reported statistical analyses of a physical activity outcome measure. Levels of evidence, accounting for methodological quality, were assessed for three types of intervention, five settings, and three target populations. RESULTS: The literature search identified 57 studies: 33 aimed at children and 24 at adolescents. Twenty four studies were of high methodological quality, including 13 studies in children. Interventions that were found to be effective achieved increases ranging from an additional 2.6 minutes of physical education related physical activity to 283 minutes per week of overall physical activity. Among children, limited evidence for an effect was found for interventions targeting children from low socioeconomic populations, and environmental interventions. Strong evidence was found that school based interventions with involvement of the family or community and multicomponent interventions can increase physical activity in adolescents. CONCLUSION: Some evidence was found for potentially effective strategies to increase children's levels of physical activity. For adolescents, multicomponent interventions and interventions that included both school and family or community involvement have the potential to make important differences to levels of physical activity and should be promoted. A lack of high quality evaluations hampers conclusions concerning effectiveness, especially among children.
PubMed Accession Number :: 18685076.

Harding, A. H.; Wareham, N. J.; Bingham, S. A.; Khaw, K.; Luben, R.; Welch, A.; Forouhi, N. G. (2008) Plasma vitamin C level, fruit and vegetable consumption, and the risk of new-onset type 2 diabetes mellitus: the European prospective investigation of cancer--Norfolk prospective study Arch Intern Med, 168 (14),1493-9 [Journal Article] Online
Abstract: BACKGROUND: Epidemiologic studies suggest that greater consumption of fruit and vegetables may decrease the risk of diabetes mellitus, but the evidence is limited and inconclusive. Plasma vitamin C level is a good biomarker of fruit and vegetable intake, but, to our knowledge, no prospective studies have examined its association with diabetes risk. This study aims to examine whether fruit and vegetable intake and plasma vitamin C level are associated with the risk of incident type 2 diabetes. METHODS: We administered a semiquantitative food frequency questionnaire to men and women from a population-based prospective cohort (European Prospective Investigation of Cancer-Norfolk) study who were aged 40 to 75 years at baseline (1993-1997) when plasma vitamin C level was determined and habitual intake of fruit and vegetables was assessed. During 12 years of follow-up between February 1993 and the end of December 2005, 735 clinically incident cases of diabetes were identified among 21 831 healthy individuals. We report the odds ratios of diabetes associated with sex-specific quintiles of fruit and vegetable intake and of plasma vitamin C levels. RESULTS: A strong inverse association was found between plasma vitamin C level and diabetes risk. The odds ratio of diabetes in the top quintile of plasma vitamin C was 0.38 (95% confidence interval, 0.28-0.52) in a model adjusted for demographic, lifestyle, and anthropometric variables. In a similarly adjusted model, the odds ratio of diabetes in the top quintile of fruit and vegetable consumption was 0.78 (95% confidence interval, 0.60-1.00). CONCLUSIONS: Higher plasma vitamin C level and, to a lesser degree, fruit and vegetable intake were associated with a substantially decreased risk of diabetes. Our findings highlight a potentially important public health message on the benefits of a diet rich in fruit and vegetables for the prevention of diabetes.
PubMed Accession Number :: 18663161.

Colagiuri, S.; Borch-Johnsen, K.; Wareham, N. J. (2008) Back to the future-Do IGT and IFG have value as clinical entities? Diabetes Res Clin Pract, 81 (2),131-3 [Journal Article] Online
PubMed Accession Number :: 18657716.

Fitzsimons, C. F.; Baker, G.; Wright, A.; Nimmo, M. A.; Ward Thompson, C.; Lowry, R.; Millington, C.; Shaw, R.; Fenwick, E.; Ogilvie, D.; Inchley, J.; Foster, C. E.; Mutrie, N. (2008) The 'Walking for Wellbeing in the West' randomised controlled trial of a pedometer-based walking programme in combination with physical activity consultation with 12 month follow-up: rationale and study design BMC Public Health, 8 (1),259 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Scotland has a policy aimed at increasing physical activity levels in the population, but evidence on how to achieve this is still developing. Studies that focus on encouraging real world participants to start physical activity in their settings are needed. The Walking for Well-being in the West study was designed to assess the effectiveness of a pedometer-based walking programme in combination with physical activity consultation. The study was multi-disciplinary and based in the community. Walking for Well-being in the West investigated whether Scottish men and women, who were not achieving the current physical activity recommendation, increased and maintained walking behaviour over a 12 month period. This paper outlines the rationale and design of this innovative and pragmatic study. METHODS: Participants were randomised into two groups: Group 1: Intervention (pedometer-based walking programme combined with a series of physical activity consultations); Group 2: Waiting list control for 12 weeks (followed by minimal pedometer-based intervention). Physical activity (primary outcome) was measured using pedometer step counts (7 day) and the International Physical Activity Questionnaire (long version). Psychological processes were measured using questionnaires relating to the Transtheoretical Model of Behaviour Change, mood (Positive and Negative Affect Schedule) and quality of life (Euroqol EQ-5D instrument). Physiological measures included anthropometric and metabolic outcomes. Environmental influences were assessed subjectively (Neighbourhood Quality of Life Survey) and objectively (neighbourhood audit tool and GIS mapping). The qualitative evaluation employed observation, semi-structured interviews and focus groups. A supplementary study undertook an economic evaluation. DISCUSSION: Data analysis is on-going. Walking for Well-being in the West will demonstrate if a pedometer based walking programme, in combination with physical activity consultation results in a sustainable increase in walking behaviour in this sample of Scottish adults over a 12 month period. The study will examine the complex relationships between behavioural change, health consequences and the role of the environment, in conjunction with the cost effectiveness of this approach and a detailed insight into the participants' experiences of the intervention. Trial registration: Current Controlled Trials ISRCTN88907382.
PubMed Accession Number :: 18655723.

Hallal, P. C.; Reichert, F. F.; Siqueira, F. V.; Dumith, S. C.; Bastos, J. P.; da Silva, M. C.; Domingues, M. R.; Azevedo, M. R.; Ekelund, U. (2008) Correlates of leisure-time physical activity differ by body-mass-index status in brazilian adults J Phys Act Health, 5 (4),571-8 [Journal Article] Online
Abstract: Objectives: The objective of this study was to evaluate physical activity (PA) levels in adults and their association with sex, age, and education level across categories of body mass index (BMI). Methods: We conducted a population-based, cross-sectional study including 3100 individuals age >20 years living in Pelotas, Brazil. PA was assessed using the leisure-time section of the long International Physical Activity Questionnaire. "No PA" was defined as zero minutes of activity/ week; "insufficient PA" was defined as <150 minutes of activity/week; "high PA" was defined as gt;500 minutes of activity/week. BMI was categorized into normal (<25 kg/m2), overweight (25-29.9 kg/m2), and obesity (>30 kg/m2). Results: The prevalence of insufficient PA was 71.6% among normal BMI subjects, 71.3% among overweight individuals, and 73.7% among obese ones (P = .67). No PA and high PA were also not associated with BMI. The associations between sex, age, and education level and PA levels tended to be stronger among normal-weight individuals compared with overweight and obese individuals. Among the obese, most associations were not significant. Among normal-weight individuals, higher PA levels were observed in men, young adults, and those with higher education. Conclusions: Variables associated with leisure-time PA differed between normalweight, overweight, and obese individuals. Studies on PA correlates might benefit from stratifying by BMI.
PubMed Accession Number :: 18648121.

Garcia, E. A.; Heude, B.; Petry, C. J.; Gueorguiev, M.; Hassan-Smith, Z. K.; Spanou, A.; Ring, S. M.; Dunger, D. B.; Wareham, N.; Sandhu, M.; Ong, K. K.; Korbonits, M. (2008) Ghrelin receptor gene polymorphisms and body size in children and adults J Clin Endocrinol Metab, 93 (5),4158-61 [Journal Article] Online
Abstract: Background: The growth hormone secretagogue receptor type 1a gene (GHSR) encodes the cognate receptor of ghrelin, a gut hormone that regulates food intake and pituitary growth hormone secretion. Previous studies in US families and in a German population suggested GHSR to be a candidate quantitative locus for association with human obesity and growth. Aim: To test common genetic variation in GHSR for association with body size in children and adults. Methods: Sequencing was performed to systematically identify novel single nucleotide polymorphisms (SNPs) in GHSR. A set of three haplotype-tagging (ht)SNPs was identified which captured all the genetic variation in GHSR. These three htSNPs were then genotyped in three large population-based UK cohort studies (two adult and one childhood cohort) comprising 5,807 adults and 843 children. Results: No significant genotype or haplotype associations were found with adult or childhood height, weight or BMI. Conclusion: Common variation in GHSR is not associated with body size in UK adults or children.
PubMed Accession Number :: 18647811.

Price, H. C.; Tucker, L.; Griffin, S. J.; Holman, R. R. (2008) The impact of individualised cardiovascular disease (CVD) risk estimates and lifestyle advice on physical activity in individuals at high risk of CVD. A Pilot 2x2 Factorial "Understanding Risk" Trial Cardiovasc Diabetol, 7 (1),21 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: There is currently much interest in encouraging individuals to increase physical activity in order to reduce CVD risk. This study has been designed to determine if personalised CVD risk appreciation can increase physical activity in adults at high risk of CVD. METHODS: In a 2x2 factorial design participants are allocated at random to a personalised 10-year CVD risk estimate or numerical CVD risk factor values (systolic blood pressure, LDL cholesterol and fasting glucose) and, simultaneously, to receive a brief lifestyle advice intervention targeting physical activity, diet and smoking cessation or not. We aim to recruit 200 participants from Oxfordshire primary care practices. Eligibility criteria include adults age 40-70 years, estimated 10-year CVD risk [greater than or equal to] 20%, ability to read and write English, no known CVD and no physical disability or other condition reducing the ability to walk. Primary outcome is physical activity measured by ActiGraph accelerometer with biochemical, anthropometrical and psychological measures as additional outcomes. Primary analysis is between group physical activity differences at one month powered to detect a difference of 30,000 total counts per day of physical activity between the groups. Additional analyses will seek to further elucidate the relationship between the provision of risk information, and intention to change behaviour and to determine the impact of both interventions on clinical and anthropometrical measures including fasting and 2 hour plasma glucose, fructosamine, serum cotinine, plasma vitamin C, body fat percentage and blood pressure. DISCUSSION: This is a pilot trial seeking to demonstrate in a real world setting, proof of principal that provision of personalised risk information can contribute to behaviour changes aimed at reducing CVD risk. This study will increase our understanding of the links between the provision of risk information and behaviour change and if successful, could be used in clinical practice with little or no modification.
PubMed Accession Number :: 18637168.

Corder, K.; Ekelund, U.; Steele, R. M.; Wareham, N. J.; Brage, S. (2008) Assessment of physical activity in youth J Appl Physiol, 105 ,977-987 [Journal Article] Online
Abstract: Despite much progress with physical activity assessment, the limitations concerning the accurate measurement of physical activity are often amplified in young people due to the cognitive, physiological, and biomechanical changes that occur during natural growth as well as a more intermittent pattern of habitual physical activity in youth compared to adults. This mini-review describes and compares methods to assess habitual physical activity in youth and discusses main issues regarding the use and interpretation of data collected with these techniques. Self-report instruments and movement sensing are currently the most frequently used methods for the assessment of physical activity in epidemiological research; others include heart rate monitoring and multi-sensor systems. Habitual energy expenditure can be estimated from these input measures with varying degree of uncertainty. Non-linear modeling techniques, using accelerometry perhaps in combination with physiological parameters like heart rate or temperature have the greatest potential for increasing the prediction accuracy of habitual physical activity energy expenditure. Although multi-sensor systems may be more accurate, this must be balanced against feasibility, a balance which shifts with technological and scientific advances and should be considered at the beginning of every new study. Key words: physical activity , measurement, children, accelerometer, heart rate.
PubMed Accession Number :: 18635884.

Wu, Y.; Li, H.; Loos, R. J.; Yu, Z.; Ye, X.; Chen, L.; Pan, A.; Hu, F. B.; Lin, X. (2008) Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8 and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population Diabetes, 57 (10),2834- 42 [Journal Article] Online
Abstract: OBJECTIVE- Genome-wide association studies have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX/IDE, EXT2 and LOC387761 loci that significantly increase risk of type 2 diabetes. We aimed to replicate these observations in a population-based cohort of Chinese Hans and examine the associations of these variants with type 2 diabetes and diabetes-related phenotypes. RESEARCH DESIGN AND METHODS- We genotyped 17 SNPs in 3,210 unrelated Chinese Hans, including 424 participants with type 2 diabetes, 878 with impaired fasting glucose (IFG) and 1,908 with normal fasting glucose (NFG). RESULTS- We confirmed the associations between type 2 diabetes and variants near CDKAL1 (OR 1.49 (1.27-1.75), P = 8.91x10(-7)) and CDKN2A/B (OR 1.31 [1.12-1.54], P = 1.0x10(-3)). We observed significant association of SNPs in IGF2BP2 (OR 1.17 [1.03-1.32], P = 0.014) and SLC30A8 (OR 1.12 [1.01-1.25], P = 0.033) with combined IFG/type 2 diabetes. The SNPs in CDKAL1, IGF2BP2 and SLC30A8 were also associated with impaired beta-cell function estimated by HOMA-B. When combined, each additional risk allele from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960 and SLC30A8-rs13266634 increased the risk for type 2 diabetes by 1.24 fold (P = 2.85x10(-7)) or for combined IFG/type 2 diabetes by 1.21 fold (P = 6.31x10(-11)). None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG. Significant association was observed between the HHEX/IDE SNPs and type 2 diabetes in individuals from Shanghai only (P < 0.013), but not in those from Beijing (P > 0.33). CONCLUSIONS- Our results indicate that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2 and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through beta-cell dysfunction.
PubMed Accession Number :: 18633108.

Amin, R.; Frystyk, J.; Ong, K.; Dalton, R. N.; Flyvbjerg, A.; Dunger, D. B. (2008) The development of microalbuminuria is associated with raised longitudinal adiponectin levels in female but not male adolescent patients with type 1 diabetes Diabetologia, 51 (9),1707-13 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: We determined the longitudinal relationship between adiponectin levels and the development of microalbuminuria in an inception cohort of children with type 1 diabetes. METHODS: Blood samples collected annually over a median of 9.0 (range 1.3-14.9) years were assayed for adiponectin and HbA(1c) in 55 children (36 girls) with type 1 diabetes and microalbuminuria whose age of onset of diabetes was 9.4 years (range 2.2-15.4). Samples were also assayed from normoalbuminuric children (controls) matched for age, sex and duration of diabetes. RESULTS: Overall, adiponectin levels were higher in girls than in boys, but only after 11 years of age (median [range]: 15.3 [5.8-124.4] vs 11.6 [4.1-26.5] mg/l, p < 0.001). Furthermore, adiponectin levels were higher in girls with microalbuminuria than in control girls, but this was only apparent after the onset of microalbuminuria (p = 0.001, adjusted for BMI, daily insulin dose, HbA(1c) and age). In boys, adiponectin levels did not differ between those with microalbuminuria and controls. Further sex-related discordant associations with adiponectin levels were observed; in girls, adiponectin levels were positively related to HbA(1c) levels (r = 0.2, p = 0.05) and urine albumin excretion (r = 0.3, p < 0.05) and inversely related to BMI (r = -0.2, p < 0.05). These associations were absent in boys. CONCLUSIONS/INTERPRETATION: In adolescent girls with type 1 diabetes but not in boys, adiponectin levels increase with increasing urine albumin excretion and onset of microalbuminuria. Although causal links cannot be inferred, this sexual dimorphism may reflect interactive effects of hyperglycaemia and sex steroids on risk of complications and adiponectin production.
PubMed Accession Number :: 18622594.

McFadden, E.; Luben, R.; Bingham, S.; Wareham, N.; Kinmonth, A. L.; Khaw, K. T. (2008) Social inequalities in self-rated health by age: Cross-sectional study of 22 457 middle-aged men and women BMC Public Health, 8 (1),230 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: We investigate the association between occupational social class and self-rated health (SRH) at different ages in men and women. METHODS: Cross sectional population study of 22 457 men and women aged 39-79 years living in the general community in Norfolk, United Kingdom, recruited using general practice age-sex registers in 1993-1997. The relationship between self-rated health and social class was examined using logistic regression, with a poor or moderate rating as the outcome. RESULTS: The prevalence of poor or moderate (lower) self-rated health increased with increasing age in both men and women. There was a strong social class gradient: in manual classes, men and women under 50 years of age had a prevalence of lower self-rated health similar to that seen in men and women in non-manual social classes over 70 years old. Even after adjustment for age, educational status, and lifestyle factors (body mass index (BMI), smoking, physical activity and alcohol consumption) there was still strong evidence of a social gradient in self-rated health, with unskilled men and women approximately twice as likely to report lower self-rated health as professionals (OR men = 2.44 (95%CI 1.69, 3.50); OR women = 1.97 (95%CI 1.45, 2.68). CONCLUSIONS: There was a strong gradient of decreased SRH with age in both men and women. We found a strong cross-sectional association between SRH and social class, which was independent of education and major health related behaviors. The social class differential in SRH was similar with age. Prospective studies to confirm this association should explore social and emotional as well as physical pathways to inequalities in self reported health.
PubMed Accession Number :: 18611263.

Fawcett, K. A.; Grimsey, N.; Loos, R. J.; Wheeler, E.; Daly, A.; Soos, M.; Semple, R.; Syddall, H.; Cooper, C.; Siniossoglou, S.; O'Rahilly, S.; Wareham, N. J.; Barroso, I. (2008) Evaluating the role of LPIN1 variation on insulin resistance, body weight and human lipodystrophy in UK populations Diabetes, 57 (9),2527-33 [Journal Article] Online
Abstract: OBJECTIVE: Loss of Lpin1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of LPIN1 common variation on adiposity and insulin sensitivity in UK populations, and to examine the role of LPIN1 mutations in insulin resistance syndromes. RESEARCH DESIGN AND METHOD: Twenty-two SNPs tagging LPIN1 common variation were genotyped in MRC Ely (N = 1709) and Hertfordshire (N = 2901) population-based cohorts. LPIN1 exons, exon/intron boundaries and 3'UTR were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients), and 48 controls. RESULTS: We found no association between LPIN1 SNPs and fasting insulin, but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K and G582R) were detected in severely insulin resistant patients. However, these did not co-segregate with disease in affected families and Lipin1 protein expression and phosphorylation in patients with variants was indistinguishable from controls. CONCLUSIONS: Our data do not support a major effect of LPIN1 common variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in UK cohorts require replication in larger cohorts.
PubMed Accession Number :: 18591397.

Forouhi, N. G.; Luan, J.; Cooper, A.; Boucher, B. J.; Wareham, N. J. (2008) Baseline serum 25-hydroxy vitamin D is predictive of future glycaemic status and insulin resistance: The MRC Ely prospective study 1990 - 2000 Diabetes, 57 ,2619-2625 [Journal Article] Online
Abstract: Objective: Accumulating epidemiological evidence suggests that hypovitaminosis D may be associated with type 2 diabetes and related metabolic risks. However, prospective data using the biomarker serum 25-hydroxyvitamin D (25(OH)D) are limited and therefore examined in the present study. Research Design and Methods: 524 randomly selected non-diabetic men and women aged 40-69 years at baseline with measurements for serum 25(OH)D and insulin-like growth factor-1 (IGF-1) in the population-based Ely Study had glycaemic status (oral glucose tolerance), lipids, insulin, anthropometry and blood pressure measured, and metabolic syndrome risk score (MS-z) derived at baseline and at 10-years of follow-up. Results: Age-adjusted baseline mean serum 25(OH)D was greater in men (64.5 (95% CI 61.2-67.9) nmol/L) than women (57.2 (54.4,60.0) nmol/L) and varied with season (highest late summer). Baseline 25(OH)D was associated inversely with 10-year risk of hyperglycemia (fasting glucose: beta -0.0023, p=0.019; 2h-glucose: beta -0.0097, p=0.006), insulin resistance (fasting insulin beta -0.1467, p=0.010; HOMA-IR: beta -0.0059, p=0.005) and MS-z score (beta -0.0016, p=0.048) after adjustment for age, sex, smoking, BMI, season and baseline value of each metabolic outcome variable. Associations with 2h-glucose, insulin and HOMA-IR remained significant after further adjustment for IGF-1, parathyroid hormone, calcium, physical activity and social class. Conclusions: This prospective study reports inverse associations between baseline serum 25(OH)D and future glycemia and insulin resistance. These associations are potentially important in understanding the etiology of abnormal glucose metabolism, and warrant investigation in larger specifically designed prospective studies and randomized controlled trials of supplementation.
PubMed Accession Number :: 18591391.

Bingham, S.; Luben, R.; Welch, A.; Low, Y. L.; Khaw, K. T.; Wareham, N.; Day, N. (2008) Associations between dietary methods and biomarkers, and between fruits and vegetables and risk of ischaemic heart disease, in the EPIC Norfolk Cohort Study Int J Epidemiol, 37 (5),978-87 [Journal Article] Online
Abstract: BACKGROUND: Methods for assessing diet are prone to measurement error, which may be substantial in large cohort investigations. Biomarkers can be used as objective measures with which to compare estimates of nutritional exposure using different methods METHODS: Cross sectional comparisons in 12 474 men and women of regression between biomarkers for vitamin C, sodium, potassium, fibre, carbohydrate, fat and phytoestrogens with intakes derived from food diaries and food frequency questionnaires (FFQ), and odds ratios for risk of ischaemic heart disease (IHD) by dietary and plasma vitamin C. RESULTS: There were strong (P < 0.001) associations between biomarkers and intakes as assessed by food diary. Coefficients were markedly attenuated for data obtained from the FFQ, especially so for vitamin C, potassium and phytoestrogens (Z P < 0.05). Risk of IHD was associated with plasma vitamin C (P < 0.001) and intake of vitamin C and fruit and vegetables assessed by food diary (P quintile trends <0.001, 0.001) but not by the FFQ (P quintile trends 0.923, 0.186). CONCLUSIONS: Nutritional data that reflect the findings from biomarkers reduce measurement error and will thus improve statistical power in studies of gene nutrient interactions in cohort studies.
PubMed Accession Number :: 18579574.

Kurokawa, N.; Young, E. H.; Oka, Y.; Satoh, H.; Wareham, N. J.; Sandhu, M. S.; Loos, R. J. (2008) The ADRB3 Trp64Arg variant and BMI: a meta-analysis of 44 833 individuals Int J Obes (Lond), 32 (8),1240-9 [Journal Article] Online
Abstract: Background:The beta-3 adrenergic receptor gene (ADRB3) is part of the adrenergic system, which is known to play a key role in energy metabolism. The association between the Trp64Arg variant in the ADRB3 and body mass index (BMI) has been widely examined, but previous studies have been small and results have been inconsistent.Methods:We assessed the association between the ADRB3 Trp64Arg variant and BMI in a large UK population-based cohort of 4854 middle-aged men and women. We also performed a meta-analysis of 97 studies, involving 44 833 individuals, to place our findings in context.Results:Although we found no significant difference in BMI (0.20 kg/m(2), P=0.40) between the Trp64Trp homozygotes and Arg64 allele carriers in our UK population-based cohort, the meta-analysis showed significant association between the Arg64Trp variant and BMI, with Arg64-allele carriers having a 0.24 kg/m(2) (P=0.0002) higher BMI compared with noncarriers. However, we also found substantial heterogeneity among the studies (P=2.2 x 10(-14)). The difference in East Asians (0.31 kg/m(2), P=0.001) was 3.9 times larger than that in Europeans in whom no significant association was observed (0.08 kg/m(2), P=0.36). This was consistent with the chronological cumulative decrease in the effect size, which decreased steadily in Europeans and reached nonsignificance after 11 studies in 1996. In East Asians, the cumulative effect size decreased after the first reports, but reached a steady state at a significant effect size of 0.24 kg/m(2) in 2000. Although the funnel plot indicated no apparent publication bias, smaller studies tended to report greater differences in BMI, compared with larger studies.Conclusions:Collectively, these data suggest that the Trp64Arg ADRB3 genetic variant might be associated with BMI in East Asians, but not Europeans. More generally, our study shows the importance of meta-analyses in the field of genetic association studies for common traits. Each genetic variant makes only a small contribution to variation in BMI, and large sample sizes are needed to reliably assess and interpret gene-phenotype associations.International Journal of Obesity advance online publication, 24 June 2008; doi:10.1038/ijo.2008.90.
PubMed Accession Number :: 18574485.

Panter, J. R.; Jones, A. P.; Van Sluijs, E. M. (2008) Environmental determinants of active travel in youth: A review and framework for future research Int J Behav Nutr Phys Act, 5 (1),34 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Many youth fail to meet the recommended guidelines for physical activity. Walking and cycling, forms of active travel, have the potential to contribute significantly towards overall physical activity levels. Recent research examining the associations between physical activity and the environment has shown that environmental factors play a role in determining behaviour in children and adolescents. However, links between the environment and active travel have received less attention. METHODS: Twenty four studies were identified which examined the associations between the environment (perceived or objectively measured) and active travel among youth aged 5-18 years. Findings were categorised according to the location of the environmental measure examined; attributes of the neighbourhood, destination and the route between home and destination. RESULTS: Results from the reviewed studies indicated that youth active travel is positively associated with social interactions, facilities to assist active travel and urban form in the neighbourhood as well as shorter route length and road safety en-route. A conceptual framework is presented which highlights the associations between active travel behaviours and environmental factors, drawing upon both existing and hypothesised relationships. CONCLUSIONS: We provide a review of the available literature and present a novel theoretical framework that integrates the environment into the wider decision making process around travel choices for children and adolescents. Further work should explore associations where gaps in understanding have been identified, and account for the main moderators of behaviour so hypothesised associations can be confirmed.
PubMed Accession Number :: 18573196.

McFadden, E.; Luben, R.; Wareham, N.; Bingham, S.; Khaw, K. T. (2008) Occupational social class, educational level, smoking and body mass index, and cause-specific mortality in men and women: a prospective study in the European Prospective Investigation of Cancer and Nutrition in Norfolk (EPIC-Norfolk) cohort Eur J Epidemiol, 23 (8),511-22 [Journal Article] Online
Abstract: Objectives To investigate the independent associations between occupational and educational based measures of socioeconomic status (SES) and cause-specific mortality, and the extent to which potentially modifiable risk factors smoking and body mass index (BMI) explain such relationships. Design, setting and participants Prospective population study of 22,486 men and women aged 39-79 years living in the general community in Norfolk, United Kingdom, recruited using general practice age-sex registers in 1993-1997 and followed up for total mortality using death certification to 2006. Main results In men a strong inverse relationship was found between social class and all cause, cardiovascular and cancer mortality, with relative risk of social class V compared to I of 2.21 for all cause mortality (95% CI 1.54-3.17, P < 0.001). This was attenuated but not abolished after adjusting for modifiable risk factors, smoking and BMI, with relative risk of social class V compared to I for all cause mortality of 1.92 (95% CI 1.34-2.77, P < 0.001). A similar, but smaller effect was seen in women. Educational status was not associated with mortality independently of social class. Conclusions Social class and education are not necessarily interchangeable measures of SES. Some but not all of the socioeconomic differential in mortality can be explained by potentially modifiable risk factors smoking and BMI. Further understanding of the mechanisms underlying the association of each socioeconomic indicator with specific health outcomes is needed if we are to reduce inequalities in health.
PubMed Accession Number :: 18553139.

Simmons, R. K.; Sharp, S.; Boekholdt, S. M.; Sargeant, L. A.; Khaw, K. T.; Wareham, N. J.; Griffin, S. J. (2008) Evaluation of the Framingham risk score in the European Prospective Investigation of Cancer-Norfolk cohort: does adding glycated hemoglobin improve the prediction of coronary heart disease events? Arch Intern Med, 168 (11),1209-16 [Journal Article] Online
Abstract: BACKGROUND: There is a continuous relationship between glycated hemoglobin (HbA(1c)) and coronary heart disease (CHD) risk, even below diagnostic thresholds for diabetes mellitus. METHODS: To evaluate the Framingham risk score in a UK population-based prospective cohort (European Prospective Investigation of Cancer [EPIC]-Norfolk) and to assess whether adding HbA(1c) improves the prediction of CHD. Participants aged 40 to 79 years were recruited from UK general practices, attended a health check, and were followed up for CHD events and death. The Framingham risk score was computed for 10,295 individuals with data on age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, diabetes mellitus, and smoking status. We developed a Cox proportional hazards regression model with the original Framingham covariates and then added HbA(1c) to determine whether this improved the prediction of CHD. Model discrimination was compared by using area under the receiver operating characteristic curves (AUROCs), and the correctness of reclassification was determined by calculating the net reclassification improvement and the integrated discrimination improvement. The main outcome measures were CHD-related hospital admission and death. RESULTS: A total of 430 men and 250 women developed CHD during 8.5 years of follow-up. The AUROC for the original Framingham risk score was 0.71. Using the Framingham variables with coefficients fitted from the EPIC-Norfolk data, the AUROC was 0.72 for men and 0.80 for women, compared with 0.73 and 0.80, respectively, in a score including HbA(1c). This difference was significant for men only (P = .005). The net reclassification improvement was 3.4% (P = .06) in men and -2.2% (P = .27) in women. CONCLUSIONS: The Framingham risk score predicts CHD in this cohort. The addition of HbA(1c) made a small but statistically significant improvement to discrimination in men but not in women, without significant improvement in reclassification of risk category.
PubMed Accession Number :: 18541829.

Duncan, M. J.; Mummery, W. K.; Steele, R. M.; Caperchione, C.; Schofield, G. (2008) Geographic location, physical activity and perceptions of the environment in Queensland adults Health Place, , [Journal Article] Online
Abstract: This study examines how physical activity and perceptions of the built environment differ by degree of urbanisation in Queensland, Australia. A statewide sample of adults (n=1208) completed a CATI survey assessing physical activity and perceptions of the environment in July-August 2005. Results indicate that residents in metropolitan areas were more likely to report the presence of shops and services, footpaths, heavy traffic and physical activity facilities than non-metropolitan residents. Although geographic location was not associated with achievement of sufficient levels of physical activity or walking, a notable interaction in the associations between both physical activity measures and the presence of footpaths in metropolitan and non-metropolitan areas was observed. This finding suggests the presence of a differential mechanism in terms of the relationships between physical activity and environmental supports by geographical location. Such effects require future investigation in terms of replication and understanding.
PubMed Accession Number :: 18539518.

Druet, C.; Ong, K. K. (2008) Early childhood predictors of adult body composition Best Pract Res Clin Endocrinol Metab, 22 (3),489-502 [Journal Article] Online
Abstract: Intra-uterine life has been identified as a possible critical period for the development of obesity risk in both adults and children; others have highlighted the importance of growth and nutrition in the first few years. It is suggested that fetal growth, as assessed by birth weight, may programme lean body mass later in life. Children who are born small for gestational age also have a predisposition to accumulating fat mass, particularly intra-abdominal fat. It is not yet clear whether this predisposition is due to their prenatal growth restraint, their rapid postnatal catch-up growth or a combination of both. Recently, genetic and heritable factors have been shown to contribute to both rapid postnatal growth and childhood obesity risk in children and adults. Future studies should explore their timing of action and potential interactions with markers of antenatal growth restraint.
PubMed Accession Number :: 18538288.

Lee, C.T.; Adler, A. I.; Forouhi, N.G.; Luben, R.; Welch, A.; Khaw, K.T.; Bingham, S.; Wareham, N.J. (2008) Cross-sectional association between fish consumption and albuminuria: The European Prospective Investigation of Cancer-Norfolk Study Am J Kidney Dis, 52 (5),876-886 [Journal Article]
Abstract: BACKGROUND: Studies have shown a potential beneficial role for fish and fish oil consumption in the management of diabetes and its complications. The aim of this study is to examine the association between fish consumption and albuminuria in individuals with and without diabetes. STUDY DESIGN: A cross-sectional analysis conducted in the European Prospective Investigation of Cancer-Norfolk population-based cohort study. SETTING & PARTICIPANTS: 22,384 men and women from general practices in the city of Norwich and vicinity, of whom 517 had diabetes by self-report and 21,867 did not report diabetes. PREDICTORS: Fish consumption was measured in a validated semiquantitative food frequency questionnaire and categorized as less than 1, 1 to 2, and more than 2 portions/wk. Interaction between fish intake and diabetes status was hypothesized a priori. OUTCOMES & MEASUREMENTS: Microalbuminuria and macroalbuminuria were defined as urinary albumin-creatinine ratio of 2.5 or greater to 24.9 and 25 mg/mmol or greater, respectively. Log-transformed albumin-creatinine ratio was used as a continuous variable. RESULTS: Prevalences of microalbuminuria were 22.6% in participants with diabetes and 11.4% in participants without diabetes. Prevalences of macroalbuminuria were 8.3% and 0.6%, respectively. Fish consumption was associated with a lower risk of macroalbuminuria in participants with diabetes (odds ratio, 0.22, >2 versus <1 portion/wk; 95% confidence interval, 0.07 to 0.70; P for trend = 0.009) after adjustment for confounding. This association was not observed in participants with diabetes with microalbuminuria or in the nondiabetic population. There was a significant interaction between diabetes status and fish consumption of 1 to 2 portions/wk (P = 0.03) and more than 2 portions/wk (P = 0.007) for risk of macroalbuminuria. LIMITATIONS: Cross-sectional nature of study. Self-report of fish intake and diabetes status. CONCLUSIONS: Greater fish intake was associated with a lower risk of macroalbuminuria in a self-defined diabetic population. These findings merit confirmation in prospective studies and intervention trials and suggest that fish intake may be beneficial for albuminuria in people with diabetes.
PubMed Accession Number :: 18534731.

Tan, Q.; Zhao, J.; Li, S.; Christiansen, L.; Kruse, T. A.; Christensen, K. (2008) Differential and correlation analyses of microarray gene expression data in the CEPH Utah families Genomics, 92 ,94-100 [Journal Article] Online
Abstract: The widespread microarray technology capable of analyzing global gene expression at the level of transcription is expanding its application not only in medicine but also in studies on basic biology. This paper presents our analysis on microarray gene expression data in the CEPH Utah families focusing on the demographic characteristics such as age and sex on differential gene expression patterns. Our results show that the differential gene expression pattern between age groups is dominated by down-regulated transcriptional activities in the old subjects. Functional analysis on age-regulated genes identifies cell-cell signaling as an important functional category implicated in human aging. Sex-dependent gene expression is characterized by genes that may escape X-inactivation and, most interestingly, such a pattern is not affected by the aging process. Analysis on sibship correlation on gene expression revealed a large number of significant genes suggesting the importance of a genetic mechanism in regulating transcriptional activities. In addition, we observe an interesting pattern of sibship correlation on gene expression that increases exponentially with the mean of gene expression reflecting the enhanced genetic control over the functionally active genes.
PubMed Accession Number :: 18519161.

Rahman, M.; Simmons, R. K.; Harding, A. H.; Wareham, N. J.; Griffin, S. J. (2008) A simple risk score identifies individuals at high risk of developing Type 2 diabetes: a prospective cohort study Fam Pract, 25 (3),191-6 [Journal Article] Online
Abstract: BACKGROUND: Randomized trials have demonstrated that Type 2 diabetes is preventable among high-risk individuals. To date, such individuals have been identified through population screening using the oral glucose tolerance test. OBJECTIVE: To assess whether a risk score comprising only routinely collected non-biochemical parameters was effective in identifying those at risk of developing Type 2 diabetes. METHODS: Population-based prospective cohort (European Prospective Investigation of Cancer-Norfolk). Participants aged 40-79 recruited from UK general practices attended a health check between 1993 and 1998 (n = 25 639) and were followed for a mean of 5 years for diabetes incidence. The Cambridge Diabetes Risk Score was computed for 24 495 individuals with baseline data on age, sex, prescription of steroids and anti-hypertensive medication, family history of diabetes, body mass index and smoking status. We examined the incidence of diabetes across quintiles of the risk score and plotted a receiver operating characteristic (ROC) curve to assess discrimination. RESULTS: There were 323 new cases of diabetes, a cumulative incidence of 2.76/1000 person-years. Those in the top quintile of risk were 22 times more likely to develop diabetes than those in the bottom quintile (odds ratio 22.3; 95% CI: 11.0-45.4). In all, 54% of all clinically incident cases occurred in individuals in the top quintile of risk (risk score > 0.37). The area under the ROC was 74.5%. CONCLUSION: The risk score is a simple, effective tool for the identification of those at risk of developing Type 2 diabetes. Such methods may be more feasible than mass population screening with biochemical tests in defining target populations for prevention programmes.
PubMed Accession Number :: 18515811.

Kellar, I.; Sutton, S.; Griffin, S.; Prevost, A. T.; Kinmonth, A. L.; Marteau, T. M. (2008) Evaluation of an informed choice invitation for type 2 diabetes screening Patient Educ Couns, 72 (2),232-8 [Journal Article] Online
Abstract: OBJECTIVE: To evaluate an innovative invitation designed to facilitate informed choices for undergoing screening for type 2 diabetes. METHODS: Four hundred and seventeen people aged 40-69 years (sex: F 53%/M 47%), without known diabetes, recruited from street locations. Participants were randomised to receive one of two hypothetical invitations for screening for type 2 diabetes; one based on General Medical Council guidelines and combined with a decisional balance sheet, the other a brief traditional invitation. Informed choice was assessed immediately after the invitation and 3 weeks later using measures of knowledge, attitudes and intentions. RESULTS: Two weeks after receipt of the invitation, the proportion of informed choices was significantly higher among participants who received the informed choice invitation compared with those who received the traditional invitation (42.9% versus 11.2%; difference=31.7%, 95% CI: 22.5-40.5%; p<0.001). Mean knowledge scores were significantly higher after the receipt of the invitation designed to facilitate informed choices than after the traditional invitation (5.49 versus 3.90; t(405)=10.106, p<0.001). Intentions to participate in screening were unaffected by receipt of the informed choice invitation. CONCLUSION: Compared with a traditional invitation, receipt of the invitation designed to facilitate informed choices increased the proportion of informed choices about type 2 diabetes screening attendance. PRACTICE IMPLICATIONS: : Although the new invitation was associated with better knowledge of screening it had no differential effect on intention and its effect on attendance still requires evaluation.
PubMed Accession Number :: 18513916.

Ogilvie, D.; Mitchell, R.; Mutrie, N.; Petticrew, M.; Platt, S. (2008) Perceived characteristics of the environment associated with active travel: development and testing of a new scale Int J Behav Nutr Phys Act, 5 (1),32 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Environmental characteristics may be associated with patterns of physical activity. However, the development of instruments to measure perceived characteristics of the local environment is still at a comparatively early stage, and published instruments are not necessarily suitable for application in all settings. We therefore developed and established the test-retest reliability of a new scale for use in a study of the correlates of active travel and overall physical activity in deprived urban neighbourhoods in Glasgow, Scotland. METHODS: We developed and piloted a 14-item scale based on seven constructs identified from the literature (aesthetics, green space, access to amenities, convenience of routes, traffic, road safety and personal safety). We administered the scale to all participants in a random postal survey (n=1322) and readministered the scale to a subset of original respondents (n=125) six months later. We used principal components analysis and Varimax rotation to identify three principal components (factors) and derived summary scores for subscales based on these factors. We examined the internal consistency of these subscales using Cronbach's alpha and examined the test-retest reliability of the individual items, the subscale summary scores and an overall summary neighbourhood score using a combination of correlation coefficients and Cohen's kappa with and without weighting. RESULTS: Public transport and proximity to shops were the items most likely to be rated positively, whereas traffic volume, traffic noise and road safety for cyclists were most likely to be rated negatively. Three principal components -- 'safe and pleasant surroundings', 'low traffic' and 'convenience for walking' -- together explained 45% of the total variance. The test-retest reliability of individual items was comparable with that of items in other published scales (intraclass correlation coefficients (ICCs) 0.34-0.70; weighted Cohen's kappa 0.24-0.59). The overall summary neighbourhood score had acceptable internal consistency (Cronbach's alpha 0.72) and test-retest reliability (ICC 0.73). CONCLUSIONS: This new scale contributes to the development of a growing set of tools for investigating the role of perceived environmental characteristics in explaining or mediating patterns of active travel and physical activity.
PubMed Accession Number :: 18513430.

McFadden, E.; Luben, R.; Wareham, N.; Bingham, S.; Khaw, K. T. (2008) Occupational social class, risk factors and cardiovascular disease incidence in men and women: a prospective study in the European Prospective Investigation of Cancer and Nutrition in Norfolk (EPIC-Norfolk) cohort Eur J Epidemiol, 23 ,449-458 [Journal Article] Online
Abstract: Objectives To investigate the association between occupational social class and cardiovascular disease (CVD) incidence, and the extent to which classical and lifestyle risk factors explain such relationships, and if any differences persist after 65 years of age. Design, Setting and Participants Prospective population study of 22,478 men and women aged 39-79 years living in the general community in Norfolk, United Kingdom, recruited using general practice age-sex registers in 1993-1997 and followed up for total mortality to 2006. Main results In both men and women an inverse relationship was observed between social class and CVD incidence, with a relative risk of social class V compared to I of 1.90 in men (95% CI 1.47 to 2.47, P < 0.001) and 1.90 in women (95% CI 1.45 to 2.49, P < 0.001). Adjusting for classical and lifestyle risk factors (age, smoking, BMI, systolic blood pressure, total blood cholesterol, history of diabetes, physical activity, weekly alcohol intake and plasma vitamin C levels) had little effect in men; the relative risk of social class V compared to I of 1.70 (95% CI 1.31 to 2.22, P < 0.001), while there was some attenuation seen in women, relative risk of social class V compared to I of 1.56 (95% CI 1.18 to 2.05, P = 0.011). The association persisted in men and women aged >/=65 years. Conclusions Some but not all of the socioeconomic differential in CVD incidence can be explained by potentially modifiable classical and lifestyle risk factors. Low social class remains a risk factor for CVD after age 65 years. Further understanding of the mechanisms underlying the association is needed if we are to reduce inequalities in health.
PubMed Accession Number :: 18509727.

Main, C.; Thomas, S.; Ogilvie, D.; Stirk, L.; Petticrew, M.; Whitehead, M.; Sowden, A. (2008) Population tobacco control interventions and their effects on social inequalities in smoking: placing an equity lens on existing systematic reviews BMC Public Health, 8 ,178 [Journal Article] Online
Abstract: BACKGROUND: With smoking increasingly confined to lower socio-economic groups, the tobacco control community has been urged to identify which population-level tobacco control interventions work in order to help tackle smoking-related health inequalities. Systematic reviews have a crucial role to play in this task. This overview was therefore carried out in order to (i) summarise the evidence from existing systematic reviews of population-level tobacco control interventions, and (ii) assess the need for a new systematic review of primary studies, with the aim of assessing the differential effects of such interventions. METHODS: Systematic review methods were used to evaluate existing systematic reviews that assessed a population-level tobacco control intervention and which reported characteristics of included participants in terms of at least one socio-demographic or socio-economic factor. RESULTS: Nineteen systematic reviews were included. Four reviews assessed interventions aimed at the population level alone, whilst fifteen included at least one primary study that examined this type of intervention. Four reviews assessed youth access restrictions, one assessed the effects of increasing the unit price of tobacco, and six assessed smoking bans or restrictions. Of the eight remaining reviews, six assessed multi-component community based interventions, in which the population-level interventions were part of a wider tobacco control programme, and two assessed the impact of smoking bans or restrictions in reducing exposure to environmental tobacco smoke. We found tentative evidence that the effect of increasing the unit price of tobacco products may vary between ethnic and socio-economic groups, and between males and females. However, differences in the context and the results of different reviews made it difficult to draw any firm conclusions. Few identified reviews explicitly attempted to examine differences in intervention effects between socio-demographic groups. Therefore on the basis of these reviews the potential for smoking bans, and youth access restrictions to decrease social inequalities in smoking remains unknown. CONCLUSION: There is preliminary evidence that increases in the unit price of tobacco may have the potential to reduce smoking related health inequalities. There is a need for equity effects to be explicitly evaluated in future systematic reviews and in primary research assessing the effects of population tobacco control interventions.
PubMed Accession Number :: 18505545.

Sattar, N.; McConnachie, A.; Shaper, A. G.; Blauw, G. J.; Buckley, B. M.; de Craen, A. J.; Ford, I.; Forouhi, N. G.; Freeman, D. J.; Jukema, J. W.; Lennon, L.; Macfarlane, P. W.; Murphy, M. B.; Packard, C. J.; Stott, D. J.; Westendorp, R. G.; Whincup, P. H.; Shepherd, J.; Wannamethee, S. G. (2008) Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies Lancet, 371 (9628),1927-35 [Journal Article] Online
Abstract: BACKGROUND: Clinical use of criteria for metabolic syndrome to simultaneously predict risk of cardiovascular disease and diabetes remains uncertain. We investigated to what extent metabolic syndrome and its individual components were related to risk for these two diseases in elderly populations. METHODS: We related metabolic syndrome (defined on the basis of criteria from the Third Report of the National Cholesterol Education Program) and its five individual components to the risk of events of incident cardiovascular disease and type 2 diabetes in 4812 non-diabetic individuals aged 70-82 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). We corroborated these data in a second prospective study (the British Regional Heart Study [BRHS]) of 2737 non-diabetic men aged 60-79 years. FINDINGS: In PROSPER, 772 cases of incident cardiovascular disease and 287 of diabetes occurred over 3.2 years. Metabolic syndrome was not associated with increased risk of cardiovascular disease in those without baseline disease (hazard ratio 1.07 [95% CI 0.86-1.32]) but was associated with increased risk of diabetes (4.41 [3.33-5.84]) as was each of its components, particularly fasting glucose (18.4 [13.9-24.5]). Results were similar in participants with existing cardiovascular disease. In BRHS, 440 cases of incident cardiovascular disease and 105 of diabetes occurred over 7 years. Metabolic syndrome was modestly associated with incident cardiovascular disease (relative risk 1.27 [1.04-1.56]) despite strong association with diabetes (7.47 [4.90-11.46]). In both studies, body-mass index or waist circumference, triglyceride, and glucose cutoff points were not associated with risk of cardiovascular disease, but all five components were associated with risk of new-onset diabetes. INTERPRETATION: Metabolic syndrome and its components are associated with type 2 diabetes but have weak or no association with vascular risk in elderly populations, suggesting that attempts to define criteria that simultaneously predict risk for both cardiovascular disease and diabetes are unhelpful. Clinical focus should remain on establishing optimum risk algorithms for each disease. FUNDING: Diabetes UK and British Heart Foundation.
PubMed Accession Number :: 18501419.

Ekelund, U. (2008) Cardiorespiratory fitness, exercise capacity and physical activity in children: are we measuring the right thing? Arch Dis Child, 93 (6),455-6 [Journal Article] Online
PubMed Accession Number :: 18495907.

Franks, P. W.; Scheele, C.; Loos, R. J.; Nielsen, A. R.; Finucane, F. M.; Wahlestedt, C.; Pedersen, B. K.; Wareham, N. J.; Timmons, J. A. (2008) Genomic variants at the PINK1 locus are associated with transcript abundance and plasma nonesterified fatty acid concentrations in European whites Faseb J, 22 (9),3135-45 [Journal Article] Online
Abstract: The purpose of this study was to characterize associations between PINK1 genotypes, PINK1 transcript levels, and metabolic phenotypes in healthy adults and those with type 2 diabetes (T2D). We measured PINK1 skeletal muscle transcript levels and 8 independent PINK1 single nucleotide polymorphisms (SNPs) in a cohort of 208 Danish whites and in a cohort of 1701 British whites (SNPs and metabolic phenotypes only). Furthermore, we assessed the effects of PINK1 transcript ablation in primary adipocytes using RNA interference (RNAi). Six PINK1 SNPs were associated with PINK1 transcript levels (P<0.04 to P<0.0001). Obesity modified the association between PINK1 transcript levels and T2D risk (interaction P=0.005); transcript levels were inversely related with T2D in obese (n=105) [odds ratio (OR) per SD increase in expression levels=0.44; 95% confidence interval (CI): 0.23, 0.84; P=0.013] but not in nonobese (n=103) (OR=1.20; 95% CI: 0.82, 1.76; P=0.34) individuals. In the British cohort, several PINK1 SNPs were associated with plasma nonesterified fatty acid concentrations. Nominal genotype associations were also observed for fasting glucose, 2-h glucose, and maximal oxygen consumption, although these were not statistically significant after correcting for multiple testing. In primary adipocytes, Pink1 knockdown affected fatty acid binding protein 4 (Fabp4) expression, indicating that PINK1 may influence substrate metabolism. We demonstrate that PINK1 polymorphisms are associated with PINK1 transcript levels and measures of fatty acid metabolism in a concordant manner, whereas our RNAi data imply that PINK1 may indirectly influence lipid metabolism.-Franks, P. W., Scheele, C., Loos, R. J. F., Nielsen, A. R., Finucane, F. M., Wahlestedt, C., Pedersen, B. K., Wareham, N. J., Timmons, J. A. Genomic variants at the PINK1 locus are associated with transcript abundance and plasma nonesterified fatty acid concentrations in European whites.
PubMed Accession Number :: 18495756.

Souren, N. Y.; Paulussen, A. D.; Steyls, A.; Loos, R. J.; Stassen, A. P.; Gielen, M.; Smeets, H. J.; Beunen, G.; Fagard, R.; Derom, C.; Vlietinck, R.; Geraedts, J. P.; Zeegers, M. P. (2008) Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins Int J Obes (Lond), 32 (8),1233-9 [Journal Article] Online
Abstract: Objective:Children born small for gestational age are at increased risk of developing type 2 diabetes in adulthood. The satiety signal leptin that regulates food intake and energy expenditure might be a possible molecular link, as umbilical cord leptin levels are positively correlated with birth weight. In the present study, we examined whether common single nucleotide polymorphisms (SNPs) in the leptin (LEP; 19G>A) gene and its receptor (LEPR; Q223R and K109R) are associated with birth weight and adult metabolic risk factors for type 2 diabetes in twins.Design:SNPs were genotyped in 396 monozygotic and 232 dizygotic twins (286 men and 342 women, mean age 25 years) recruited from the East Flanders Prospective Twin Survey. Data were analysed using linear mixed models.Results:The LEPR K109R SNP was associated with birth weight (KK, KR and RR (95% confidence interval, CI): 2511 (2465-2557), 2575 (2516-2635) and 2726 (2606-2845) gram; P(additive)=0.001). Also the LEPR Q223R SNP showed a significant association with weight at birth (QQ, QR and RR (95% CI): 2492 (2431-2554), 2545 (2495-2595) and 2655 (2571-2740) gram; P(additive)=0.003). Furthermore, an interaction between the LEPR K109R and the Q223R SNP on birth weight was observed (P=0.014). G allele carriers of the LEP 19G>A SNP had higher high-density lipoprotein (HDL) cholesterol levels compared to 19A homozygotes (GX vs AA (95% CI): 1.62 (1.58-1.66) vs 1.49 (1.40-1.58) mmol l(-1); P(recessive)=0.013).Conclusions:This study indicates that leptin may act as a growth-promoting signal during fetal development, and suggests a possible role for the LEPR in explaining the inverse relationship between birth weight and the development of metabolic diseases in adulthood. Additionally, these results suggest that the LEP 19G>A SNP affect HDL cholesterol levels.International Journal of Obesity advance online publication, 20 May 2008; doi:10.1038/ijo.2008.68.
PubMed Accession Number :: 18490929.

Assah, F. K.; Brage, S.; Ekelund, U.; Wareham, N. J. (2008) The association of intensity and overall level of physical activity energy expenditure with a marker of insulin resistance Diabetologia, 51 (8),1399-407 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Physical activity is important in preventing insulin resistance, but it is unclear which dimension of activity confers this benefit. We examined the association of overall level and intensity of physical activity with fasting insulin level, a marker of insulin resistance. METHODS: This was a cross-sectional analysis of the Medical Research Council Ely population-based cohort study (2000-2002). Physical activity energy expenditure (PAEE) in kJ kg(-1) min(-1) was measured by heart rate monitoring with individual calibration over a period of 4 days. The percentage of time spent above 1.5, 1.75 and 2 times resting heart rate (RHR) represented all light-to-vigorous, moderate-to-vigorous and vigorous activity, respectively. RESULTS: Data from a total of 643 non-diabetic individuals (319 men, 324 women) aged 50 to 75 years were analysed. In multivariate linear regression analyses, adjusting for age, sex and body fat percentage, PAEE was significantly associated with fasting insulin (pmol/l) (beta = -0.875, p = 0.006). Time (% of total) spent above 1.75 x RHR and also time spent above 2 x RHR were both significantly associated with fasting insulin (beta = -0.0109, p = 0.007 and beta = -0.0365, p = 0.001 respectively), after adjusting for PAEE, age, sex and body fat percentage. Time spent above 1.5 x RHR was not significantly associated with fasting insulin in a similar model (beta = -0.0026, p = 0.137). CONCLUSIONS/INTERPRETATION: The association between PAEE and fasting insulin level, a marker of insulin resistance, may be attributable to the time spent in moderate-to-vigorous and vigorous activity, but not to time spent in light-intensity physical activity.
PubMed Accession Number :: 18488189.

Vimaleswaran, K. S.; Luan, J.; Andersen, G.; Muller, Y. L.; Wheeler, E.; Brito, E. C.; O'Rahilly, S.; Pedersen, O.; Baier, L. J.; Knowler, W. C.; Barroso, I.; Wareham, N. J.; Loos, R. J.; Franks, P. W. (2008) The Gly482Ser genotype at the PPARGC1A gene and elevated blood pressure: a meta-analysis of 13,949 individuals J Appl Physiol, 105 (4),1352-8 [Journal Article] Online
Abstract: The PPARGC1A gene product is expressed at high levels in metabolically active tissues and controls oxidative stress via reactive oxygen species detoxification. Recent reports suggest that the PPARGC1A Gly482Ser (rs8192678) missense polymorphism may relate inversely with blood pressure. We used meta-analysis to assess associations between Gly482Ser and systolic (SBP) or diastolic (DBP) blood pressures or hypertension in 13,949 individuals from 17 studies, of which 6,042 were previously unpublished observations. The cohorts included White European adults, Asian and American Indian adults, and South American adolescents. Ethnicity-stratified analyses were conducted to control for population-stratification. Pooled genotype frequencies were 0.47 (Gly482Gly), 0.42 (Gly482Ser) and 0.11 (Ser482Ser). We found no evidence of association between Gly482Ser and SBP (P=0.409) or DBP (P=0.651), nor of genotype-sex interactions (SBP, Pinteraction=0.966; DBP, Pinteraction=0.715), as reported elsewhere. We were also unable to confirm the previously reported association between the Ser482 allele and hypertension (odds ratio: 0.97,95% CI=0.87-1.08,P=0.585). Results were materially unchanged when analyses were focused on Whites. However, statistical evidence of gene-age interaction was apparent (DBP: Pinteraction<0.0001; SBP: Pinteraction=0.026); in younger individuals (<50yrs; n=2511) the 482Ser allele was associated with higher DBP (P=4.20x10-12) and SBP (P=7.20x10-12), but no association was evident in those older than 50yrs (n=5088) (SBP, P=0.41; DBP, P=0.51). Our findings suggest that the PPARGC1A Gly482Ser genotype may be associated with higher blood pressure, but this is only apparent in younger adults. Such interactions may be driven by the modifying effects of age-specific environmental exposures such as diet or physical activity levels. Key words: PPARGC1A, Blood pressure, meta-analysis.
PubMed Accession Number :: 18467552.

Vimaleswaran, K. S.; Radha, V.; Ramya, K.; Babu, H. N.; Savitha, N.; Roopa, V.; Monalisa, D.; Deepa, R.; Ghosh, S.; Majumder, P. P.; Rao, M. R.; Mohan, V. (2008) A novel association of a polymorphism in the first intron of adiponectin gene with type 2 diabetes, obesity and hypoadiponectinemia in Asian Indians Hum Genet, , [Journal Article] Online
Abstract: Adiponectin is an adipose tissue specific protein that is decreased in subjects with obesity and type 2 diabetes. The objective of the present study was to examine whether variants in the regulatory regions of the adiponectin gene contribute to type 2 diabetes in Asian Indians. The study comprised of 2,000 normal glucose tolerant (NGT) and 2,000 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. We identified two proximal promoter SNPs (-11377C-->G and -11282T-->C), one intronic SNP (+10211T-->G) and one exonic SNP (+45T-->G) by SSCP and direct sequencing in a pilot study (n = 500). The +10211T-->G SNP alone was genotyped using PCR-RFLP in 4,000 study subjects. Logistic regression analysis revealed that subjects with TG genotype of +10211T-->G had significantly higher risk for diabetes compared to TT genotype [Odds ratio 1.28; 95% Confidence Interval (CI) 1.07-1.54; P = 0.008]. However, no association with diabetes was observed with GG genotype (P = 0.22). Stratification of the study subjects based on BMI showed that the odds ratio for obesity for the TG genotype was 1.53 (95%CI 1.3-1.8; P < 10(-7)) and that for GG genotype, 2.10 (95% CI 1.3-3.3; P = 0.002). Among NGT subjects, the mean serum adiponectin levels were significantly lower among the GG (P = 0.007) and TG (P = 0.001) genotypes compared to TT genotype. Among Asian Indians there is an association of +10211T-->G polymorphism in the first intron of the adiponectin gene with type 2 diabetes, obesity and hypoadiponectinemia.
PubMed Accession Number :: 18465144.

Beynon, C. M.; McMinn, A. M.; Marr, A. J. (2008) Factors predicting drop out from, and retention in, specialist drug treatment services: a case control study in the North West of England BMC Public Health, 8 (1),149 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: In the United Kingdom (UK), the National Treatment Agency for Substance Misuse (NTA) considers retention to be the best available measure of drug treatment effectiveness. Accordingly, the NTA has set local treatment systems the annual target of retaining 75% of clients for 12 weeks or more, yet little assessment of this target or factors that improve retention has occurred. This study aims to quantify the proportion of people retained in treatment for 12 weeks in the North West of England and to identify factors associated with premature drop out. METHODS: The North West National Drug Treatment Monitoring System (NDTMS) was used to identify treatment durations for everyone beginning a treatment episode between 1st April 2005 and 31st March 2006 (N=16626). Odds ratios, chi-square and logistic regression analyses compared clients retained for 12 weeks to clients whose discharge record showed they had prematurely dropped out before 12 weeks. Individuals with other outcomes were excluded from analyses. RESULTS: 75% of clients (N=12230) were retained for 12 weeks and 10% (N=1649) dropped out prematurely. Multivariate analyses showed drop out was more likely among Asian drug users (adjusted odds ratio 1.52, 95% CI 1.12 to 2.08) than their white equivalents. Drop out was more likely among residents of Cumbria and Lancashire (adjusted odds ratio 1.80, 95% CI 1.51 to 2.15) and Greater Manchester (adjusted odds ratio 2.00, 95% CI 1.74 to 2.29) than Cheshire and Merseyside and less likely among alcohol users (adjusted odds ratio 0.73, 95% CI 0.59 to 0.91). A significant interaction between age and deprivation was observed. For those aged 18 to 24 years and 25 to 34 years, drop out was significantly more likely among those living in affluent areas. For those in the older age groups the converse effect was observed. CONCLUSIONS: In combination, the drug treatment systems of the North West achieved the Government's retention target in 2005/06. A number of factors associated with drop out were identified; these should be considered in strategies that aim to improve retention. Drop out and retention are measures that capture the joint effect of many factors. Further work is required to evaluate the effect of deprivation.
PubMed Accession Number :: 18460202.

Loos, R. J.; Lindgren, C. M.; Li, S.; Wheeler, E.; Zhao, J. H.; Prokopenko, I.; Inouye, M.; Freathy, R. M.; Attwood, A. P.; Beckmann, J. S.; Berndt, S. I.; Jacobs, K. B.; Chanock, S. J.; Hayes, R. B.; Bergmann, S.; Bennett, A. J.; Bingham, S. A.; Bochud, M.; Brown, M.; Cauchi, S.; Connell, J. M.; Cooper, C.; Smith, G. D.; Day, I.; Dina, C.; De, S.; Dermitzakis, E. T.; Doney, A. S.; Elliott, K. S.; Elliott, P.; Evans, D. M.; Sadaf Farooqi, I.; Froguel, P.; Ghori, J.; Groves, C. J.; Gwilliam, R.; Hadley, D.; Hall, A. S.; Hattersley, A. T.; Hebebrand, J.; Heid, I. M.; Lamina, C.; Gieger, C.; Illig, T.; Meitinger, T.; Wichmann, H. E.; Herrera, B.; Hinney, A.; Hunt, S. E.; Jarvelin, M. R.; Johnson, T.; Jolley, J. D.; Karpe, F.; Keniry, A.; Khaw, K. T.; Luben, R. N.; Mangino, M.; Marchini, J.; McArdle, W. L.; McGinnis, R.; Meyre, D.; Munroe, P. B.; Morris, A. D.; Ness, A. R.; Neville, M. J.; Nica, A. C.; Ong, K. K.; O'Rahilly, S.; Owen, K. R.; Palmer, C. N.; Papadakis, K.; Potter, S.; Pouta, A.; Qi, L.; Kraft, P.; Hankinson, S. E.; Hunter, D. J.; Hu, F. B.; Randall, J. C.; Rayner, N. W.; Ring, S. M.; Sandhu, M. S.; Scherag, A.; Sims, M. A.; Song, K.; Soranzo, N.; Speliotes, E. K.; Lyon, H. N.; Voight, B. F.; Ridderstrale, M.; Groop, L.; Syddall, H. E.; Teichmann, S. A.; Timpson, N. J.; Tobias, J. H.; Uda, M.; Scheet, P.; Sanna, S.; Abecasis, G. R.; Albai, G.; Nagaraja, R.; Schlessinger, D.; Ganz Vogel, C. I.; Wallace, C.; Waterworth, D. M.; Weedon, M. N.; Willer, C. J.; Jackson, A. U.; Tuomilehto, J.; Collins, F. S.; Boehnke, M.; Mohlke, K. L.; Wraight, V. L.; Yuan, X.; Zeggini, E.; Hirschhorn, J. N.; Strachan, D. P.; Ouwehand, W. H.; Caulfield, M. J.; Samani, N. J.; Frayling, T. M.; Vollenweider, P.; Waeber, G.; Mooser, V.; Deloukas, P.; McCarthy, M. I.; Wareham, N. J.; Barroso, I. (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity Nat Genet, 40 (6),768-75 [Journal Article] Online
Abstract: To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
PubMed Accession Number :: 18454148.

Sandbaek, A.; Griffin, S. J.; Rutten, G.; Davies, M.; Stolk, R.; Khunti, K.; Borch-Johnsen, K.; Wareham, N. J.; Lauritzen, T. (2008) Stepwise screening for diabetes identifies people with high but modifiable coronary heart disease risk. The ADDITION study Diabetologia, 51 (7),1127-34 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The Anglo-Danish-Dutch study of intensive treatment in people with screen-detected diabetes in primary care (ADDITION) is a pragmatic randomised controlled trial of the effectiveness of intensified multi-factorial treatment on 5 year cardiovascular morbidity and mortality rates in people with screen-detected type 2 diabetes in the Netherlands, UK and Denmark. This paper describes the baseline characteristics of the study population, their estimated risk of coronary heart disease and the extent to which that risk is potentially modifiable. METHODS: Stepwise screening strategies were performed using risk questionnaires and routine general practice data plus random blood glucose, HbA(1c) and fasting blood glucose measurement. Diabetes was diagnosed using the 1999 World Health Organization criteria and estimated 10 year coronary heart disease risk was calculated using the UK Prospective Diabetes Study risk engine. RESULTS: Between April 2001 and December 2006, 3,057 people with screen-detected diabetes were recruited to the study (mean age 59.7 years, 58% men) after a stepwise screening programme involving 76,308 people screened in 334 general practices in three countries. Their median estimated 10 year risk of coronary heart disease was 11% in women (interquartile range 7-16%) and 21% (15-30%) in men. There were differences in the distribution of risk factors by country, linked to differences in approaches to screening and the extent to which risk factors had already been detected and treated. The mean HbA(1c) at recruitment was 7.0% (SD 1.6%). Of the people recruited, 73% had a blood pressure >/=140/90 and of these 58% were not on antihypertensive medication. Cholesterol levels were above 5.0 mmol/l in 70% of participants, 91% of whom were not being treated with lipid-lowering drugs. CONCLUSIONS/INTERPRETATION: People with type 2 diabetes detected by screening and included in the ADDITION study have a raised and potentially modifiable risk of CHD. ClinicalTrials.gov ID no.: NCT 00237549.
PubMed Accession Number :: 18443762.

Jassal, S. K.; Langenberg, C.; von Muhlen, D.; Bergstrom, J.; Barrett-Connor, E. (2008) Usefulness of microalbuminuria versus the metabolic syndrome as a predictor of cardiovascular disease in women and men>40 years of age (from the Rancho Bernardo Study) Am J Cardiol, 101 (9),1275-80 [Journal Article] Online
Abstract: To examine the sex-specific contributions of the metabolic syndrome and microalbuminuria to cardiovascular disease (CVD) and coronary heart disease (CHD) mortality in community-dwelling older adults, 869 women and 575 men aged 40 to 96 years (mean age 71) completed questionnaires, physical examinations, and fasting laboratory tests between 1992 and 1995. Participants were followed over an average of 8 years. CVD and CHD mortality were analyzed using Cox proportional hazards models. At baseline, 267 participants had the Adult Treatment Panel III metabolic syndrome, 151 had microalbuminuria, and 34 had both. During follow-up, there were 180 CVD deaths, including 83 CHD deaths. In women, microalbuminuria was associated with a twofold increased risk of CVD and CHD mortality (p<or=0.01). Women with both microalbuminuria and the metabolic syndrome (n=18) had a threefold increased risk of CVD mortality and a fivefold increased risk of CHD mortality compared with women without either (n=657). A significant interaction existed between microalbuminuria and the metabolic syndrome in the prediction of both CVD and CHD (p=0.02). In men, neither the combination of the metabolic syndrome and microalbuminuria (n=16), nor either alone, significantly increased the risk of CVD or CHD mortality. In conclusion, in this cohort, microalbuminuria and the metabolic syndrome together were a more powerful predictor of CVD mortality than either alone in women but not in men. Screening for microalbuminuria in older women may identify women at high risk for CVD mortality beyond that conferred by risk factors included in the metabolic syndrome.
Keywords: Adult Age Factors Aged Aged, 80 and over Albuminuria/*epidemiology Cardiovascular Diseases/*mortality Data Interpretation, Statistical Female Health Status Indicators Humans Longitudinal Studies Male Metabolic Syndrome X/*epidemiology Middle Aged Predictive Value of Tests Prevalence Sex Factors
PubMed Accession Number :: 18435957.

Thomas, S.; Fayter, D.; Misso, K.; Ogilvie, D.; Petticrew, M.; Sowden, A.; Whitehead, M.; Worthy, G. (2008) Population tobacco control interventions and their effects on social inequalities in smoking: systematic review Tob Control, 17 (4),230-7 [Journal Article] Online
Abstract: OBJECTIVE: To assess the effects of population tobacco control interventions on social inequalities in smoking. DATA SOURCES: Medical, nursing, psychological, social science and grey literature databases, bibliographies, hand-searches, and contact with authors. STUDY SELECTION: Studies were included (n=84) if they reported the effects of any population-level tobacco control intervention on smoking behaviour or attitudes in individuals or groups with different demographic or socio-economic characteristics. DATA EXTRACTION: Data extraction and quality assessment for each study were conducted by one reviewer and checked by a second. DATA SYNTHESIS: Data were synthesised using graphical ('harvest plot') and narrative methods. No strong evidence of differential effects was found for smoking restrictions in workplaces and public places, although those in higher occupational groups may be more likely to change their attitudes or behaviour. Smoking restrictions in schools may be more effective in girls. Restrictions on sales to minors may be more effective in girls and younger children. Increasing the price of tobacco products may be more effective in reducing smoking among lower-income adults and those in manual occupations, although there was also some evidence to suggest that adults with higher levels of education may be more price-sensitive. Young people aged under 25 are also affected by price increases, with some evidence that boys and non-white young people may be more sensitive to price. CONCLUSIONS: Population-level tobacco control interventions have the potential to benefit more disadvantaged groups and thereby contribute to reducing health inequalities.
PubMed Accession Number :: 18426867.

Farmer, A. J.; Prevost, T.; Hardeman, W.; Craven, A.; Sutton, S.; Griffin, S.; Kinmonth, A. L.; Sams, S. A. (2008) Protocol for SAMS (Support and Advice for Medication Study): a randomised controlled trial of an intervention to support patients with type 2 diabetes with adherence to medication BMC Fam Pract, 9 (1),20 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Although some interventions have been shown to improve adherence to medication for diabetes, results are not consistent. We have developed a theory-based intervention which we will evaluate in a well characterised population to test efficacy and guide future intervention development and trial design. Methods and design The SAMS (Supported Adherence to Medication Study) trial is a primary care based multi-centre randomised controlled trial among 200 patients with type 2 diabetes and an HbA1c of 7.5% or above. It is designed to evaluate the efficacy of a two-component motivational intervention based on the Theory of Planned Behaviour and volitional action planning to support medication adherence compared with standard care. The intervention is delivered by practice nurses. Nurses were trained using a workshop approach with role play and supervised using assessment of tape-recorded consultations. The trial has a two parallel groups design with an unbalanced three-to-two individual randomisation eight weeks after recruitment with twelve week follow-up. The primary outcome is medication adherence measured using an electronic medication monitor over 12 weeks and expressed as the difference between intervention and control in mean percentage of days on which the correct number of medication doses is taken. Subgroup analyses will explore impact of number of medications taken, age, HbA1c, and self-reported adherence at baseline on outcomes. The study also measures the effect of dispensing medication to trial participants packaged in the electronic medication-monitoring device compared with conventional medication packaging. This will be achieved through one-to-one randomisation at recruitment to these conditions with assessment of the difference between groups in self-report of medication adherence and change in mean HbA1c from baseline to eight weeks. Anonymised demographic data are collected on non-respondents. Central randomisation is carried out independently of trial co-ordination and practices using minimisation to adjust for selected confounders. DISCUSSION: The SAMS intervention and trial design address weaknesses of previous research by recruitment from a well-characterised population, definition of a feasible theory based intervention to support medication taking and careful measurement to estimate and interpret efficacy. The results will inform practice and the design of a cost-effectiveness trial. [ISRCTN30522359].
PubMed Accession Number :: 18405345.

Purslow, L. R.; Young, E. H.; Wareham, N. J.; Forouhi, N.; Brunner, E. J.; Luben, R. N.; Welch, A. A.; Khaw, K. T.; Bingham, S. A.; Sandhu, M. S. (2008) Socioeconomic position and risk of short-term weight gain: prospective study of 14,619 middle-aged men and women BMC Public Health, 8 (1),112 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: The association between socioeconomic position in middle age and risk of subsequent, short-term weight gain is unknown. We therefore assessed this association in a prospective population based cohort study in Norfolk, UK. METHODS: We analysed data on 14,619 middle-aged men and women (aged between 40-75 at baseline) with repeated objective measures of weight and height at baseline (1993-1997) and follow up (1998-2000). RESULTS: During follow up 5,064 people gained more than 2.5kg. Compared with the highest social class, individuals in the lowest social class had around a 30% greater risk of gaining more than 2.5kg (OR 1.29; 95% CI 1.11-1.51; p for trend =0.002). This association remained statistically significant following adjustment for sex, age, baseline BMI, smoking, and follow up time (OR 1.25; CI 1.07-1.46; p for trend <0.001). We also found no material difference between unadjusted models and those including all confounders and potential mediators. CONCLUSION: Individuals of low socioeconomic position are at greatest risk of gaining weight during middle age, which is not explained by classical correlates of socioeconomic position and risk factors for obesity.
PubMed Accession Number :: 18400100.

Verzilli, C.; Shah, T.; Casas, J. P.; Chapman, J.; Sandhu, M.; Debenham, S. L.; Boekholdt, M. S.; Khaw, K. T.; Wareham, N. J.; Judson, R.; Benjamin, E. J.; Kathiresan, S.; Larson, M. G.; Rong, J.; Sofat, R.; Humphries, S. E.; Smeeth, L.; Cavalleri, G.; Whittaker, J. C.; Hingorani, A. D. (2008) Bayesian meta-analysis of genetic association studies with different sets of markers Am J Hum Genet, 82 (4),859-72 [Journal Article] Online
Abstract: Robust assessment of genetic effects on quantitative traits or complex-disease risk requires synthesis of evidence from multiple studies. Frequently, studies have genotyped partially overlapping sets of SNPs within a gene or region of interest, hampering attempts to combine all the available data. By using the example of C-reactive protein (CRP) as a quantitative trait, we show how linkage disequilibrium in and around its gene facilitates use of Bayesian hierarchical models to integrate informative data from all available genetic association studies of this trait, irrespective of the SNP typed. A variable selection scheme, followed by contextualization of SNPs exhibiting independent associations within the haplotype structure of the gene, enhanced our ability to infer likely causal variants in this region with population-scale data. This strategy, based on data from a literature based systematic review and substantial new genotyping, facilitated the most comprehensive evaluation to date of the role of variants governing CRP levels, providing important information on the minimal subset of SNPs necessary for comprehensive evaluation of the likely causal relevance of elevated CRP levels for coronary-heart-disease risk by Mendelian randomization. The same method could be applied to evidence synthesis of other quantitative traits, whenever the typed SNPs vary among studies, and to assist fine mapping of causal variants.
PubMed Accession Number :: 18394581.

Sattar, N.; Wannamethee, S. G.; Forouhi, N. G. (2008) Novel biochemical risk factors for type 2 diabetes: pathogenic insights or prediction possibilities? Diabetologia, 51 (6),926-40 [Journal Article] Online
Abstract: This review critically appraises studies examining the association of novel factors with diabetes. We show that many of the most studied novel and apparently 'independent' risk factors are correlated with each other by virtue of their common origins or pathways, and that residual confounding is likely. Available studies also have other limitations, including differences in methodology or inadequate statistical analyses. Furthermore, although most relevant work in this area has focused on improving our understanding of the pathogenesis of diabetes, association studies in isolation cannot prove causality; intervention studies with specific agents (if available) are required, and genetic studies may help. With respect to the potential value of novel risk factors for diabetes risk prediction, we illustrate why this work is very much in its infancy and currently not guaranteed to reach clinical utility. Indeed, the existence of several more easily measured powerful predictors of diabetes, suggests that the additional value of novel markers may be limited. Nevertheless, several suggestions to improve relevant research are given. Finally, we show that several risk factors for diabetes are only weakly associated with the risk of incident vascular events, an observation that highlights the limitations of attempting to devise unified criteria (e.g. metabolic syndrome) to identify individuals at risk of both CHD and diabetes.
PubMed Accession Number :: 18392804.

Weedon, M. N.; Lango, H.; Lindgren, C. M.; Wallace, C.; Evans, D. M.; Mangino, M.; Freathy, R. M.; Perry, J. R.; Stevens, S.; Hall, A. S.; Samani, N. J.; Shields, B.; Prokopenko, I.; Farrall, M.; Dominiczak, A.; Johnson, T.; Bergmann, S.; Beckmann, J. S.; Vollenweider, P.; Waterworth, D. M.; Mooser, V.; Palmer, C. N.; Morris, A. D.; Ouwehand, W. H.; Caulfield, M.; Munroe, P. B.; Hattersley, A. T.; McCarthy, M. I.; Frayling, T. M.; Zhao, J. H.; Li, S.; Loos, R. J.; Barroso, I.; Deloukas, P.; Sandhu, M. S.; Wheeler, E.; Soranzo, N.; Inouye, M.; Wareham, N. J. (2008) Genome-wide association analysis identifies 20 loci that influence adult height Nat Genet, 40 (5),575-83 [Journal Article] Online
Abstract: Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.
PubMed Accession Number :: 18391952.

Hemmingsson, E.; Hellenius, M. L.; Ekelund, U.; Bergstrom, J.; Rossner, S. (2008) Impact of Social Support Intensity on Walking in the Severely Obese: A Randomized Clinical Trial Obesity (Silver Spring), 16 (6),308-13 [Journal Article] Online
Abstract: Objective:There are few established methods for promoting physical activity (PA) in the severely obese. Because social support is a potential method for promoting PA, we compared mean steps/day during 18 weeks in severely obese outpatients receiving either standard support (SS) or added support (AS).Methods and Procedures:Eighty severely obese outpatients from an obesity clinic were invited; 66 provided written consent, 55 were randomized, and 42 were included in final analyses (9 men, 33 women; age 44.4 +/- 13.1 years; BMI 41.9 +/- 5.5 kg/m(2)). All participants received a pedometer and a walking promotion booklet. In addition to SS, the AS group received ten 2-h group counseling sessions aimed at increasing weekly accumulated steps, every second week during the study. Each participant was asked to complete a 7-day walking diary every second week (10 observations).Results:Baseline steps/day was 6,912 for the AS group and 5,311 for the SS group (P = 0.023). Data at 18 weeks showed that the AS group recorded 10,136 steps/day and the SS group 6,118 steps/day (P = 0.024). There was no allocation x time interaction (P = 0.46). During the follow-up period as a whole, the AS group recorded 1,794 more steps/day than the SS group (P = 0.0074).Discussion:The AS group recorded more steps/day than the SS group, reaching a mean level of approximately 10,000 steps/day. However, the nonsignificant interaction between allocation x time suggests that this difference was present already at baseline and did not increase during follow-up.Obesity (2008) doi:10.1038/oby.2008.204.
PubMed Accession Number :: 18388901.

Li, S.; Loos, R. J. (2008) Progress in the genetics of common obesity: size matters Curr Opin Lipidol, 19 (2),113-21 [Journal Article] Online
Abstract: PURPOSE OF REVIEW: Over the past two decades serious efforts has been invested in the search for genes that predispose to common obesity, but progress has been slow and success limited. Genome-wide association, however, has revived optimism. Here we review recent advances in the field of obesity genetics and discuss the most important findings of candidate gene, genome-wide linkage studies and genome-wide association studies. We conclude by speculating about the way forward in the near future. RECENT FINDINGS: Although large-scale candidate gene studies have placed MC4R more firmly on the human obesity map, the major breakthrough in obesity genetics was the discovery of FTO through genome-wide association. Variants located in the first intron of FTO were unequivocally associated with a 1.67-fold increased risk for obesity and a 0.40-0.66 kg/m increase in body mass index. SUMMARY: Genome-wide association promises to enhance greatly our understanding of the genetic basis of common obesity, although candidate gene studies will remain a valuable approach because they allow more detailed analyses of biologically relevant candidates. A key factor contributing to continued success lies in large-scale data integration through international collaboration, which will provide the sample sizes required to identify genetic association with conclusive evidence.
PubMed Accession Number :: 18388690.

Teo, Y. Y.; Inouye, M.; Small, K. S.; Fry, A. E.; Potter, S. C.; Dunstan, S. J.; Seielstad, M.; Barroso, I.; Wareham, N. J.; Rockett, K. A.; Kwiatkowski, D. P.; Deloukas, P. (2008) Whole genome-amplified DNA: insights and imputation Nat Methods, 5 (4),279-80 [Journal Article] Online
PubMed Accession Number :: 18376389.

Loos, R. J.; Bouchard, C. (2008) FTO: the first gene contributing to common forms of human obesity Obes Rev, 9 (3),246-50 [Journal Article] Online
Abstract: Genome-wide association, the latest gene-finding strategy, has led to the first major success in the field of obesity genetics with the discovery of FTO (fat mass and obesity associated gene) as an obesity-susceptibility gene. A cluster of variants in the first intron of FTO showed a strong and highly significant association with obesity-related traits in three independent genome-wide association studies, a finding that has been replicated in several other studies including adults and children of European descent. Homozygotes for the risk allele weigh on average 3-4 kg more and have a 1.67-fold increased risk of obesity compared with those who did not inherit a risk allele. We are still at an early stage in our understanding of the pathways through which FTO confers to increased obesity risk. Studies in humans and rodents have suggested a central role for FTO through regulation of food intake, whereas others have proposed a peripheral role through an effect on lipolytic activity in adipose tissue. There is no doubt that many more obesity-susceptibility loci remain to be discovered. Progress on this front will therefore require major collaborative efforts and pooling of compatible datasets. We stand to learn a lot about the genetic architecture of human obesity in the coming years. The expectations are high but many challenges remain. Among the latter, translating new advances into useful guidelines for prevention and treatment of obesity will be the most demanding.
PubMed Accession Number :: 18373508.

Zeggini, E.; Scott, L. J.; Saxena, R.; Voight, B. F.; Marchini, J. L.; Hu, T.; de Bakker, P. I.; Abecasis, G. R.; Almgren, P.; Andersen, G.; Ardlie, K.; Bostrom, K. B.; Bergman, R. N.; Bonnycastle, L. L.; Borch-Johnsen, K.; Burtt, N. P.; Chen, H.; Chines, P. S.; Daly, M. J.; Deodhar, P.; Ding, C. J.; Doney, A. S.; Duren, W. L.; Elliott, K. S.; Erdos, M. R.; Frayling, T. M.; Freathy, R. M.; Gianniny, L.; Grallert, H.; Grarup, N.; Groves, C. J.; Guiducci, C.; Hansen, T.; Herder, C.; Hitman, G. A.; Hughes, T. E.; Isomaa, B.; Jackson, A. U.; Jorgensen, T.; Kong, A.; Kubalanza, K.; Kuruvilla, F. G.; Kuusisto, J.; Langenberg, C.; Lango, H.; Lauritzen, T.; Li, Y.; Lindgren, C. M.; Lyssenko, V.; Marvelle, A. F.; Meisinger, C.; Midthjell, K.; Mohlke, K. L.; Morken, M. A.; Morris, A. D.; Narisu, N.; Nilsson, P.; Owen, K. R.; Palmer, C. N.; Payne, F.; Perry, J. R.; Pettersen, E.; Platou, C.; Prokopenko, I.; Qi, L.; Qin, L.; Rayner, N. W.; Rees, M.; Roix, J. J.; Sandbaek, A.; Shields, B.; Sjogren, M.; Steinthorsdottir, V.; Stringham, H. M.; Swift, A. J.; Thorleifsson, G.; Thorsteinsdottir, U.; Timpson, N. J.; Tuomi, T.; Tuomilehto, J.; Walker, M.; Watanabe, R. M.; Weedon, M. N.; Willer, C. J.; Illig, T.; Hveem, K.; Hu, F. B.; Laakso, M.; Stefansson, K.; Pedersen, O.; Wareham, N. J.; Barroso, I.; Hattersley, A. T.; Collins, F. S.; Groop, L.; McCarthy, M. I.; Boehnke, M.; Altshuler, D. (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes Nat Genet, , [Journal Article] Online
Abstract: Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
PubMed Accession Number :: 18372903.

Steele, R. M.; Brage, S.; Corder, K.; Wareham, N. J.; Ekelund, U. (2008) Physical activity, cardio-respiratory fitness and the metabolic syndrome in youth J Appl Physiol, 105 ,342-351 [Journal Article] Online
Abstract: The metabolic syndrome is defined as the co-existence of multiple cardiovascular and diabetes risk factors, the prevalence of which has increased dramatically in adult populations in the last decades. More recently, the same cluster of metabolic risk factors has also been recognized in children and adolescents. Epidemiological evidence suggests that high levels of cardiorespiratory fitness (CRF) and physical activity are associated with a favourable metabolic risk profile in adults. However, in youth the role of these factors is less clear. Therefore, the purpose of this mini-review is to examine the recent evidence between objectively measured habitual physical activity and CRF with clustered metabolic risk in youth. In general, it appears that both physical activity and CRF are separately and independently associated with metabolic risk factors in youth, possibly through different causal pathways. Further research is necessary to quantify how much physical activity is needed to prevent the metabolic syndrome and the diseases with which it is associated. Public health approaches that encourage increased physical activity and reduce sedentary behaviors may prove useful in reducing the population burden associated with metabolic risk. Key words: Metabolic syndrome, fitness, physical activity, youth.
PubMed Accession Number :: 18369096.

Mattocks, C.; Ness, A.; Leary, S.; Tilling, K.; Blair, S. N.; Shield, J.; Deere, K.; Saunders, J.; Kirkby, J.; Smith, G. D.; Wells, J.; Wareham, N.; Reilly, J.; Riddoch, C. (2008) Use of accelerometers in a large field-based study of children: protocols, design issues, and effects on precision J Phys Act Health, 5 Suppl 1 ,S98-111 [Journal Article] Online
Abstract: BACKGROUND: Objective methods can improve accuracy of physical activity measurement in field studies but uncertainties remain about their use. METHODS: Children age 11 years from the Avon Longitudinal Study of Parents and Children (ALSPAC), were asked to wear a uni-axial accelerometer (MTI Actigraph) for 7 days. RESULTS: Of 7159 children who attended for assessment, 5595 (78%) provided valid measures. The reliability coefficient for 3 days of recording was .7 and the power to detect a difference of 0.07 SDs (P<or=.05) was > 90%. Measures tended to be higher on the first day of recording (17 counts/min; 95% CI, 10-24) and if children wore the monitor for fewer days, but these differences were small. The children who provided valid measures of activity were different from those who did not, but the differences were modest. CONCLUSION: Objective measures of physical activity can be incorporated into large longitudinal studies of children.
PubMed Accession Number :: 18364528.

Gielen, M.; Lindsey, P. J.; Derom, C.; Loos, R. J.; Souren, N. Y.; Paulussen, A. D.; Zeegers, M. P.; Derom, R.; Vlietinck, R.; Nijhuis, J. G. (2008) Twin-Specific Intrauterine 'Growth' Charts Based on Cross-Sectional Birthweight Data Twin Res Hum Genet, 11 (2),224-235 [Journal Article] Online
Abstract: Abstract The assessment of fetal growth is an essential component of good antenatal care, especially for twins. The aims of this study are to develop twin-specific intrauterine 'growth' charts, based on cross-sectional birthweight data, for monochorionic and dichorionic twins according to sex and parity, and to detect twins at risk for neonatal death by comparing the use of twin-specific and singleton charts. The study sample consisted of 76,471 singletons and 8454 twins (4227 pairs) born in East Flanders (Belgium). Birthweights were analyzed using a nonlinear Gaussian regression. After 33 weeks of gestation, the birthweights of twins started to deviate from singletons (difference of 900 grams at 42 weeks). Birthweights of dichorionic twins continued to increase, whereas those of monochorionic twins decreased after week 40 (difference of more than 300 g at 42 weeks). After 31 weeks of gestation, neonatal mortality increased as centile decreased, and was especially high if birthweight was below the twin-specific third centile: .032 (below) versus .007 (above). Using singleton centiles, this was less obvious. In conclusion, twin-specific growth charts, taking chorionicity into account, are more accurate to detect twins at risk for neonatal death. Therefore the presented charts, based on cross-sectional birthweight data, enable an improved assessment of twin growth.
PubMed Accession Number :: 18361725.

Caperchione, C. M.; Duncan, M. J.; Mummery, K.; Steele, R.; Schofield, G. (2008) Mediating relationship between body mass index and the direct measures of the Theory of Planned Behaviour on physical activity intention Psychol Health Med, 13 (2),168-79 [Journal Article] Online
Abstract: This research examines (a) the interrelationships between body mass index (BMI), the direct measures of the Theory of Planned Behaviour (TPB) and physical activity intention and (b) the potential mediation effects of the direct measures of the TPB in the relationship between BMI and physical activity intention in a sample of Australian adults. A total sample of 1,062 respondents participated in a computer-assisted telephone-interview (CATI) survey comprised of a standardised introduction; questions regarding TPB and physical activity; and standard demographic questions. BMI for each participant was calculated from self-reported height and weight. Separate regression analyses were performed to examine the mediating effects of each of the direct measures of the TPB on the predictive relationship between the BMI and physical activity intention, as proposed by Baron and Kenny (Journal of Personality and Social Psychology, 51(6), 1173 - 1182, 1986). Findings indicated that the direct measure of attitude and perceived behavioural control mediated the relationship between BMI and physical activity intention. However, the direct measure of subjective norm failed to act as a mediating mechanism. To date there has been no research that has examined the mechanism by which body mass may affect physical activity behaviour. Given the current focus for health promotion specialists on promoting physical activity as a strategy for reducing overweight and obesity, a theoretical understanding of weight-related barriers to physical activity may aid in the development of future interventions and community physical activity programs, particularly those targeting overweight and obese populations.
PubMed Accession Number :: 18350461.

Hemingway, H.; Langenberg, C.; Damant, J.; Frost, C.; Pyorala, K.; Barrett-Connor, E. (2008) Prevalence of angina in women versus men: a systematic review and meta-analysis of international variations across 31 countries Circulation, 117 (12),1526-36 [Journal Article] Online
Abstract: BACKGROUND: In the absence of previous international comparisons, we sought to systematically evaluate, across time and participant age, the sex ratio in angina prevalence in countries that differ widely in the rate of mortality due to myocardial infarction. METHODS AND RESULTS: We searched MEDLINE and EMBASE until February 2006 for healthy population studies published in any language that reported the prevalence of angina (Rose questionnaire) in women and men. We obtained myocardial infarction mortality rates from the World Health Organization. A total of 74 reports of 13,331 angina cases in women and 11,511 cases in men from 31 countries were included. Angina prevalence varied widely across populations, from 0.73% to 14.4% (population weighted mean 6.7%) in women and from 0.76% to 15.1% (population weighted mean 5.7%) in men, and was strongly correlated within populations between the sexes (r=0.80, P<0.0001). Angina prevalence showed a small female excess with a pooled random-effects sex ratio of 1.20 (95% CI 1.14 to 1.28, P<0.0001). This female excess was found across countries with widely differing myocardial infarction mortality rates in women (interquartile range 12.7 to 126.5 per 100,000), was particularly high in the American studies (1.40, 95% CI 1.28 to 1.52), and was higher among nonwhite ethnic groups than among whites. This sex ratio did not differ significantly by participant's age, the year the survey began, or the sex ratio for mortality due to myocardial infarction. CONCLUSIONS: Over time and at different ages, independent of diagnostic and treatment practices, women have a similar or slightly higher prevalence of angina than men across countries with widely differing myocardial infarction mortality rates.
PubMed Accession Number :: 18347213.

Lakshman, R.; Forouhi, N.; Luben, R.; Bingham, S.; Khaw, K.; Wareham, N.; Ong, K. K. (2008) Association between age at menarche and risk of diabetes in adults: results from the EPIC-Norfolk cohort study Diabetologia, 51 (5),781-786 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Earlier age at menarche is associated with increased BMI and obesity risk from early childhood through to adulthood. We hypothesised that earlier age at menarche would also predict subsequent diabetes risk. METHODS: This was a population-based prospective cohort study of 13,308 women, who were aged 40 to 75 years between 1993 and 1997 and participating in the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). We used data on age at menarche and ascertained diabetes incidence to 2005. RESULTS: There were 734 cases of diabetes (363 incident and 371 prevalent cases). Mean age at menarche was lower in women with diabetes than in non-diabetic women (12.8 vs 13.0 years, p = 0.008). Compared with the earliest quintile (menarche at 8-11 years), women in the oldest quintile (menarche at 15-18 years) had lower BMI (25.5 vs 27.4 kg/m(2), p < 0.0001) and a reduced risk of diabetes (OR 0.66 [95% CI 0.51-0.86] adjusted for age, family history, physical activity, smoking, occupational social class, parity and use of hormonal preparations). The association between age at menarche and diabetes was linear (adjusted OR 0.91 [95% CI 0.87-0.96] per 1 year later menarche) and appeared to be completely mediated by adult BMI or waist circumference (OR 0.98 [95% CI 0.93-1.03], further adjusted for BMI at age 40-75 years). CONCLUSIONS/INTERPRETATION: Earlier age at menarche increases the risk of diabetes in women and this association appears to be mediated by increased adiposity. History of earlier menarche may help to identify women with increased subsequent risk of diabetes.
PubMed Accession Number :: 18320165.

Simmons, R. K.; Griffin, S. J.; Steele, R.; Wareham, N. J.; Ekelund, U. (2008) Increasing overall physical activity and aerobic fitness is associated with improvements in metabolic risk: cohort analysis of the ProActive trial Diabetologia, 51 (5),787-794 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Our aim was to examine the association between change in physical activity energy expenditure (PAEE), total body movement (counts per day) and aerobic fitness (maximum oxygen consumption [[Formula: see text]]) over 1 year and metabolic risk among individuals with a family history of diabetes. METHODS: Three hundred and sixty-five offspring of people with type 2 diabetes underwent measurement of energy expenditure (PAEE measured using the flex heart rate method), total body movement (daily activity counts from accelerometry data), [Formula: see text] predicted from a submaximal graded treadmill exercise test and anthropometric and metabolic status at baseline and 1 year (n = 321) in the ProActive trial. Clustered metabolic risk was calculated by summing standardised values for waist circumference, fasting triacylglycerol, insulin and glucose, blood pressure and the inverse of HDL-cholesterol. Linear regression was used to quantify the association between changes in PAEE, total body movement and fitness and clustered metabolic risk at follow-up. RESULTS: Participants increased their activity by 0.01 units PAEE kJ kg(-1) day(-1) over 1 year. Total body movement increased by an average of 9,848 counts per day. Change in total body movement (beta = -0.066, p = 0.004) and fitness (beta = -0.056, p = 0.003) was associated with clustered metabolic risk at follow-up, independently of age, sex, smoking status, socioeconomic status and baseline metabolic score. CONCLUSIONS/INTERPRETATION: Small increases in activity and fitness were associated with a reduction in clustered metabolic risk in this cohort of carefully characterised at-risk individuals. Further research to quantify the reduction in risk of type 2 diabetes associated with feasible changes in these variables should inform preventive interventions. Clinical trial registration number: ISRCTN61323766.
PubMed Accession Number :: 18317727.

Vella, A.; Bouatia-Naji, N.; Heude, B.; Cooper, J. D.; Lowe, C. E.; Petry, C.; Ring, S. M.; Dunger, D. B.; Todd, J. A.; Ong, K. K. (2008) Association analysis of the IGF1 gene with childhood growth, IGF-1 concentrations and type 1 diabetes Diabetologia, 51 (5),811-5 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Insulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism. MATERIALS AND METHODS: Variants in IGF1 were identified by direct resequencing of the exons, exon-intron boundaries and 5' and 3' regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent-child trios). We also genotyped a previously reported CA repeat in the region 5' to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) >/=0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action. RESULTS: Resequencing detected 27 SNPs in IGF1, of which 11 had a MAF > 0.05 and were novel. Variants with MAF >/= 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5' to IGF1 showed no association with any phenotype. CONCLUSIONS/INTERPRETATION: Common genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes.
PubMed Accession Number :: 18317720.

Surtees, P. G.; Wainwright, N. W.; Luben, R. N.; Wareham, N. J.; Bingham, S. A.; Khaw, K. T. (2008) Psychological distress, major depressive disorder, and risk of stroke Neurology, 70 (10),788-94 [Journal Article] Online
Abstract: BACKGROUND: Studies have suggested that mood status is associated with an increased risk of stroke, though mostly based on measures of depression defined by symptoms alone rather than diagnostic criteria representative of clinically important distress and impairment. We investigated this association based upon a large population-based prospective cohort study. METHODS: Baseline assessment of major depressive disorder (MDD) and of mental health well-being (defined by the Mental Health Inventory, MHI-5) was completed by 20,627 stroke-free participants, aged 41 to 80 years, in the United Kingdom European Prospective Investigation into Cancer-Norfolk study. RESULTS: During 8.5 years of follow-up, 595 incident (fatal and nonfatal) stroke endpoints were recorded. Neither past year nor lifetime MDD was associated with stroke. A one SD decrease in MHI-5 scale score (representing greater emotional distress) was associated with an 11% increased risk of stroke after adjustment for age, sex, cigarette smoking, systolic blood pressure, cholesterol, obesity, preexisting myocardial infarction, diabetes, social class, education, hypertension treatment, family history of stroke, and antidepressant medication use (hazard ratio 1.11, 95% CI 1.00 to 1.22). This association was consistent for men and for women, for fatal and nonfatal stroke, and conformed to a dose-response relationship. CONCLUSIONS: Findings from this large prospective cohort study suggest that increased psychological distress is associated with elevated stroke risk. Episodic major depressive disorder was not associated with incident stroke in this study.
PubMed Accession Number :: 18316690.

Ogilvie, D.; Fayter, D.; Petticrew, M.; Sowden, A.; Thomas, S.; Whitehead, M.; Worthy, G. (2008) The harvest plot: a method for synthesising evidence about the differential effects of interventions BMC Med Res Methodol, 8 (1),8 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: One attraction of meta-analysis is the forest plot, a compact overview of the essential data included in a systematic review and the overall 'result'. However, meta-analysis is not always suitable for synthesising evidence about the effects of interventions which may influence the wider determinants of health. As part of a systematic review of the effects of population-level tobacco control interventions on social inequalities in smoking, we designed a novel approach to synthesis intended to bring aspects of the graphical directness of a forest plot to bear on the problem of synthesising evidence from a complex and diverse group of studies. METHODS: We coded the included studies (n=85) on two methodological dimensions (suitability of study design and quality of execution) and extracted data on effects stratified by up to six different dimensions of inequality (income, occupation, education, gender, race or ethnicity, and age), distinguishing between 'hard' (behavioural) and 'intermediate' (process or attitudinal) outcomes. Adopting a hypothesis-testing approach, we then assessed which of three competing hypotheses (positive social gradient, negative social gradient, or no gradient) was best supported by each study for each dimension of inequality. RESULTS: We plotted the results on a matrix ('harvest plot') for each category of intervention, weighting studies by the methodological criteria and distributing them between the competing hypotheses. These matrices formed part of the analytical process and helped to encapsulate the output, for example by drawing attention to the finding that increasing the price of tobacco products may be more effective in discouraging smoking among people with lower incomes and in lower occupational groups. CONCLUSIONS: The harvest plot is a novel and useful method for synthesising evidence about the differential effects of population-level interventions. It contributes to the challenge of making best use of all available evidence by incorporating all relevant data. The visual display assists both the process of synthesis and the assimilation of the findings. The method is suitable for adaptation to a variety of questions in evidence synthesis and may be particularly useful for systematic reviews addressing the broader type of research question which may be most relevant to policymakers.
PubMed Accession Number :: 18298827.

Sandhu, M. S.; Waterworth, D. M.; Debenham, S. L.; Wheeler, E.; Papadakis, K.; Zhao, J. H.; Song, K.; Yuan, X.; Johnson, T.; Ashford, S.; Inouye, M.; Luben, R.; Sims, M.; Hadley, D.; McArdle, W.; Barter, P.; Kesaniemi, Y. A.; Mahley, R. W.; McPherson, R.; Grundy, S. M.; Bingham, S. A.; Khaw, K. T.; Loos, R. J.; Waeber, G.; Barroso, I.; Strachan, D. P.; Deloukas, P.; Vollenweider, P.; Wareham, N. J.; Mooser, V. (2008) LDL-cholesterol concentrations: a genome-wide association study Lancet, 371 (9611),483-91 [Journal Article] Online
Abstract: BACKGROUND: LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations. METHODS: We used genome-wide association data from up to 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290,140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations. FINDINGS: In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L. INTERPRETATION: We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.
PubMed Accession Number :: 18262040.

van der Steeg, W. A.; Holme, I.; Boekholdt, S. M.; Larsen, M. L.; Lindahl, C.; Stroes, E. S.; Tikkanen, M. J.; Wareham, N. J.; Faergeman, O.; Olsson, A. G.; Pedersen, T. R.; Khaw, K. T.; Kastelein, J. J. (2008) High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies J Am Coll Cardiol, 51 (6),634-42 [Journal Article] Online
Abstract: OBJECTIVES: This study was designed to assess the relationship of high-density-lipoprotein cholesterol (HDL-C), HDL particle size, and apolipoprotein A-I (apoA-I) with the occurrence of coronary artery disease (CAD), with a focus on the effect of very high values of these parameters. BACKGROUND: High plasma levels of HDL-C and apoA-I are inversely related to the risk of CAD. However, recent data suggest that this relationship does not hold true for very high HDL-C levels, particularly when a preponderance of large HDL particles is observed. METHODS: We conducted a post-hoc analysis of 2 prospective studies: the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering; n = 8,888) trial comparing the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events, and the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk case-control study, including apparently healthy individuals who did (cases, n = 858) or did not (control patients, n = 1,491) develop CAD during follow-up. In IDEAL, only HDL-C and apoA-I were available; in EPIC-Norfolk, nuclear magnetic resonance spectroscopy-determined HDL particle sizes were also available. RESULTS: In the IDEAL study, higher HDL-C proved a significant major cardiac event risk factor following adjustment for age, gender, smoking, apoA-I, and apoB. A similar association was observed for HDL particle size in EPIC-Norfolk. Increased risk estimates were particularly present in the high ends of the distributions. In contrast, apoA-I remained negatively associated across the major part of its distribution in both studies. CONCLUSIONS: When apoA-I and apoB are kept constant, HDL-C and HDL particle size may confer risk at very high values. This does not hold true for very high levels of apoA-I at fixed levels of HDL-C and apoB. These findings may have important consequences for assessment and treatment of CAD risk.
PubMed Accession Number :: 18261682.

Vimaleswaran, K. S.; Franks, P. W.; Barroso, I.; Brage, S.; Ekelund, U.; Wareham, N. J.; Loos, R. J. (2008) Habitual Energy Expenditure Modifies the Association Between NOS3 Gene Polymorphisms and Blood Pressure Am J Hypertens, 21 (3),297-302 [Journal Article] Online
Abstract: BackgroundThe endothelial nitric-oxide synthase (NOS3) gene encodes the enzyme (eNOS) that synthesizes the molecule nitric oxide, which facilitates endothelium-dependent vasodilation in response to physical activity. Thus, energy expenditure may modify the association between the genetic variation at NOS3 and blood pressure.MethodsTo test this hypothesis, we genotyped 11 NOS3 polymorphisms, capturing all common variations, in 726 men and women from the Medical Research Council (MRC) Ely Study (age (mean +/- s.d.): 55 +/- 10 years, body mass index: 26.4 +/- 4.1 kg/m(2)). Habitual/non-resting energy expenditure (NREE) was assessed via individually calibrated heart rate monitoring over 4 days.ResultsThe intronic variant, IVS25+15 [G-->A], was significantly associated with blood pressure; GG homozygotes had significantly lower levels of diastolic blood pressure (DBP) (-2.8 mm Hg; P = 0.016) and systolic blood pressure (SBP) (-1.9 mm Hg; P = 0.018) than A-allele carriers. The interaction between NREE and IVS25+15 was also significant for both DBP (P = 0.006) and SBP (P = 0.026), in such a way that the effect of the GG-genotype on blood pressure was stronger in individuals with higher NREE (DBP: -4.9 mm Hg, P = 0.02. SBP: -3.8 mm Hg, P= 0.03 for the third tertile). Similar results were observed when the outcome was dichotomously defined as hypertension.ConclusionsIn summary, the NOS3 IVS25+15 is directly associated with blood pressure and hypertension in white Europeans. However, the associations are most evident in the individuals with the highest NREE. These results need further replication and have to be ideally tested in a trial before being informative for targeted disease prevention. Eventually, the selection of individuals for lifestyle intervention programs could be guided by knowledge of genotype.American Journal of Hypertension (2008) doi:10.1038/ajh.2007.69American Journal of Hypertension (2008) doi:10.1038/ajh.2007.69.
PubMed Accession Number :: 18246059.

Surtees, P. G.; Wainwright, N. W.; Luben, R. N.; Wareham, N. J.; Bingham, S. A.; Khaw, K. T. (2008) Depression and Ischemic Heart Disease Mortality: Evidence From the EPIC-Norfolk United Kingdom Prospective Cohort Study Am J Psychiatry, 165 (4),515-23 [Journal Article] Online
Abstract: Objective The authors investigated the association between major depressive disorder, including its clinical course, and mortality from ischemic heart disease. Method This was a prospective cohort study of 8,261 men and 11,388 women 41-80 years of age who were free of clinical manifestations of heart disease and participated in the Norfolk, U.K., cohort of the European Prospective Investigation Into Cancer. The authors conducted a cross-sectional assessment of major depressive disorder during the period 1996-2000 and ascertained subsequent deaths from ischemic heart disease through linkage with data from the U.K. Office for National Statistics. Results As of July 31, 2006, 274 deaths from ischemic heart disease were recorded over a total follow-up of 162,974 person-years (the median follow-up period was 8.5 years). Participants who had major depression during the year preceding baseline assessment were 2.7 times more likely to die from ischemic heart disease over the follow-up period than those who did not, independently of age, sex, smoking, systolic blood pressure, cholesterol, physical activity, body mass index, diabetes, social class, heavy alcohol use, and antidepressant medication use. This association remained after exclusion of the first 6 years of follow-up data. Consideration of measures of major depression history (including recency of onset, recurrence, chronicity, and age at first onset) revealed recency of onset to be associated most strongly with ischemic heart disease mortality. Conclusions Major depression was associated with an increased risk of ischemic heart disease mortality. The association was independent of established risk factors for ischemic heart disease and remained undiminished several years after the original assessment.
PubMed Accession Number :: 18245176.

Peeters, M. W.; Thomis, M. A.; Loos, R. J.; Derom, C. A.; Fagard, R.; Vlietinck, R. F.; Beunen, G. P. (2008) Clustering of metabolic risk factors in young adults: Genes and environment Atherosclerosis, 200 ,168-176 [Journal Article] Online
Abstract: OBJECTIVE: Evidence of a genetic basis of metabolic risk factors (MRFs) is growing. Studies examining the genetic and environmental basis of the clustering of MRFs, grouped together in the metabolic syndrome (MetS), are however sparse. The aim of this study therefore was to study the heritabilities of the MRFs and the genetic and environmental correlations between the MRFs. METHODS: Study participants were 768 Caucasian twins coming from 418 pairs (18-34 years). MRFs were those included in the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS. Multivariate path analysis on the continuous MRFs of the MetS was implemented. RESULTS: Heritabilities ranged between 47.0% and 80.2% (men) and 58.5% and 77.9% (women) for the individual MRFs. Evidence was found for overarching genetic (A) and environmental (E) sources of variance, both however loading mainly on waist circumference. Furthermore, the model included a 'lipids' and a 'blood pressure'-factor both in part attributable to A and E. The majority of the variance however was MRF-specific. CONCLUSION: Based on our sample of young adults with a low prevalence of the MetS, it can be concluded that both genes and environment contribute significantly to the clustering of the MRFs although the majority of the variation is MRF-specific. Therefore, future QTL searches in young adults may want to focus on MRF-specific loci, rather than 'cluster-phenotypes' such as the MetS.
PubMed Accession Number :: 18242619.

Savage, D. B.; Zhai, L.; Ravikumar, B.; Choi, C. S.; Snaar, J. E.; McGuire, A. C.; Wou, S. E.; Medina-Gomez, G.; Kim, S.; Bock, C. B.; Segvich, D. M.; Vidal-Puig, A.; Wareham, N. J.; Shulman, G. I.; Karpe, F.; Taylor, R.; Pederson, B. A.; Roach, P. J.; O'Rahilly, S.; DePaoli-Roach, A. A. (2008) A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice PLoS Med, 5 (1),e27 [Journal Article] Online
Abstract: BACKGROUND: Stored glycogen is an important source of energy for skeletal muscle. Human genetic disorders primarily affecting skeletal muscle glycogen turnover are well-recognised, but rare. We previously reported that a frameshift/premature stop mutation in PPP1R3A, the gene encoding RGL, a key regulator of muscle glycogen metabolism, was present in 1.36% of participants from a population of white individuals in the UK. However, the functional implications of the mutation were not known. The objective of this study was to characterise the molecular and physiological consequences of this genetic variant. METHODS AND FINDINGS: In this study we found a similar prevalence of the variant in an independent UK white population of 744 participants (1.46%) and, using in vivo (13)C magnetic resonance spectroscopy studies, demonstrate that human carriers (n = 6) of the variant have low basal (65% lower, p = 0.002) and postprandial muscle glycogen levels. Mice engineered to express the equivalent mutation had similarly decreased muscle glycogen levels (40% lower in heterozygous knock-in mice, p < 0.05). In muscle tissue from these mice, failure of the truncated mutant to bind glycogen and colocalize with glycogen synthase (GS) decreased GS and increased glycogen phosphorylase activity states, which account for the decreased glycogen content. CONCLUSIONS: Thus, PPP1R3A C1984DeltaAG (stop codon 668) is, to our knowledge, the first prevalent mutation described that directly impairs glycogen synthesis and decreases glycogen levels in human skeletal muscle. The fact that it is present in approximately 1 in 70 UK whites increases the potential biomedical relevance of these observations.
PubMed Accession Number :: 18232732.

Gao, W. (2008) Does the constellation of risk factors with and without abdominal adiposity associate with different cardiovascular mortality risk? Int J Obes (Lond), 32 (5),757-62 [Journal Article] Online
Abstract: AIMS: To evaluate whether the metabolic syndrome (MetS) defined by the International Diabetes Federation (IDF) criteria, which has abdominal adiposity as a mandatory element, predicts cardiovascular disease (CVD) mortality better than the cluster of other IDF-defined abnormalities not including abdominal adiposity. METHODS: Data from nine European population-based studies, including 7782 men and 7739 women (aged 30-89 years), with a median follow-up of 8.55 years, were jointly analyzed. Hazard ratios for CVD mortality were calculated with Cox regression models. RESULTS: In total, 41% of the men and 38% of the women had the IDF MetS. Individuals with the IDF MetS were by definition more obese and had a higher prevalence of diabetes than non-obese subjects with > or = 2 IDF abnormalities; whereas non-obese men with > or = 3 factors had more atherogenic lipid profiles. Multivariate adjusted hazard ratio for CVD death in men and women with the IDF MetS was 2.44 (1.69-2.98) and 2.32 (1.27-4.23); in non-obese men with 2 and > or = 3 factors the hazard ratio was 1.60 (1.12-2.30) and 2.44 (1.62-3.66), respectively, and in non-obese women with 2 factors the hazard ratio was 2.41 (1.09-5.33). CONCLUSIONS: The cluster of the CVD risk factors predicted CVD mortality regardless of the presence or absence of the abdominal adiposity. Inclusion of abdominal adiposity as a prerequisite will miss those non-obese individuals who have increased CVD mortality.
PubMed Accession Number :: 18209738.

Nilsson, A.; Brage, S.; Riddoch, C.; Anderssen, S. A.; Sardinha, L. B.; Wedderkopp, N.; Andersen, L. B.; Ekelund, U. (2008) Comparison of equations for predicting energy expenditure from accelerometer counts in children Scand J Med Sci Sports, 18 ,643-650 [Journal Article] Online
Abstract: Several prediction equations developed to convert body movement measured by accelerometry into energy expenditure have been published. The aim of this study was to examine the degree of agreement between three different prediction equations, when applied to data on physical activity in a large sample of children. We examined 1321 children (663 boys, 658 girls; mean age 9.6+/-0.4 years) from four different countries. Physical activity was measured by the MTI accelerometer. One equation, derived from doubly labeled water (DLW) measurements, was compared with one treadmill-based (TM) and one room calorimeter-based (CAL) equation (mixture of activities). Predicted physical activity energy expenditure (PAEE) was the main outcome variable. In comparison with DLW-predicted PAEE, both laboratory-derived equations significantly (P<0.001) overestimated PAEE by 17% and 83%, respectively, when based on a 24-h prediction, while the TM equation significantly (P<0.001) underestimated PAEE by 46%, when based on awake time only. In contrast, the CAL equation agreed better with the DLW equation under the awake time assumption. Predicted PAEE differ substantially between equations, depending on time-frame assumptions, and interpretations of average levels of PAEE in children from available equations should be made with caution. Further development of equations applicable to free-living scenarios is needed.
PubMed Accession Number :: 18208433.

Zhang, Z.; Zhang, S.; Wong, M. Y.; Wareham, N. J.; Sha, Q. (2008) An ensemble learning approach jointly modeling main and interaction effects in genetic association studies Genet Epidemiol, 32 (4),285-300 [Journal Article] Online
Abstract: Complex diseases are presumed to be the results of interactions of several genes and environmental factors, with each gene only having a small effect on the disease. Thus, the methods that can account for gene-gene interactions to search for a set of marker loci in different genes or across genome and to analyze these loci jointly are critical. In this article, we propose an ensemble learning approach (ELA) to detect a set of loci whose main and interaction effects jointly have a significant association with the trait. In the ELA, we first search for "base learners" and then combine the effects of the base learners by a linear model. Each base learner represents a main effect or an interaction effect. The result of the ELA is easy to interpret. When the ELA is applied to analyze a data set, we can get a final model, an overall P-value of the association test between the set of loci involved in the final model and the trait, and an importance measure for each base learner and each marker involved in the final model. The final model is a linear combination of some base learners. We know which base learner represents a main effect and which one represents an interaction effect. The importance measure of each base learner or marker can tell us the relative importance of the base learner or marker in the final model. We used intensive simulation studies as well as a real data set to evaluate the performance of the ELA. Our simulation studies demonstrated that the ELA is more powerful than the single-marker test in all the simulation scenarios. The ELA also outperformed the other three existing multi-locus methods in almost all cases. In an application to a large-scale case-control study for Type 2 diabetes, the ELA identified 11 single nucleotide polymorphisms that have a significant multi-locus effect (P-value=0.01), while none of the single nucleotide polymorphisms showed significant marginal effects and none of the two-locus combinations showed significant two-locus interaction effects. Genet. Epidemiol. (c) 2008 Wiley-Liss, Inc.
PubMed Accession Number :: 18205210.

Batty, G. D.; Gale, C. R.; Mortensen, L. H.; Langenberg, C.; Shipley, M. J.; Deary, I. J. (2008) Pre-morbid intelligence, the metabolic syndrome and mortality: the Vietnam Experience Study Diabetologia, 51 (3),436-43 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: We examined the relationship between pre-morbid intelligence quotient (IQ) and the metabolic syndrome, and assessed the role of the metabolic syndrome as a mediating factor in the association of IQ with total and cardiovascular disease (CVD) mortality. METHODS: In this cohort study, 4,157 men with IQ test results from late adolescence or early adulthood [mean age (range) 20.4 (16-30) years] attended a clinical examination in middle-age [38.3 (31-46) years] at which the components of the metabolic syndrome were measured. They were then followed for 15 years to assess mortality. RESULTS: In age-adjusted analyses, IQ was significantly inversely related to four of the five individual components comprising the metabolic syndrome: hypertension, high BMI, high triglycerides and high blood glucose, but not low HDL-cholesterol. After controlling for a range of covariates that included socioeconomic position, higher IQ scores were associated with a reduced prevalence of the metabolic syndrome itself (odds ratio(1 SD increase in IQ) 0.87, 95% CI 0.78-0.98). Structural equation modelling revealed that education was not a mediator of the relationship between IQ and the metabolic syndrome. The metabolic syndrome partially mediated the relationship between IQ and CVD but not that between IQ and total mortality. CONCLUSIONS/INTERPRETATION: In this cohort, higher scores on a pre-morbid IQ test were associated with a lower prevalence of the metabolic syndrome and most of its components. The metabolic syndrome was a mediating variable in the IQ-CVD relationship.
Keywords: Adolescent Adult Cardiovascular Diseases/*mortality/psychology Great Britain Humans *Intelligence Interviews as Topic Metabolic Syndrome X/complications/*psychology *Military Personnel Retrospective Studies *Vietnam Conflict
PubMed Accession Number :: 18204831.

Khaw, K. T.; Wareham, N.; Bingham, S.; Welch, A.; Luben, R.; Day, N. (2008) Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study PLoS Med, 5 (1),e12 [Journal Article] Online
Abstract: BACKGROUND: There is overwhelming evidence that behavioural factors influence health, but their combined impact on the general population is less well documented. We aimed to quantify the potential combined impact of four health behaviours on mortality in men and women living in the general community. METHODS AND FINDINGS: We examined the prospective relationship between lifestyle and mortality in a prospective population study of 20,244 men and women aged 45-79 y with no known cardiovascular disease or cancer at baseline survey in 1993-1997, living in the general community in the United Kingdom, and followed up to 2006. Participants scored one point for each health behaviour: current non-smoking, not physically inactive, moderate alcohol intake (1-14 units a week) and plasma vitamin C >50 mmol/l indicating fruit and vegetable intake of at least five servings a day, for a total score ranging from zero to four. After an average 11 y follow-up, the age-, sex-, body mass-, and social class-adjusted relative risks (95% confidence intervals) for all-cause mortality(1,987 deaths) for men and women who had three, two, one, and zero compared to four health behaviours were respectively, 1.39 (1.21-1.60), 1.95 (1.70--2.25), 2.52 (2.13-3.00), and 4.04 (2.95-5.54) p < 0.001 trend. The relationships were consistent in subgroups stratified by sex, age, body mass index, and social class, and after excluding deaths within 2 y. The trends were strongest for cardiovascular causes. The mortality risk for those with four compared to zero health behaviours was equivalent to being 14 y younger in chronological age. CONCLUSIONS: Four health behaviours combined predict a 4-fold difference in total mortality in men and women, with an estimated impact equivalent to 14 y in chronological age.
PubMed Accession Number :: 18184033.

Kinmonth, A. L.; Wareham, N. J.; Hardeman, W.; Sutton, S.; Prevost, A. T.; Fanshawe, T.; Williams, K. M.; Ekelund, U.; Spiegelhalter, D.; Griffin, S. J. (2008) Efficacy of a theory-based behavioural intervention to increase physical activity in an at-risk group in primary care (ProActive UK): a randomised trial Lancet, 371 (9606),41-8 [Journal Article] Online
Abstract: BACKGROUND: Declining physical activity is associated with a rising burden of global disease. Efforts to reverse this trend have not been successful. We aimed to assess the efficacy of a facilitated behavioural intervention to increase the physical activity of sedentary individuals at familial risk of diabetes. METHODS: We enrolled 365 sedentary adults who had a parental history of type 2 diabetes. They were recruited from either diabetes or family history registers at 20 general practice clinics in the UK. Eligible participants were randomly assigned to one of two intervention groups, or to a comparison group. All participants were posted a brief advice leaflet. One intervention group was offered a 1-year behaviour-change programme, to be delivered by trained facilitators in participants' homes, and the other the same programme by telephone. The programme was designed to alter behavioural determinants, as defined by the theory of planned behaviour, and to teach behaviour-change strategies. The principal outcome at 1 year was daytime physical activity, which was objectively measured as a ratio to resting energy expenditure. Analysis was by intention to treat. This study is registered as ISRCTN61323766. FINDINGS: Of 365 patients, we analysed primary endpoints for 321 (88%) for whom we had data after 1 year of follow-up. At 1 year, the physical-activity ratio of participants who received the intervention, by either delivery route, did not differ from the ratio in those who were given a brief advice leaflet. The mean difference in daytime physical-activity ratio, adjusted for baseline, was -0.04 (95% CI -0.16 to 0.08). The physical-activity ratio did not differ between participants who were delivered the intervention face-to-face or by telephone (mean difference -0.05; 95% CI -0.19 to 0.10). INTERPRETATION: A facilitated theory-based behavioural intervention was no more effective than an advice leaflet for promotion of physical activity in an at-risk group; therefore health-care providers should remain cautious about commissioning behavioural programmes into individual preventive health-care services.
PubMed Accession Number :: 18177774.

Myint, P. K.; Luben, R. N.; Welch, A. A.; Bingham, S. A.; Wareham, N. J.; Khaw, K. T. (2008) Plasma vitamin C concentrations predict risk of incident stroke over 10 y in 20 649 participants of the European Prospective Investigation into Cancer Norfolk prospective population study Am J Clin Nutr, 87 (1),64-9 [Journal Article] Online
Abstract: BACKGROUND: The relation between plasma vitamin C and risk of stroke remains unclear. Although clinical trials showed no significant benefit of vitamin C supplementation in reducing stroke risk, they were not able to examine the relation between plasma vitamin C concentrations and stroke risk in a general population. OBJECTIVE: The objective was to examine the relation between baseline plasma vitamin C concentrations and risk of incident stroke in a British population. DESIGN: A population-based prospective study was conducted in 20 649 men and women aged 40-79 y without prevalent stroke at baseline and participating in the European Prospective Investigation into Cancer-Norfolk prospective population study. The participants completed a health questionnaire and attended a clinic during 1993-1997 and were followed up for incident strokes through March 2005. RESULTS: Over 196 713 total person-years (average follow-up: 9.5 y), 448 incident strokes occurred. In a Cox proportional hazards model, persons in the top quartiles of baseline plasma vitamin C concentrations had a 42% lower risk (relative risk: 0.58; 95% CI: 0.43, 0.78) than did those in the bottom quartile, independently of age, sex, smoking, body mass index, systolic blood pressure, cholesterol, physical activity, prevalent diabetes and myocardial infarction, social class, alcohol consumption, and any supplement use. Similar results were obtained after exclusion of persons with illnesses, users of ascorbic acid-containing supplements, and persons with a history of early strokes during the initial 2 y of follow-up. CONCLUSIONS: Plasma vitamin C concentrations may serve as a biological marker of lifestyle or other factors associated with reduced stroke risk and may be useful in identifying those at high risk of stroke.
PubMed Accession Number :: 18175738.

Peters, T. M.; Ekelund, U.; Leitzmann, M.; Easton, D.; Warren, R.; Luben, R.; Bingham, S.; Khaw, K. T.; Wareham, N. J. (2008) Physical Activity and Mammographic Breast Density in the EPIC-Norfolk Cohort Study Am J Epidemiol, 167 (5),579-85 [Journal Article] Online
Abstract: Physical inactivity and high mammographic breast density have both been associated with increased breast cancer risk. However, the association between physical activity and mammographic breast density remains inconsistent. In the European Prospective Investigation of Cancer (EPIC)-Norfolk population-based cohort study (United Kingdom), the authors investigated the cross-sectional association between physical activity level at baseline during 1993-1997 and breast density among 1,394 postmenopausal, cancer-free women. Usual physical activity was assessed by a brief, validated questionnaire. Percentage breast density was determined visually from mammograms by three trained radiologists using the Boyd six-category scale. The association between physical activity level and breast density risk category was examined. No statistically significant association between physical activity and percentage breast density was observed in the unadjusted or adjusted regression models. A suggested increase in breast density for the most active women in the unadjusted regression analysis (odds ratio = 1.13, 95% confidence interval: 0.71, 1.80) was reversed after inclusion of body mass index and reproductive and lifestyle variables (odds ratio = 0.78, 95% confidence interval: 0.45, 1.34). The lack of an association between physical activity and percentage breast density suggests that an association between physical activity and breast cancer risk is unlikely to be mediated through an effect on mammographic breast density.
PubMed Accession Number :: 18162477.

Sandhu, M. S.; Debenham, S. L.; Barroso, I.; Loos, R. J. (2008) Mendelian randomisation studies of type 2 diabetes: future prospects Diabetologia, 51 (2),211-3 [Journal Article] Online
PubMed Accession Number :: 18094955.

Purslow, L. R.; Sandhu, M. S.; Forouhi, N.; Young, E. H.; Luben, R. N.; Welch, A. A.; Khaw, K. T.; Bingham, S. A.; Wareham, N. J. (2008) Energy Intake at Breakfast and Weight Change: Prospective Study of 6,764 Middle-aged Men and Women Am J Epidemiol, 167 (2),188-92 [Journal Article] Online
Abstract: To investigate the association between percentage of total daily energy intake consumed at breakfast and weight change in middle-aged men and women, the authors analyzed data from a prospective population-based cohort study from Norfolk, United Kingdom. Participants were 6,764 men and women aged 40-75 years at baseline (1993-1997). Participants completed a 7-day food diary at baseline, and objective measurements of height and weight were carried out at baseline and follow-up (1998-2000). Mean baseline body mass index (weight (kg)/height (m)(2)) was lowest among persons in the highest quintile of percentage of daily energy consumed at breakfast (mean values were 26.0 in the highest quintile and 26.3 in the lowest quintile), despite higher daily total energy intake in this group. Although all participants gained weight, increased percentage of daily energy consumed at breakfast was associated with relatively lower weight gain (adjusted beta coefficient = -0.021, 95% confidence interval: -0.035, -0.007; p = 0.004). The association between percentage of daily energy intake consumed at breakfast and weight gain was independent of age, sex, smoking, total energy intake, macronutrient intake, social class, and physical activity. Redistribution of daily energy intake, so that more energy is consumed at breakfast and less energy is consumed later in the day, may help to reduce weight gain in middle-aged adults.
PubMed Accession Number :: 18079134.

Sardinha, L. B.; Andersen, L. B.; Anderssen, S. A.; Quiterio, A. L.; Ornelas, R.; Froberg, K.; Riddoch, C. J.; Ekelund, U. (2008) Objectively measured time spent sedentary is associated with insulin resistance independent of overall and central body fat in 9 to 10 year old Portuguese children Diabetes Care, 31 (3),569-75 [Journal Article] Online
Abstract: Objective: We examined the independent relationships between objectively measured physical activity and insulin resistance in Portuguese children. Research Design and Methods: School-based, cross-sectional study in 147 randomly selected girls (9.8 +/- 0.3 years; 27.8 +/- 9.3 % body fat) and 161 boys (9.8 +/- 0.3 years; 22.0 +/- 9.2 % body fat). Physical activity was assessed by the Actigraph accelerometer for 4 days and summarised as time spent sedentary (accelerometer counts < 500/min), in light intensity (accelerometer counts 500-2000/min) and moderate and vigorous intensity activity (accelerometer counts >2001/min). We measured total and central fat mass by dual X-ray absorptiometry. Insulin resistance was expressed as the Homeostasis Model Assessment score. Results: Time (min/d) spent sedentary was significantly and positively associated with insulin resistance (B-coefficient=0.001, 95% CI; 0.0002; 0.002, p=0.013). Time spent in MVPA (B-coefficient=-0.002, 95% CI;-0.003;-0.001, p=0.0009) and overall physical activity (B-coefficient=-0.001, 95% CI;-0.008; 0.003; p<0.0001) were significantly and inversely associated with insulin resistance. All associations remained statistically significant, although were attenuated after further adjustments for gender, birth weight, sexual maturity and total or central fat mass (p<0.03). Conclusions: Physical activity is associated with insulin resistance independent of total and central fat mass in children. Our results emphasise the importance of decreasing sedentary behaviour and increasing time spent in moderate and vigorous intensity activity in children, which may have beneficial effects on metabolic risk factors regardless of the degree of adiposity.
PubMed Accession Number :: 18070991.

Florez, J. C.; Jablonski, K. A.; McAteer, J.; Sandhu, M. S.; Wareham, N. J.; Barroso, I.; Franks, P. W.; Altshuler, D.; Knowler, W. C. (2008) Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program Diabetologia, 51 (3),451-457 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is caused by mutations in the WFS1 gene. Recently, single nucleotide polymorphisms (SNPs) in WFS1 have been reproducibly associated with type 2 diabetes. We therefore examined the effects of these variants on diabetes incidence and response to interventions in the Diabetes Prevention Program (DPP), in which a lifestyle intervention or metformin treatment was compared with placebo. METHODS: We genotyped the WFS1 SNPs rs10010131, rs752854 and rs734312 (H611R) in 3,548 DPP participants and performed Cox regression analysis using genotype, intervention and their interactions as predictors of diabetes incidence. We also evaluated the effect of these SNPs on insulin resistance and beta cell function at 1 year. RESULTS: Although none of the three SNPs was associated with diabetes incidence in the overall cohort, white homozygotes for the previously reported protective alleles appeared less likely to develop diabetes in the lifestyle arm. Examination of the publicly available Diabetes Genetics Initiative genome-wide association dataset revealed that rs10012946, which is in strong linkage disequilibrium with the three WFS1 SNPs (r (2) = 0.88-1.0), was associated with type 2 diabetes (allelic odds ratio 0.85, 95% CI 0.75-0.97, p = 0.026). In the DPP, we noted a trend towards increased insulin secretion in carriers of the protective variants, although for most SNPs this was seen as compensatory for the diminished insulin sensitivity. CONCLUSIONS/INTERPRETATION: The previously reported protective effect of select WFS1 alleles may be magnified by a lifestyle intervention. These variants appear to confer an improvement in beta cell function.
PubMed Accession Number :: 18060660.

Franks, P. W.; Rolandsson, O.; Debenham, S. L.; Fawcett, K. A.; Payne, F.; Dina, C.; Froguel, P.; Mohlke, K. L.; Willer, C.; Olsson, T.; Wareham, N. J.; Hallmans, G.; Barroso, I.; Sandhu, M. S. (2008) Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations Diabetologia, 51 (3),458-63 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Mutations at the gene encoding wolframin (WFS1) cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. Thus, our aim was to replicate those associations in a northern Swedish case-control study of type 2 diabetes. We also performed a meta-analysis of published and previously unpublished data from Sweden, Finland and France, to obtain updated summary effect estimates. METHODS: Four WFS1 SNPs (rs10010131, rs6446482, rs752854 and rs734312 [H611R]) were genotyped in a type 2 diabetes case-control study (n = 1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex and BMI. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 patients and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. RESULTS: In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk [odds ratio (OR) 0.85, 95% CI 0.75-0.96, p = 0.010]. Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131 and correlated variants showed evidence for statistical association (OR 0.87, 95% CI 0.82-0.93, p = 4.5 x 10(-5)). In an updated meta-analysis of all 11 studies, strong evidence of statistical association was also observed (OR 0.89, 95% CI 0.86-0.92; p = 4.9 x 10(-11)). CONCLUSIONS/INTERPRETATION: In this study of WFS1 variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and the risk of type 2 diabetes.
PubMed Accession Number :: 18040659.

Moayyeri, A.; Luben, R. N.; Bingham, S. A.; Welch, A. A.; Wareham, N. J.; Khaw, K. T. (2008) Measured height loss predicts fractures in middle-aged and older men and women: the EPIC-Norfolk prospective population study J Bone Miner Res, 23 (3),425-32 [Journal Article] Online
Abstract: In this large population-based prospective study among middle-aged and older men and women, we found that height loss of >2 cm over a period of 4 yr is a significant predictor of future fractures. Serial measurement of height is, therefore, recommended among the elderly people. INTRODUCTION: Height change can be easily measured and may contribute to fracture risk prediction. We assessed measured height loss and fracture incidence in a prospective population study. MATERIALS AND METHODS: Height was measured in participants in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) between 1993 and 1997 and repeated between 1997 and 2000. Incident fractures to 2006 were ascertained by hospital record linkage. RESULTS: In 14,921 men and women 42-82 yr of age, during a mean follow-up period of 7.1 yr, there were 390 fractures, including 122 hip fractures. Prior annual height loss in those who had an incident fracture (1.8 +/- 0.3 [SD] mm) was significantly greater than other participants (0.9 +/- 0.2 mm; p < 0.001). Participants with annual height loss >0.5 cm had an age- and sex-adjusted hazard ratio of any fracture of 1.76 (95% CI, 1.16-2.67) and of hip fracture of 2.08 (95% CI, 1.07-4.05) compared with those with no height loss. Each 1 cm/yr height loss was associated with a hazard ratio of 1.86 (95% CI, 1.28-2.72) for all fractures and 2.24 (95% CI, 1.23-4.09) for hip fracture after adjustment for age, sex, past history of fracture, smoking, body mass index, alcohol intake, and heel ultrasound measures. Annual height loss of 1 cm was comparable to having a past history of fracture and equivalent to being approximately 14 yr older in chronological age in terms of the magnitude of relationship with fracture risk. CONCLUSIONS: Middle-aged and older men and women with annual height loss >0.5 cm are at increased risk of hip and any fracture. Serial height measurements can contribute to fracture risk prediction.
PubMed Accession Number :: 17997714.

Myint, P. K.; Luben, R. N.; Wareham, N. J.; Welch, A. A.; Bingham, S. A.; Khaw, K. T. (2008) Physical activity and fibrinogen concentrations in 23,201 men and women in the EPIC-Norfolk population-based study Atherosclerosis, 198 (2),419-25 [Journal Article] Online
Abstract: OBJECTIVE: To examine the relationship between usual physical activity and fibrinogen concentrations in a free-living population of men and women. METHODS AND RESULTS: We examined the cross-sectional relationship between habitual combined work and leisure physical activity derived from a validated physical activity questionnaire and plasma fibrinogen concentrations in a population-based study of 23,201 men and women aged 40-79 years. Mean plasma fibrinogen concentrations were lower in people who were physically active compared to those who were physically less active. Mean fibrinogen concentrations were 2.82+/-0.02, 2.87+/-2.87(0.02), 2.90+/-0.02, and 2.97+/-0.02g/L (p for trend<0.0001) for men in the active, moderately active, moderately inactive and inactive physical activity categories respectively, independently of age, smoking, body mass index (BMI), prevalent illnesses, social class and alcohol consumption. The corresponding values for women were 2.95+/-0.02, 2.94+/-0.01, 2.98+/-0.01, and 3.04+/-0.01g/L (p for trend<0.0001). Similar results were observed after adjusting for hormone replacement therapy (HRT) in women. CONCLUSIONS: Higher physical activity is significantly inversely associated with plasma fibrinogen concentration independently of other related factors. This might provide an additional plausible mechanism for the cardiovascular health benefits of physical activity.
PubMed Accession Number :: 17977548.

Cosgrove, M. P.; Sargeant, L. A.; Griffin, S. J. (2008) Does depression increase the risk of developing type 2 diabetes? Occup Med (Lond), 58 (1),7-14 [Journal Article] Online
Abstract: BACKGROUND: Members of a scheme awarding injury pensions may allege that the onset of diabetes was precipitated or caused by depression induced by work in order to claim an injury award. AIMS: To quantify the association between depression and subsequent development of type 2 diabetes in order to determine whether an individual in a pension scheme that awards injury pensions, who develops type 2 diabetes, should be awarded an injury pension, if the development of the diabetes followed a work-related depressive episode. METHODS: Electronic and hand literature searches up to December 2006. Relative risk estimates from cohort studies of adults were pooled using fixed and random effects models. Attributable risk fraction was calculated using the Levin formula. RESULTS: The presence of depression or depressive symptoms was associated with increased risk of subsequently developing type 2 diabetes. The pooled fully adjusted relative risk estimate from the three highest quality studies was 1.25 (95% CI: 1.02-1.48) and was homogenous. However, depression was no more frequent among those with and without prevalent, but previously undiagnosed, type 2 diabetes. CONCLUSION: Depression is associated with subsequent development of type 2 diabetes. However, the relative risk estimate is small and only 20% of cases of diabetes can be attributed to depression in people with both conditions. Further research is needed to determine possible causal mechanisms for the association and to ascertain whether depression and diabetes may have a common aetiology.
PubMed Accession Number :: 17965449.

Li, H.; Wu, Y.; Loos, R. J.; Hu, F. B.; Liu, Y.; Wang, J.; Yu, Z.; Lin, X. (2008) Variants in the fat mass- and obesity-associated (FTO) gene are not associated with obesity in a Chinese Han population Diabetes, 57 (1),264-8 [Journal Article] Online
Abstract: OBJECTIVE: Recently, genome-wide association studies have provided evidence that several common variants within the fat mass-and obesity-associated (FTO) gene were significantly associated with obesity in populations of European origin. However, their effects in other ethnic populations remain to be elucidated. RESEARCH DESIGN AND METHODS: In this study, we examined the association between three FTO variants (rs8050136, rs9939609, and rs9930506) and obesity and related traits in a population-based study of 3,210 unrelated Chinese Han subjects from Shanghai and Beijing. In secondary analyses, we also tested for association with type 2 diabetes and related traits. Logistics regression and generalized linear models were used to test for additive and dominant effects of the risk alleles. RESULTS: The minor allele frequencies of rs8050136, rs9939609, and rs9930506 in our population (0.12, 0.12, and 0.20, respectively) were substantially lower than those observed for populations of European descent (e.g., for CEU population of HapMap: 0.45, 0.48, and 0.45, respectively). Despite our study being sufficiently powered to detect effects similar to those previously reported, none of the FTO SNPs were found to be associated with obesity, overweight, BMI, waist circumference, or body fat percentage. In addition, none of the SNPs exhibited significant associations with fasting levels of plasma glucose, A1C, insulin, or beta-cell function (estimated via homeostasis model assessment) under either an additive or a dominant model in the quantitative trait analyses. Analyses stratified by sex or geographical region did not change these observations. CONCLUSIONS: Our data do not support that the FTO common variants are major contributors of obesity or type 2 diabetes in the Chinese Han population.
PubMed Accession Number :: 17959933.

Wright, C.; Lakshman, R.; Emmett, P.; Ong, K. (2008) Implications of adopting the WHO 2006 Child Growth Standard in the UK: two prospective cohort studies Arch Dis Child, 93 ,566-569 [Journal Article] Online
Abstract: OBJECTIVE: The WHO 2006 Child Growth Standard is based on data from international optimally nourished breastfed infants from birth to age 5 years. We assessed the potential impact of its use on weight and growth monitoring of UK children. PARTICIPANTS: Full-term members of two population-based UK birth cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC) Children in Focus sub-cohort (n=1335), and the Gateshead Millenium Baby Study (GMS; n=923). DESIGN: Growth data from birth to 5 years were converted to Z scores relative to the WHO 2006 Standard. RESULTS: Compared to the WHO Standard, both UK cohorts had relatively higher birth weights (mean Z scores: GMS 0.17; ALSPAC 0.34) and ALSPAC had higher birth lengths. After birth, length showed a good fit at all ages. By 2-4mo, both cohorts were similar in weight to the WHO median (at 4 months GMS= 0.01; ALSPAC: -0.07), but thereafter the UK cohorts were heavier (mean WHO weight Z score at 12mo: GMS: 0.57; ALSPAC: 0.65). At age 12mo the risk of being classified as underweight (weight <2nd centile) was considerably lower according to the WHO Standard than by the UK 1990 Growth Reference (relative risk: 0.15, 95% CI 0.07-0.32), while the risk of being classified as obese at 4-5 years (BMI >98th centile) was slightly increased (1.35, 95% CI 1.02-1.78). CONCLUSIONS: Adoption of the WHO 2006 Growth Charts would set a markedly lower standard of weight gain beyond age 4mo for UK infants and could support efforts to avoid future childhood obesity. However, the WHO Standard is not representative of size at birth in the UK.
PubMed Accession Number :: 17908712.

Badii, R.; Bener, A.; Zirie, M.; Al-Rikabi, A.; Simsek, M.; Al-Hamaq, A. O.; Ghoussaini, M.; Froguel, P.; Wareham, N. J. (2008) Lack of association between the Pro(12)Ala polymorphism of the PPAR-gamma2 gene and type 2 diabetes mellitus in the Qatari consanguineous population Acta Diabetol, 45 (1),15-21 [Journal Article] Online
Abstract: Peroxisome proliferators-activated receptor gamma (PPARgamma) is a nuclear hormone receptor that serves as a master regulator for adipocytes-specific genes contributing to adipocytes differentiation, insulin sensitivity and lipid metabolism. The substitution of proline to alanine at codon 12 of the PPAR gamma2 gene (Pro12Ala polymorphism) is most widely studied, and the associations with diabetes, obesity, and other clinical parameters have been reported and discussed in several ethnic groups. Among native Qatar ethnicity, however, there is no report about this polymorphism. The aim of this study was to estimate the allele frequency of the Pro(12)Ala polymorphism of PPAR gamma2 gene among Qatari population and investigate the association between this polymorphism and obesity or type 2 diabetes. This is a matched case-control study. It was carried out among diabetic patients and healthy subjects at the Primary Healthcare Clinics, and the survey was conducted from February 2003 to March 2006 in Qatari male and female nationals aged 35 to 60 years. The study was based on matched age, sex, and ethnicity of 400 cases (with diabetes) and 450 controls (without diabetes). Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI), and obesity. Their health status was assessed by medical conditions, family history, and blood pressure measurements. The allele frequency of Pro(12)Ala polymorphism in PPAR gamma2 gene among Qataris is lower than that in many Caucasian ethnic groups. No association is seen between the Pro(12)Ala and type 2 Diabetes (0.055 vs 0.059, OR = 1.1311, P = 0.669). Nearly half of the diabetic type 2 patients (48.5%) were obese (BMI > 30) compared to nondiabetic subjects (29.8%) (P < 0.001). In this study, no association is seen between the Pro(12)Ala polymorphism in PPAR gamma2 gene and the type2 diabetes in Qatar.
PubMed Accession Number :: 17805473.

Chan, M. F.; Dowsett, M.; Folkerd, E.; Wareham, N.; Luben, R.; Welch, A.; Bingham, S.; Khaw, K. T. (2008) Past oral contraceptive and hormone therapy use and endogenous hormone concentrations in postmenopausal women Menopause, 15 (2),332-339 [Journal Article] Online
Abstract: OBJECTIVE:: Exogenous sex hormone use is associated with many health effects. Current exogenous hormone use influences endogenous sex hormone levels, but little is known about longer term effects on endogenous hormones after cessation of use. The aim of this study was to examine the relationship between past hormone use and current endogenous hormone status. DESIGN:: This was a cross-sectional study of 1,983 postmenopausal women aged 55 to 81 years from the general community. The women were not currently using exogenous hormones. Past use of oral contraceptives (OCs) and hormone therapy (HT) as well as circulating endogenous sex hormones and sex hormone-binding globulin concentrations were evaluated. RESULTS:: Past OC users had significantly lower endogenous estradiol, estrone, androstenedione, testosterone, and sex hormone-binding globulin concentrations compared with never users independent of age, body mass index, smoking, physical activity, and reproductive factors. Past HT users had significantly lower testosterone and 17alpha-hydroxyprogesterone concentrations. Past OC use and HT use were both independently associated with lower testosterone concentrations: -9% (95% CI: -16% to -2%) for ever OC use compared with never OC use and -7% (95% CI: -17% to -2%) for ever HT use compared with never HT use. The magnitude of 5% to 10% differences in endogenous hormone concentrations was similar or greater for past OC use compared with past HT use, although OC use occurred earlier in the past. CONCLUSIONS:: Past OC use and HT use seem to be related to long-term differences in endogenous sex hormones and sex hormone-binding globulin concentrations in postmenopausal women many years after cessation of use. These findings have implications for understanding the longer term effects of exogenous hormone exposures earlier in life with health and disease risk in later life.
PubMed Accession Number :: 17667152.

Tillin, T.; Forouhi, N. G.; Davey-Smith, G.; McKeigue, P. M.; Chaturvedi, N. (2008) Cardiovascular Disease Mortality in Relation to Childhood and Adulthood Socio-Economic Markers in British South Asian Men Heart, 94 (4),476-81 [Journal Article] Online
Abstract: Objective To study the effects of childhood and adulthood socio-economic position (SEP) including length of education on rates of cardiovascular disease (CVD) mortality in British South Asians. Design Cross-sectional study with ongoing mortality follow-up. Setting West London Borough of Ealing, population-based study. Patients 1,400 South Asian men (52% Punjabi Sikh origin) aged 40-69, first studied 1988 -1990 and followed for mortality to October 2006. Main outcome measures Deaths due to cardiovascular disease. Results 143 men have died from CVD. Men in non-manual adult occupations were less likely to die from CVD than those in unskilled manual occupations (age adjusted hazard ratio (HR) =0.55 (95% CI: 0.35, 0.88). Men with 11+ years of education had reduced risk compared with those with <11 years of education (HR: 0.66 (0.47, 0.94)). Men who had both non-manual occupations and 11+years of education were less likely to die from CVD (15 deaths, 282 men HR: 0.39, 95% CI: 0.21, 0.73) than those who were most socially disadvantaged during childhood and adulthood (27deaths, 187 men,). These associations remained after adjustment for other markers of SEP, lifestyle and conventional risk factors. Similar, but weaker, associations were observed when paternal occupation defined childhood SEP. Conclusions Years of education, and to a lesser extent paternal occupation, as markers of childhood SEP, had cumulative effects with adulthood socioeconomic circumstances on risk of CVD death; these cumulative effects were strongest in men whose own occupation was non-manual and were unexplained by conventional risk factors measured in middle age.
PubMed Accession Number :: 17646197.

Beunen, G. P.; Peeters, M. W.; Maes, H. H.; Loos, R. J.; Claessens, A. L.; Derom, C.; Vlietinck, R.; Thomis, M. A. (2007) The Leuven Longitudinal Twin Study (LLTS): Major Findings Twin Res Hum Genet, 10 (supp),15-18 [Journal Article] Online
Abstract: Abstract Alongitudinal study of growth and physical fitness of twins and their parents was designed in 1985. The major aims of this Leuven Longitudinal Twin Study were to quantify the genetic and environmental determination of (1) somatic characteristics, biological maturation and physical performance characteristics during the growth process, (2) the growth and developmental patterns, and (3) the covariation in somatic and performance characteristics.
PubMed Accession Number :: 18241116.

Loos, R. J.; Derom, C.; Eeckels, R.; Derom, R.; Vlietinck, R. (2007) Gestation and Birthweight in Dizygotic Twins: Girls Call the Tune Twin Res Hum Genet, 10 (supp),6-7 [Journal Article] Online
Abstract: Abstract Unlike-sex twins provide a unique natural experiment to investigate the influence of sex on gestation. Our data showed that length of gestation of unlike-sex pairs is similar to that of female same-sex pairs, and significantly (0.4 wks, p = .02) longer than that of male same-sex pairs. Birthweight of female unlike-sex twins was similar to female same-sex twins, but male unlike-sex twins weighed 78 g more than male same-sex twins ( p = .001). These data show that in unlikesex pairs it is the girl that prolongs gestation for her brother, resulting in a higher birthweight than that of same-sex boys.
PubMed Accession Number :: 18241113.

Prevost, A. T.; Mason, D.; Griffin, S.; Kinmonth, A. L.; Sutton, S.; Spiegelhalter, D. (2007) Allowing for correlations between correlations in random-effects meta-analysis of correlation matrices Psychol Methods, 12 (4),434-50 [Journal Article] Online
Abstract: Practical meta-analysis of correlation matrices generally ignores covariances (and hence correlations) between correlation estimates. The authors consider various methods for allowing for covariances, including generalized least squares, maximum marginal likelihood, and Bayesian approaches, illustrated using a 6-dimensional response in a series of psychological studies concerning prediction of exercise behavior change. Quantities of interest include the overall population mean correlation matrix, the contrast between the mean correlations, the predicted correlation matrix in a new study, and the conflict between the existing studies and a new correlation matrix. The authors conclude that accounting for correlations between correlations is unnecessary when interested in individual correlations but potentially important if concerned with a composite measure involving 2 or more correlations. A simulation study indicates the asymptotic normal assumption appears reasonable. Because of potential instability in the generalized least squares methods, they recommend a model-based approach, either the maximum marginal likelihood approach or a full Bayesian analysis. (PsycINFO Database Record (c) 2008 APA, all rights reserved).
PubMed Accession Number :: 18179354.

Peters, T. M.; Ekelund, U.; Leitzmann, M.; Easton, D.; Warren, R.; Luben, R.; Bingham, S.; Khaw, K. T.; Wareham, N. J. (2007) Physical Activity and Mammographic Breast Density in the EPIC-Norfolk Cohort Study Am J Epidemiol, , [Journal Article] Online
Abstract: Physical inactivity and high mammographic breast density have both been associated with increased breast cancer risk. However, the association between physical activity and mammographic breast density remains inconsistent. In the European Prospective Investigation of Cancer (EPIC)-Norfolk population-based cohort study (United Kingdom), the authors investigated the cross-sectional association between physical activity level at baseline during 1993-1997 and breast density among 1,394 postmenopausal, cancer-free women. Usual physical activity was assessed by a brief, validated questionnaire. Percentage breast density was determined visually from mammograms by three trained radiologists using the Boyd six-category scale. The association between physical activity level and breast density risk category was examined. No statistically significant association between physical activity and percentage breast density was observed in the unadjusted or adjusted regression models. A suggested increase in breast density for the most active women in the unadjusted regression analysis (odds ratio = 1.13, 95% confidence interval: 0.71, 1.80) was reversed after inclusion of body mass index and reproductive and lifestyle variables (odds ratio = 0.78, 95% confidence interval: 0.45, 1.34). The lack of an association between physical activity and percentage breast density suggests that an association between physical activity and breast cancer risk is unlikely to be mediated through an effect on mammographic breast density.
PubMed Accession Number :: 18162477.

Stevenson, C. R.; Critchley, J. A.; Forouhi, N. G.; Roglic, G.; Williams, B. G.; Dye, C.; Unwin, N. C. (2007) Diabetes and the risk of tuberculosis: a neglected threat to public health? Chronic Illn, 3 (3),228-45 [Journal Article] Online
Abstract: OBJECTIVES: Tuberculosis (TB) remains a major global public health problem. In the past, a relationship between TB and diabetes mellitus (DM) was recognized, and its importance was acknowledged through joint treatment clinics. However, this is rarely highlighted in current research or control priorities. This paper aims to evaluate the evidence for an association between these two diseases. METHODS: A Medline literature search was undertaken, supplemented by checking references and contacting experts. We critically appraised studies that quantified the association between TB and DM, and were published after 1995. We assessed study quality according to criteria such as sample size, method of selection of cases and controls, losses to follow-up, quality and method of control of confounding, and summarized the results narratively and in tabular form. RESULTS: All studies identified statistically significant and clinically important associations, with the increase in risk or odds of TB varying between 1.5- and 7.8-fold for those with DM. Risk was highest at younger ages. Most studies had not measured and controlled adequately for potential major confounders. DISCUSSION: There is strong evidence for an association between TB and DM, which has potential public health implications. Further well-designed studies are needed to assess the magnitude precisely.
PubMed Accession Number :: 18083679.

Myint, P. K.; Surtees, P. G.; Wainwright, N. W.; Luben, R. N.; Welch, A. A.; Bingham, S. A.; Wareham, N. J.; Khaw, K. T. (2007) Physical health-related quality of life predicts stroke in the EPIC-Norfolk Neurology, 69 (24),2243-8 [Journal Article] Online
Abstract: OBJECTIVE: To examine the relationship between Short Form (SF)-36 physical functional health-related quality of life and incident stroke. METHODS: A total of 13,615 men and women participating in the European Prospective Investigation into Cancer-Norfolk who were free of stroke, myocardial infarction, and cancer at baseline were included in the study. Participants completed a health and lifestyle questionnaire and attended a health examination during 1993 to 1997. Self-reported physical functional health was assessed using physical component summary scores of SF-36 18 months later. Stroke incidence was ascertained by death certification and hospital record linkage up to 2005. RESULTS: There were 244 incident strokes (total person years = 99,191). People who reported better physical functional health had significantly lower risk of incident stroke. Using Cox proportional hazard models adjusting for age, sex, body mass index, systolic blood pressure, cholesterol, smoking, diabetes, physical activity, social class, alcohol consumption, and respiratory function, men and women who were in the top quartile of SF-36 physical component summary scores had half the risk of stroke (RR = 0.50 [0.31, 0.78]) compared to the people in the bottom quartile. The relationships remained unchanged after excluding strokes occurring within the first 2 years of follow-up. CONCLUSIONS: Physical functional health-related quality of life measured as Short Form-36 predicts subsequent stroke risk independently of known risk factors in a general population. Poor physical functional health may indicate a high-risk population for stroke who may benefit most from targeted preventive interventions such as management of known risk factors.
PubMed Accession Number :: 18071144.

Canoy, D.; Boekholdt, S. M.; Wareham, N.; Luben, R.; Welch, A.; Bingham, S.; Buchan, I.; Day, N.; Khaw, K. T. (2007) Body fat distribution and risk of coronary heart disease in men and women in the European Prospective Investigation Into Cancer and Nutrition in Norfolk cohort: a population-based prospective study Circulation, 116 (25),2933-43 [Journal Article] Online
Abstract: BACKGROUND: Body fat distribution has been cross-sectionally associated with atherosclerotic disease risk factors, but the prospective relation with coronary heart disease remains uncertain. METHODS AND RESULTS: We examined the prospective relation between fat distribution indices and coronary heart disease among 24,508 men and women 45 to 79 years of age using proportional hazards regression. During a mean 9.1 years of follow-up, 1708 men and 892 women developed coronary heart disease. The risk for developing subsequent coronary heart disease increased continuously across the range of waist-hip ratio. Hazard ratios (95% CI) of the top versus bottom fifth of waist-hip ratio were 1.55 (1.28 to 1.73) in men and 1.91 (1.44 to 2.54) in women after adjustment for body mass index and other coronary heart disease risk factors. Hazard ratios increased with waist circumference, but risk estimates for waist circumference without hip circumference adjustment were lower by 10% to 18%. After adjustment for waist circumference, body mass index, and coronary heart disease risk factors, hazard ratios for 1-SD increase in hip circumference were 0.80 (95% CI, 0.74 to 0.87) in men and 0.80 (95% CI, 0.69 to 0.93) in women. Hazard ratios for body mass index were greatly attenuated when we adjusted for waist-hip ratio or waist circumference and other covariates. CONCLUSIONS: Indices of abdominal obesity were more consistently and strongly predictive of coronary heart disease than body mass index. These simple and inexpensive measurements could be used to assess obesity-related coronary heart disease risk in relatively healthy men and women.
PubMed Accession Number :: 18071080.

Corder, K.; Brage, S.; Mattocks, C.; Ness, A.; Riddoch, C.; Wareham, N. J.; Ekelund, U. (2007) Comparison of Two Methods to Assess PAEE during Six Activities in Children Med Sci Sports Exerc, 39 (12),2180-8 [Journal Article] Online
Abstract: PURPOSE:: The purpose of this study was to compare the accuracy of physical activity energy expenditure (PAEE)-prediction models using accelerometry alone (ACC) and accelerometry combined with heart rate monitoring (HR+ACC) to estimate PAEE during six common activities in children (lying, sitting, slow and brisk walking, hop-scotch, running). Three PAEE-prediction models derived using the current data, and five previously published prediction models were cross-validated to estimate PAEE in this sample. METHODS:: PAEE was assessed using ACC, HR+ACC, and indirect calorimetry during six activities in 145 children (12.4 +/- 0.2 yr). One ACC and two HR+ACC PAEE-prediction models were derived using linear regression on data from the current study. These three new models were cross-validated using a jackknife approach, and a modified Bland-Altman method was used to assess the validity of all eight models. RESULTS:: PAEE predictions using the one ACC and two HR+ACC models derived in the current study correlated strongly with measured values (RMSE = 97.3-118.0 J.min.kg). All five previously published models agreed well overall (RMSE = 115.6-245.3 J.min.kg), but systematic error was present for most of these, to a greater extent for ACC. CONCLUSIONS:: ACC and HR+ACC can both be used to predict overall PAEE during these six activities in children; however, systematic error was present in all predictions. Although both ACC and HR+ACC provide accurate predictions of overall PAEE, according to the activities in this study, PAEE-prediction models using HR+ACC may be more accurate and widely applicable than those based on accelerometry alone.
PubMed Accession Number :: 18046189.

Frohlich-Reiterer, E. E.; Ong, K. K.; Regan, F.; Salzano, G.; Acerini, C. L.; Dunger, D. B. (2007) A randomized cross-over trial to identify the optimal use of insulin glargine in prepubertal children using a three-times daily insulin regimen Diabet Med, 24 (12),1406-11 [Journal Article] Online
Abstract: Aims The long-acting insulin analogue glargine reduces nocturnal hypoglycaemia and stabilizes morning blood glucose levels in patients with Type 1 diabetes (T1DM) on multiple injection therapy. However, young children may not tolerate such intensive insulin regimens. We investigated the effects of glargine in various three-injections-daily insulin combinations on 24-h glucose control in prepubertal children. Methods Seventeen T1DM prepubertal children (10 boys), median age 10.2 years (range 6.0-12.4), glycated haemoglobin (HbA(1c)) 8.8% (6.8-11.5) were recruited to a randomized, open-label, cross-over study. After a 2-week run-in period (with NPH pre-bed), every child underwent three different 3-week treatment blocks in random order. All treatment blocks included glargine pre-bed, but used different morning insulins: block 1, soluble only; block 2, soluble + NPH; block 3, aspart + NPH. Continuous glucose monitoring was performed for 3 days at the end of the run-in and each treatment block. Results Compared with the run-in period on NPH, the three glargine treatment blocks were associated with lower (P < 0.0001) and less variable (P < 0.05) pre-breakfast glucose levels, and with an 8-15% reduction in total daily insulin dose (P < 0.0001). Risk of nocturnal hypoglycaemia detected by continuous glucose monitoring varied significantly between the three glargine treatment blocks, and was lowest when children were given aspart + NPH in the morning (block 3). Conclusion Insulin glargine pre-bed can be used in three-injections-daily regimens in prepubertal children to lower and stabilize pre-breakfast glucose levels. However, to avoid the risk of nocturnal hypoglycaemia, the pre-bed glargine dose should be lowered by giving a further long-acting insulin, such as NPH, in the morning.
PubMed Accession Number :: 18042082.

Khaw, K. T.; Dowsett, M.; Folkerd, E.; Bingham, S.; Wareham, N.; Luben, R.; Welch, A.; Day, N. (2007) Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men. European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) Prospective Population Study Circulation, 116 ,2694-701 [Journal Article] Online
Abstract: BACKGROUND: -The relation between endogenous testosterone concentrations and health in men is controversial. Methods and Results-We examined the prospective relationship between endogenous testosterone concentrations and mortality due to all causes, cardiovascular disease, and cancer in a nested case-control study based on 11 606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003. Among those without prevalent cancer or cardiovascular disease, 825 men who subsequently died were compared with a control group of 1489 men still alive, matched for age and date of baseline visit. Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes (825 deaths), cardiovascular disease (369 deaths), and cancer (304 deaths). Odds ratios (95% confidence intervals) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 0.75 (0.55 to 1.00), 0.62 (0.45 to 0.84), and 0.59 (0.42 to 0.85), respectively (P<0.001 for trend after adjustment for age, date of visit, body mass index, systolic blood pressure, blood cholesterol, cigarette smoking, diabetes mellitus, alcohol intake, physical activity, social class, education, dehydroepiandrosterone sulfate, androstanediol glucuronide, and sex hormone binding globulin). An increase of 6 nmol/L serum testosterone ( approximately 1 SD) was associated with a 0.81 (95% confidence interval 0.71 to 0.92, P<0.01) multivariable-adjusted odds ratio for mortality. Inverse relationships were also observed for deaths due to cardiovascular causes and cancer and after the exclusion of deaths that occurred in the first 2 years. Conclusions-In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.
PubMed Accession Number :: 18040028.

Beardsall, K.; Ogilvy-Stuart, A. L.; Frystyk, J.; Chen, J. W.; Thompson, M.; Ahluwalia, J.; Ong, K. K.; Dunger, D. B. (2007) Early elective insulin therapy can reduce hyperglycemia and increase insulin-like growth factor-I levels in very low birth weight infants J Pediatr, 151 (6),611-7, 617 e1 [Journal Article] Online
Abstract: OBJECTIVE: To investigate the use of insulin throughout the first week of life in very low birth weight (VLBW) infants (birth weight <1.5 kg) to improve glucose control and increase insulin-like growth factor-I (IGF-I) levels. IGF-I is the dominant hormone involved in fetal growth, and low levels have been implicated in neonatal morbidities, such as retinopathy of prematurity. STUDY DESIGN: In this pilot randomized controlled study (n = 16), the intervention group received insulin (0.025 U/kg/hr) on days 1 to 7, with 20% dextrose to maintain normoglycemia. Control infants received standard neonatal care. All infants received continuous glucose monitoring. RESULTS: The intervention and standard care groups had similar mean gestational age (+/- standard deviation), 26.2 (+/- 2.5) vs 26.9 (+/- 2.7) weeks, and birth weight, 0.79 (+/- 0.26) vs 0.73 (+/- 0.16) kg. The standard care infants were hyperglycemic (sensor glucose >10 mmol/L [180 mg/dL]) for 35.9% of the study period, compared with 7.6% for the insulin-treated infants (P = .035). The duration of time with hypoglycemia (<2.6 mmol/L [47 mg/dL]) did not differ between the 2 groups (P = .746). The insulin-treated group had a 2.4-fold increase in mean IGF-I bioactivity (P = .005). CONCLUSIONS: Early insulin therapy improves blood glucose control and increases IGF-I bioactivity levels. This could result in less morbidity associated with hyperglycemia and reduced IGF-I levels.
PubMed Accession Number :: 18035140.

van Sluijs, E. M.; Griffin, S. J.; van Poppel, M. N. (2007) A cross-sectional study of awareness of physical activity: associations with personal, behavioral and psychosocial factors Int J Behav Nutr Phys Act, 4 (1),53 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Interventions to promote physical activity frequently target hypothesized mediators of change, but these might be affected by a person's awareness of their own physical activity behavior. The paper aims to characterize a high-risk population by levels of awareness and to study associations between awareness and selected personal, behavioral and psychosocial factors. METHODS: Data were collected on physical activity behavior, physical activity awareness, behavioral and psychosocial factors and anthropometry cross-sectionally at 6-month follow-up in a physical activity promotion trial. Awareness was assessed by comparing dichotomous self-rated physical activity with achieving activity levels according to international guidelines. Four groups were distinguished: 'Realistic Active', 'Realistic Inactive', 'Overestimator', and 'Underestimator'. Data were analyzed with ANCOVA, correcting for previous interventions and current physical activity level. RESULTS: Of 632 participants (mean age: 56.3 years), 321 were inactive, 61.4% of whom rated themselves as active ('Overestimators'). Compared to 'Realistic Inactives', 'Overestimators' were older, less likely to be smokers or to intend to increase their physical activity level, and had a lower body mass index. Furthermore, 'Overestimators' had similar scores to the 'Realistic Actives' on the psychological factors, but differed significantly from the 'Realistic Inactives'. CONCLUSIONS: People who overestimate their physical activity level appear to be healthier than people who aware of their low activity level. Overestimators also scored more positively on various psychosocial factors and were also less likely to intend to change their physical activity behavior, making awareness a potential barrier in physical activity promotion. Physical activity promotion strategies might include interventions with a focus on increasing awareness in this hard to reach population.
PubMed Accession Number :: 17996060.

Ong, K. K.; de Zegher, F.; Lopez-Bermejo, A.; Dunger, D. B.; Ibanez, L. (2007) Flutamide metformin for post-menarcheal girls with preclinical ovarian androgen excess: evidence for differential response by androgen receptor genotype Eur J Endocrinol, 157 (5),661-8 [Journal Article] Online
Abstract: OBJECTIVE: Addition of androgen receptor (AR) blockade (flutamide) to insulin-sensitising therapy (metformin) may confer synergistic benefits in girls with hyperinsulinaemic androgen excess. We hypothesised that girls with shorter AR gene CAG repeat alleles, and thus greater receptor sensitivity, might benefit more from the addition of low-dose flutamide. DESIGN: Open randomised crossover study. METHODS: In this study, 32 post-menarcheal girls (mean age 12.1 years) with a history of low birth weight and precocious pubarche were subgrouped by CAG genotype ('short': CAG mean length 20, n=14; 'long': CAG >20, n=18). Within each subgroup, girls were 1:1 randomised to metformin alone (850 mg/day) or in combination with flutamide (62.5 mg/day) for 12 months. To allow comparisons with no treatment, long-CAG girls randomised to flutamide-metformin, and short-CAG girls randomised to metformin alone were observed for 12 months before treatment. Body composition by absorptiometry, fasting lipid profiles and levels of insulin, glucose and androgens were measured during the first 12 months on each treatment. RESULTS: In all girls, 12 months flutamide-metformin lowered body fat and improved lipid profiles when compared with no treatment. Compared with metformin alone, flutamide-metformin achieved greater reductions in the percentage of body fat and abdominal fat mass in the short-CAG subgroup (P=0.001 to P<0.0001). In contrast, in the long-CAG subgroup, flutamide-metformin produced no further improvements when compared with metformin alone. CONCLUSIONS: In young post-menarcheal girls with preclinical androgen excess, low-dose flutamide-metformin improved body composition and key endocrine-metabolic abnormalities. However, only those girls with genetic markers of greater AR sensitivity may benefit from the addition of flutamide above metformin alone.
Keywords: Adolescent Age Factors Child Cross-Over Studies Drug Therapy, Combination Female Flutamide/*administration & dosage Genotype Humans Hyperandrogenism/drug therapy/*genetics Menarche/drug effects/*genetics Metformin/*administration & dosage Ovarian Diseases/drug therapy/*genetics Receptors, Androgen/*genetics
PubMed Accession Number :: 17984247.

Wu, K.; Bowman, R.; Welch, A. A.; Luben, R. N.; Wareham, N.; Khaw, K. T.; Bingham, S. A. (2007) Apolipoprotein E polymorphisms, dietary fat and fibre, and serum lipids: the EPIC Norfolk study Eur Heart J, 28 (23),2930-6 [Journal Article] Online
Abstract: Aims To investigate whether blood lipid response to dietary fat and fibre vary according to the apolipoprotein E (APOE) gene locus. Methods and results Regression analysis of intake of dietary fat and lipid fractions according to APOE gene loci was assessed by Pyrosequencing and validated with restriction fragment length polymorphism in 22 915 participants of the Norfolk arm of the European Prospective Investigation of Cancer. There were significant (P < 0.001) differences in serum lipids according to genotype, highest total and low-density lipoprotein (LDL) cholesterol, and lowest high-density lipoprotein and triglycerides in epsilon4/epsilon4 individuals. There were positive associations between total and saturated fat and serum total and LDL cholesterol, and significant inverse associations (P < 0.001) between polyunsaturated fat and dietary fibre and lipid fractions overall. Associations were in the same direction for epsilon2, epsilon3, and epsilon4 expressing individuals with no significant interactions between diet and genotype group on blood lipids, except in the 3% individuals expressing epsilon2/epsilon4 (P < 0.05) in whom the associations were doubled. Conclusion In this largest study to date, ApoE gene loci status does not confer exemption from population targets to reduce dietary saturated fat and increase dietary fibre in order to reduce blood lipids and risk of coronary heart disease.
PubMed Accession Number :: 17982164.

Arsenault, B. J.; Lemieux, I.; Despres, J. P.; Wareham, N. J.; Luben, R.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2007) Cholesterol levels in small LDL particles predict the risk of coronary heart disease in the EPIC-Norfolk prospective population study Eur Heart J, 28 (22),2770-7 [Journal Article] Online
Abstract: Aims To evaluate the association of low-density lipoprotein cholesterol (LDL-C) levels in small and large LDL particles with risk of incident coronary heart disease (CHD). Methods and results We performed a prospective case-control study nested in the EPIC-Norfolk cohort. Cases were apparently healthy men and women aged 45-79 years who developed fatal or non-fatal CHD (n = 1035), and who were matched by age, gender, and enrollment time to 1920 controls who remained free of CHD. Electrophoretic characteristics of LDL particles were measured using 2-16% polyacrylamide gradient gel electrophoresis. Concentrations of LDL-C(<255 A) were higher in cases than controls in men (1.34 +/- 0.88 vs. 1.15 +/- 0.80 mmol/L, P < 0.001) as well as in women (1.12 +/- 0.84 vs. 0.94 +/- 0.74 mmol/L, P < 0.001). The unadjusted odds ratio (OR) for future CHD in men of the top tertile of LDL-C(<255 A) was 1.68 (95% CI, 1.33-2.13; P < 0.001) whereas in women the unadjusted OR was 1.53 (95% CI, 1.13-2.07; P < 0.001). However, after further adjustments for confounding variables, the association between LDL-C(<255 A) and CHD was no longer significant in men and in women. Conclusion Cholesterol concentrations in different LDL subclasses show different relationships with CHD risk in this European cohort.
PubMed Accession Number :: 17947216.

Ong, K. K. (2007) Catch-up growth in small for gestational age babies: good or bad? Curr Opin Endocrinol Diabetes Obes, 14 (1),30-4 [Journal Article] Online
Abstract: PURPOSE OF REVIEW: Most small for gestational age infants show rapid early postnatal growth and weight gain. Increasing trends towards childhood overweight and its metabolic consequences, and their epidemiological associations with lower birth weight, have led to critical assessments of the benefits and disadvantages of rapid early growth. RECENT FINDINGS: In the last 12 months, three systematic reviews have described the consistent association between rapid infancy growth and subsequent obesity risk in childhood and later life. Recent studies have also described the very early development of insulin resistance in small for gestational age children who show catch-up growth, and this insulin resistance may, in turn, adversely affect body composition, growth and puberty. Long-term randomized trials of growth hormone therapy, however, remind us of the persisting short stature and significant adult height deficit in untreated children without early spontaneous catch-up. SUMMARY: Even in modern societies with low rates of childhood infection and mortality, the small for gestational age infant may face a dilemma over whether or not to catch up. Current nutritional strategies that promote catch-up growth should include some monitoring of weight-for-length and adiposity, and the concept of 'healthy catch-up growth' should be the goal of future research.
PubMed Accession Number :: 17940416.

Tan, Q.; Christiansen, L.; Brasch-Andersen, C.; Zhao, J. H.; Li, S.; Kruse, T. A.; Christensen, K. (2007) Retrospective analysis of main and interaction effects in genetic association studies of human complex traits BMC Genet, 8 ,70 [Journal Article] Online
Abstract: BACKGROUND: The etiology of multifactorial human diseases involves complex interactions between numerous environmental factors and alleles of many genes. Efficient statistical tools are demanded in identifying the genetic and environmental variants that affect the risk of disease development. This paper introduces a retrospective polytomous logistic regression model to measure both the main and interaction effects in genetic association studies of human discrete and continuous complex traits. In this model, combinations of genotypes at two interacting loci or of environmental exposure and genotypes at one locus are treated as nominal outcomes of which the proportions are modeled as a function of the disease trait assigning both main and interaction effects and with no assumption of normality in the trait distribution. Performance of our method in detecting interaction effect is compared with that of the case-only model. RESULTS: Results from our simulation study indicate that our retrospective model exhibits high power in capturing even relatively small effect with reasonable sample sizes. Application of our method to data from an association study on the catalase -262C/T promoter polymorphism and aging phenotypes detected significant main and interaction effects for age-group and allele T on individual's cognitive functioning and produced consistent results in estimating the interaction effect as compared with the popular case-only model. CONCLUSION: The retrospective polytomous logistic regression model can be used as a convenient tool for assessing both main and interaction effects in genetic association studies of human multifactorial diseases involving genetic and non-genetic factors as well as categorical or continuous traits.
Keywords: Aged Aging/genetics Alleles Cognition Environmental Exposure Genetic Predisposition to Disease/*genetics Haplotypes Humans Logistic Models Middle Aged *Models, Genetic *Quantitative Trait, Heritable Retrospective Studies
PubMed Accession Number :: 17937824.

Birjmohun, R. S.; Dallinga-Thie, G. M.; Kuivenhoven, J. A.; Stroes, E. S.; Otvos, J. D.; Wareham, N. J.; Luben, R.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2007) Apolipoprotein A-II is inversely associated with risk of future coronary artery disease Circulation, 116 (18),2029-35 [Journal Article] Online
Abstract: BACKGROUND: Although the vasculoprotective effects of apolipoprotein A-I (apoA-I), the major protein associated with high-density lipoprotein, have been universally accepted, apoA-II has been suggested to have poor antiatherogenic or even proatherogenic properties. To study this suggestion more closely, we evaluated how serum levels of apoA-II and apoA-I relate to the risk of future coronary artery disease (CAD) in a large, prospective study. METHODS AND RESULTS: We performed a nested case-control study in the prospective EPIC-Norfolk (European Prospective Investigation into Cancer and Nutrition-Norfolk) cohort. Case subjects (n=912) were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Control subjects (n=1635) were matched by age, gender, and enrollment time. Conditional logistic regression was used to quantify the relationship between serum apoA-II levels and risk of CAD. Serum apoA-II concentration was significantly lower in case subjects (34.5+/-6.3 mg/dL) than in control subjects (35.2+/-5.8 mg/dL) and was inversely associated with risk of CAD, such that patients in the upper quartile (>38.1 mg/dL) had an odds ratio of 0.59 (95% confidence interval 0.46 to 0.76) versus those in the lowest quartile (<31.1 mg/dL; P for linearity <0.0001). After adjustment for fasting time, alcohol use, and cardiovascular risk factors (systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index, smoking, diabetes mellitus, and C-reactive protein), the corresponding risk estimate was 0.48 (95% confidence interval 0.34 to 0.67, P for linearity <0.0001). Surprisingly, additional adjustment for serum apoA-I levels did not affect risk prediction of apoA-II for future CAD (odds ratio 0.49, 95% confidence interval 0.34 to 0.68, P for linearity <0.0001). Also, after adjustment for high-density lipoprotein particle number and size, apoA-II was still associated with the risk of future CAD (odds ratio 0.62, 95% confidence interval 0.43 to 0.90, P for linearity 0.02). CONCLUSIONS: ApoA-II is associated with a decreased risk of future CAD in apparently healthy people. These findings imply that apoA-II itself exerts effects on specific antiatherogenic pathways. On the basis of these findings, discussion of the potential proatherogenic effects of apoA-II can cease.
Keywords: Aged Apolipoprotein A-II/*blood Case-Control Studies Coronary Artery Disease/*blood/epidemiology/*prevention & control Female Follow-Up Studies Forecasting Humans Male Middle Aged Prospective Studies Risk Factors
PubMed Accession Number :: 17923573.

Rana, J. S.; Boekholdt, S. M.; Ridker, P. M.; Jukema, J. W.; Luben, R.; Bingham, S. A.; Day, N. E.; Wareham, N. J.; Kastelein, J. J.; Khaw, K. T. (2007) Differential leucocyte count and the risk of future coronary artery disease in healthy men and women: the EPIC-Norfolk Prospective Population Study J Intern Med, 262 ,678-89 [Journal Article] Online
Abstract: Background: We examined the relationship between granulocyte, lymphocyte and monocyte counts and risk of coronary heart disease (CHD) and cardiovascular disease (CVD) in men and women. There is paucity of data on the differential leucocyte count and its relationship with the risk of CHD and CVD. Methods: This prospective study comprised 7073 men and 9035 women who were 45-79 years of age and were residents of Norfolk. United Kingdom. Results: During an average of 8 years of follow-up we identified 857 incident CHD events and 2581 CVD incident events. Increased total leucocyte count was associated with increased risk for both CHD and CVD. The highest quartile of granulocyte count was associated with increased risk when compared to lowest quartile for CHD (men HR 1.70 95% CI: 1.30-2.21; women HR 1.24 95% CI: 0.91-1.69) and for CVD (men HR 1.46 95% CI: 1.24-1.71; women HR 1.20 95% CI: 1.02-1.42). The association remained unchanged when the analyses were restricted to nonsmokers and when risk was assessed for every 1000 cells L(-1) increase in cell count. In multivariable models, despite adjusting for C-reactive protein (CRP), the granulocyte count remained an independent predictor of CHD and CVD risk, especially amongst men. Lymphocyte or monocyte counts were not significantly associated with increased risk. In all analyses, additionally adjusting for CRP did not affect the results materially. Conclusions: In conclusion, we found that the higher risk for CHD and CVD associated with increased total leucocyte count seems to be accounted for by the increased granulocyte count.
PubMed Accession Number :: 17908163.

Petry, C. J.; Ong, K. K.; Dunger, D. B. (2007) Does the fetal genotype affect maternal physiology during pregnancy? Trends Mol Med, 13 ,414-21 [Journal Article] Online
Abstract: Conventional wisdom states that associations between fetal growth and diseases in pregnancy, such as pregnancy-induced hypertension (PIH) and gestational diabetes (GDM), result from effects of the mother's genotype or environment acting on her physiology which subsequently affect the fetus. However, recent evidence from human mothers carrying macrosomic offspring with Beckwith Wiedemann syndrome and pregnant mice carrying p57(kip2)-null offspring suggest that variation in the fetal genome can modify maternal physiology to increase fetal nutrient delivery and optimise growth. These are some of the first documented examples of such effects, whereby the genome of one individual directly affects the physiology of another related individual from the same species. We propose that this mechanism is involved in the aetiology of PIH and GDM.
PubMed Accession Number :: 17900986.

Simmons, R. K.; Griffin, S. J.; Wareham, N. J. (2007) Researching how to realize the potential of diabetes prevention Diabet Med, 24 (10),1055-7 [Journal Article] Online
PubMed Accession Number :: 17888126.

van Sluijs, E. M.; McMinn, A. M.; Griffin, S. J. (2007) Effectiveness of interventions to promote physical activity in children and adolescents: systematic review of controlled trials Bmj, 335 (7622),703-707 [Journal Article] Online
Abstract: OBJECTIVE: To review the published literature on the effectiveness of interventions to promote physical activity in children and adolescents. DESIGN: Systematic review. DATA SOURCES: Literature search using PubMed, SCOPUS, Psychlit, Ovid Medline, Sportdiscus, and Embase up to December 2006. Review methods Two independent reviewers assessed studies against the following inclusion criteria: controlled trial, comparison of intervention to promote physical activity with no intervention control condition, participants younger than 18 years, and reported statistical analyses of a physical activity outcome measure. Levels of evidence, accounting for methodological quality, were assessed for three types of intervention, five settings, and three target populations. RESULTS: The literature search identified 57 studies: 33 aimed at children and 24 at adolescents. Twenty four studies were of high methodological quality, including 13 studies in children. Interventions that were found to be effective achieved increases ranging from an additional 2.6 minutes of physical education related physical activity to 283 minutes per week of overall physical activity. Among children, limited evidence for an effect was found for interventions targeting children from low socioeconomic populations, and environmental interventions. Strong evidence was found that school based interventions with involvement of the family or community and multicomponent interventions can increase physical activity in adolescents. CONCLUSION: Some evidence was found for potentially effective strategies to increase children's levels of physical activity. For adolescents, multicomponent interventions and interventions that included both school and family or community involvement have the potential to make important differences to levels of physical activity and should be promoted. A lack of high quality evaluations hampers conclusions concerning effectiveness, especially among children.
PubMed Accession Number :: 17884863.

Ong, K. K.; Elmlinger, M.; Jones, R.; Emmett, P.; Holly, J.; Ranke, M. B.; Dunger, D. B. (2007) Growth hormone binding protein levels in children are associated with birth weight, postnatal weight gain, and insulin secretion Metabolism, 56 (10),1412-1417 [Journal Article] Online
Abstract: Rapid infancy weight gain is associated with subsequent higher circulating insulin-like growth factor (IGF) I levels in normal children. We hypothesized that circulating levels of growth hormone binding protein (GHBP), a putative marker of GH sensitivity, may also be associated with postnatal weight gain and insulin secretion. In 751 normal children aged 7 to 8 years, we measured insulin, glucose, GHBP, IGF-I, IGF binding protein (IGFBP) 1, and IGFBP-3 levels in a fasting venous blood sample. Insulin secretion was assessed by measuring insulin and glucose levels 30 minutes after an oral glucose load. After adjustment for current weight, birth weight was inversely related to IGF-I and GHBP levels. Children with lower birth weight and rapid weight gain between birth and 3 years had higher IGF-I and GHBP levels and also lower IGFBP-1 levels than other children. Allowing for current body mass index, GHBP levels were positively related to insulin secretion. In conclusion, children who showed rapid early postnatal weight gain after low birth weight have higher levels of GHBP than other children. Increased GH sensitivity in such children could contribute to links between rapid infancy weight gain and subsequent faster rates of childhood growth and maturation.
PubMed Accession Number :: 17884454.

Corder, K.; Brage, S.; Ramachandran, A.; Snehalatha, C.; Wareham, N.; Ekelund, U. (2007) Comparison of two Actigraph models for assessing free-living physical activity in Indian adolescents J Sports Sci, 25 (14),1607-1611 [Journal Article] Online
Abstract: This aim of this study was to compare the new Actigraph (GT1M) with the widely used Model 7164. Seven days of free-living physical activity were measured simultaneously using both the Model 7164 and GT1M in 30 Indian adolescents (mean age 15.8 years, s = 0.6). The GT1M was on average 9% lower per epoch than model 7164, thus a correction factor of 0.91 is suggested for comparison between the two monitors. The differences between monitors increased in magnitude with intensity of activity (P < 0.001) but remained randomly distributed (r = 0.01, P = 0.96). No significant difference was observed between monitors for time spent in moderate (P = 0.31) and vigorous (P = 0.34) physical activity when using the same epoch length. The Model 7164 classified less time as sedentary (P < 0.001) and more time as light-intensity activity (P < 0.001) than the GT1M. In conclusion, data from the GT1M can be compared with historical data using average counts per minute with a correction factor, and the two models might be comparable for assessing time spent in moderate to vigorous physical activity in children when using the same epoch length.
PubMed Accession Number :: 17852668.

Peeters, M. W.; Beunen, G. P.; Maes, H. H.; Loos, R. J.; Claessens, A. L.; Vlietinck, R.; Thomis, M. A. (2007) Genetic and environmental determination of tracking in subcutaneous fat distribution during adolescence Am J Clin Nutr, 86 (3),652-60 [Journal Article] Online
Abstract: BACKGROUND: The distribution of fat and adipose tissue is an important predictor of disease risk. Variation in fat distribution during adolescence is correlated with fat distribution in adulthood. OBJECTIVE: The objective was to gain insight into the relative contribution of genes and environment to the stability of subcutaneous fat distribution from early adolescence into young adulthood. DESIGN: Ratio of trunk to extremity skinfold thickness (TER) data from the Leuven Longitudinal Twin Study (n = 105 Belgian twin pairs followed from 10 to 18 y of age) was entered into a longitudinal path analysis. RESULTS: The best-fitting model included additive genetic sources of variance and nonshared environment. Heritabilities ranged between 84.3% (95% CI: 63.9-92.3%) and 88.6% (95% CI: 76.5-94.1%) in boys and between 78.4% (95% CI: 59.3-88.3%) and 88.3% (95% CI: 77.0-93.8%) in girls. The majority of the phenotypic tracking (boys: 0.40-0.78; girls: 0.38-0.72) could be attributed to the moderate-to-high genetic correlations (rG) (between 0.27-0.84 and 0.38-0.80 for the various age intervals in boys and girls, respectively). This rG could be attributed to both genetic sources of variance, which are the same throughout adolescence, as well as genetic sources of variance that are "switched-on" at a certain age, the effect of which is then transmitted to subsequent observations. Environmental correlations (rE) in boys ranged between 0.51 and 0.70 but contributed relatively little to phenotypic tracking because the amount of variance explained by the environment was low (11.4-15.7%). In girls rE was low to moderate at best (0.09-0.48). CONCLUSION: Phenotypic tracking in subcutaneous fat distribution during adolescence is predominantly explained by additive genetic sources of variance.
PubMed Accession Number :: 17823430.

Stevenson, C. R.; Forouhi, N. G.; Roglic, G.; Williams, B. G.; Lauer, J. A.; Dye, C.; Unwin, N. (2007) Diabetes and tuberculosis: the impact of the diabetes epidemic on tuberculosis incidence BMC Public Health, 7 (1),234 [Journal Article] Online
Abstract: ABSTRACT: BACKGROUND: Tuberculosis (TB) remains a major cause of mortality in developing countries, and in these countries diabetes prevalence is increasing rapidly. Diabetes increases the risk of TB. Our aim was to assess the potential impact of diabetes as a risk factor for incident pulmonary tuberculosis, using India as an example. METHODS: We constructed an epidemiological model using data on tuberculosis incidence, diabetes prevalence, population structure, and relative risk of tuberculosis associated with diabetes. We evaluated the contribution made by diabetes to both tuberculosis incidence, and to the difference between tuberculosis incidence in urban and rural areas. RESULTS: In India in 2000 there were an estimated 20.7 million adults with diabetes, and 900,000 incident adult cases of pulmonary tuberculosis. Our calculations suggest that diabetes accounts for 14.8% (uncertainty range 7.1% to 23.8%) of pulmonary tuberculosis and 20.2% (8.3% to 41.9%) of smear-positive (i.e. infectious) tuberculosis. We estimate that the increased diabetes prevalence in urban areas is associated with a 15.2% greater smear-positive tuberculosis incidence in urban than rural areas - over a fifth of the estimated total difference. CONCLUSIONS: Diabetes makes a substantial contribution to the burden of incident tuberculosis in India, and the association is particularly strong for the infectious form of tuberculosis. The current diabetes epidemic may lead to a resurgence of tuberculosis in endemic regions, especially in urban areas. This potentially carries a risk of global spread with serious implications for tuberculosis control and the achievement of the United Nations Millennium Development Goals.
PubMed Accession Number :: 17822539.

Eborall, H.; Davies, R.; Kinmonth, A. L.; Griffin, S.; Lawton, J. (2007) Patients' experiences of screening for type 2 diabetes: prospective qualitative study embedded in the ADDITION (Cambridge) randomised controlled trial Bmj, 335 (7618),490 [Journal Article] Online
Abstract: OBJECTIVES: To provide insight into factors that contribute to the anxiety reported in a quantitative study of the psychological effect of screening for type 2 diabetes. To explore expectations of and reactions to the screening experience of patients with positive, negative, and intermediate results. DESIGN: Prospective qualitative interview study of patients attending a screening programme for type 2 diabetes. SETTING: Seven general practices in the ADDITION (Cambridge) trial in the east of England. PARTICIPANTS: 23 participants (aged 50-69) attending different stages in the screening process. RESULTS: Participants' perceptions changed as they progressed through the screening programme; the stepwise process seemed to help them adjust psychologically. The first screening test was typically considered unimportant and was attended with no thought about its implications. By the final diagnostic test, type 2 diabetes was considered a strong possibility, albeit a "mild" form. After diagnosis, people with screen detected type 2 diabetes tended to downplay its importance and talked confidently about their plans to control it. Participants with intermediate results seemed uncertain about their diagnosis, and those who screened negative were largely unaware of their remaining high risk. CONCLUSIONS: This study helps in understanding the limited psychological impact of screening for type 2 diabetes quantified previously, in particular by the quantitative substudy of ADDITION (Cambridge). The findings have implications for implementing such a screening programme in terms of timing and content.
Keywords: Adult Aged *Attitude to Health Diabetes Mellitus, Type 2/diagnosis/*psychology Female Humans Male Mass Screening/*psychology Middle Aged Prospective Studies
PubMed Accession Number :: 17762000.

Eborall, H. C.; Griffin, S. J.; Prevost, A. T.; Kinmonth, A. L.; French, D. P.; Sutton, S. (2007) Psychological impact of screening for type 2 diabetes: controlled trial and comparative study embedded in the ADDITION (Cambridge) randomised controlled trial Bmj, 335 (7618),486 [Journal Article] Online
Abstract: OBJECTIVE: To quantify the psychological impact of primary care based stepwise screening for type 2 diabetes. DESIGN: Controlled trial and comparative study embedded in a randomised controlled trial. SETTING: 15 practices (10 screening, five control) in the ADDITION (Cambridge) trial in the east of England. PARTICIPANTS: 7380 adults (aged 40-69) in the top fourth for risk of having undiagnosed type 2 diabetes (6416 invited for screening, 964 controls). INTERVENTIONS: Invited for screening for type 2 diabetes or not invited (controls), incorporating a comparative study of subgroups of screening attenders. Attenders completed questionnaires after a random blood glucose test and at 3-6 months and 12-15 months later. Controls were sent questionnaires at corresponding time points. Non-attenders were sent questionnaires at 3-6 months and 12-15 months. MAIN OUTCOME MEASURES: State anxiety (Spielberger state anxiety inventory), anxiety and depression (hospital anxiety and depression scale), worry about diabetes, and self rated health. RESULTS: No significant differences were found between the screening and control participants at any time-for example, difference in means (95% confidence intervals) for state anxiety after the initial blood glucose test was -0.53, -2.60 to 1.54, at 3-6 months was 1.51 (-0.17 to 3.20), and at 12-15 months was 0.57, -1.11 to 2.24. After the initial test, compared with participants who screened negative, those who screened positive reported significantly poorer general health (difference in means -0.19, -0.25 to -0.13), higher state anxiety (0.93, -0.02 to 1.88), higher depression (0.32, 0.08 to 0.56), and higher worry about diabetes (0.25, 0.09 to 0.41), although effect sizes were small. Small but significant trends were found for self rated health across the screening subgroups at 3-6 months (P=0.047) and for worry about diabetes across the screen negative groups at 3-6 months and 12-15 months (P=0.001). CONCLUSIONS: Screening for type 2 diabetes has limited psychological impact on patients. Implementing a national screening programme based on the stepwise screening procedure used in the ADDITION (Cambridge) trial is unlikely to have significant consequences for patients' psychological health. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99175498 [controlled-trials.com].
Keywords: Adult Aged Anxiety Disorders/*etiology Blood Glucose/analysis Depressive Disorder/*etiology Diabetes Mellitus, Type 2/diagnosis/*psychology Humans Mass Screening/*psychology Middle Aged Patient Acceptance of Health Care/statistics & numerical data
PubMed Accession Number :: 17761995.

Honour, J. W.; Jones, R.; Leary, S.; Golding, J.; Ong, K. K.; Dunger, D. B. (2007) Relationships of urinary adrenal steroids at age 8 years with birth weight, postnatal growth, blood pressure, and glucose metabolism J Clin Endocrinol Metab, 92 (11),4340-5 [Journal Article] Online
Abstract: INTRODUCTION: Overactivity of the hypothalamic-pituitary-adrenal axis through a program set by early growth patterns is hypothesized to lead to central obesity, insulin resistance, and hypertension. We therefore examined links between adrenal steroid production and birth weight, rapid early growth, and body mass index (BMI), blood pressure, waist circumference, and resistance to insulin in early childhood through the action of adrenal steroids. METHODS: Timed overnight urine samples were collected in 461 children from a large representative birth cohort. In total 244 boys and 188 girls aged 8.2-8.4 yr completed the protocol. The excretion rates of individual steroids were measured to determine total androgen and cortisol metabolites. Indices of activity of 5alpha-androgen reduction of androgens and cortisol metabolites and 11beta-hydroxy steroid dehydrogenase activity were calculated. RESULTS: In both boys and girls, total urinary androgen and cortisol metabolites were positively related to current height, weight, BMI, and waist circumference. Girls had higher urine androgen metabolite levels and 5alpha-androgen indexes than boys, and in girls higher androgen metabolite excretion was associated with lower birth weight and faster postnatal weight gain. After adjustment for current BMI, total cortisol metabolites and 11beta-hydroxy steroid dehydrogenase index were not related to birth weight or postnatal weight gain in either sex. CONCLUSIONS: These data confirm early growth associations in this cohort seen with plasma levels of adrenal androgens at age 8 yr, at least in girls. Larger studies and follow-up during puberty are needed to exclude the possibility of programming of cortisol metabolism by early growth.
Keywords: Adrenal Cortex Function Tests Adrenal Cortex Hormones/*urine Androgens/blood Birth Weight/*physiology Blood Pressure/*physiology Child England/epidemiology Female Glucose/*metabolism Growth/*physiology Humans Infant, Newborn Longitudinal Studies Male Reference Values Sex Characteristics Steroids/*urine
PubMed Accession Number :: 17726082.

Souren, N. Y.; Paulussen, A. D.; Loos, R. J.; Gielen, M.; Beunen, G.; Fagard, R.; Derom, C.; Vlietinck, R.; Zeegers, M. P. (2007) Anthropometry, carbohydrate and lipid metabolism in the East Flanders Prospective Twin Survey: heritabilities Diabetologia, 50 (10),2107--16 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: We determined the genetic contribution of 18 anthropometric and metabolic risk factors of type 2 diabetes using a young healthy twin population. METHODS: Traits were measured in 240 monozygotic (MZ) and 138 dizygotic (DZ) twin pairs aged 18 to 34 years. Twins were recruited from the Belgian population-based East Flanders Prospective Twin Survey, which is characterised by its accurate zygosity determination and extensive collection of perinatal and placental data, including information on chorionicity. Heritability was estimated using structural equation modelling implemented in the Mx software package. RESULTS: Intra-pair correlations of the anthropometric and metabolic characteristics did not differ between MZ monochorionic and MZ dichorionic pairs; consequently heritabilities were estimated using the classical twin approach. For body mass, BMI and fat mass, quantitative sex differences were observed; genetic variance explained 84, 85 and 81% of the total variation in men and 74, 75 and 70% in women, respectively. Heritability estimates of the waist-to-hip ratio, sum of four skinfold thicknesses and lean body mass were 70, 74 and 81%, respectively. The heritability estimates of fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance and beta cell function, as well as insulin-like growth factor binding protein-1 levels were 67, 49, 48, 62 and 47%, in that order. Finally, for total cholesterol, LDL-cholesterol, HDL-cholesterol, total cholesterol:HDL-cholesterol ratio, triacylglycerol, NEFA and leptin levels, genetic factors explained 75, 78, 76, 79, 58, 37 and 53% of the total variation, respectively. CONCLUSIONS/INTERPRETATION: Genetic factors explain the greater part of the variation in traits related to obesity, glucose intolerance/insulin resistance and dyslipidaemia.
PubMed Accession Number :: 17694296.

Corder, K.; Brage, S.; Ekelund, U. (2007) Accelerometers and pedometers: methodology and clinical application Curr Opin Clin Nutr Metab Care, 10 (5),597-603 [Journal Article] Online
Abstract: PURPOSE OF REVIEW: The relationship between physical activity and health varies considerably, partly due to the difficulty of assessing physical activity accurately. This review examines recent literature on the validation of movement sensors to assess habitual physical activity. Recommendations are given for the use of movement sensors during free-living conditions and methods of data analysis and interpretation are discussed. RECENT FINDINGS: Recent progress in physical-activity research includes detailed comparative studies of different monitor brands. The move away from using linear-regression equations and the use of novel data-analysis strategies is increasing the accuracy with which energy expenditure can be estimated from accelerometry. New technologies, including the combination of accelerometry with the measurement of physiological parameters, have great potential for the increased accuracy of physical-activity assessment. SUMMARY: Accelerometry is able to adequately assess physical activity and its association with health outcomes but currently methods have limited accuracy for the estimation of free-living energy expenditure. Pedometers provide an inexpensive overall measure of physical activity but are unable to assess intensity, frequency and duration of activity or to estimate energy expenditure. Interpretation of monitor output is best kept as close to the measurement domain as possible.
PubMed Accession Number :: 17693743.

Bingham, S.; Luben, R.; Welch, A.; Tasevska, N.; Wareham, N.; Khaw, K. T. (2007) Epidemiologic assessment of sugars consumption using biomarkers: comparisons of obese and nonobese individuals in the European prospective investigation of cancer norfolk Cancer Epidemiol Biomarkers Prev, 16 (8),1651-4 [Journal Article] Online
Abstract: We have previously shown that urinary sugars excretion in 24 h urine collections can serve as an independent biomarker of sugars consumption. In the European Prospective Investigation of Cancer (EPIC) Norfolk study of nutrition and cancer, this biomarker in spot urines has been assessed in a cross-sectional comparison of 404 obese individuals aged 45 to 75 years with a body mass index (BMI) of >30 kg/m(2) and 471 normal weight individuals aged 45 to 75 years with a BMI of <25 kg/m(2). In individuals of normal weight, sucrose, protein, and vitamin C intake were positively and highly significantly related to biomarkers in spot urine or plasma (P < 0.001), but there were no significant associations between biomarkers and food intake reports in the obese. Odds ratios for a BMI of >30 were significantly elevated for urinary sucrose [trend per milligram per liter quintile, 1.13; 95% confidence interval (95% CI), 1.02-1.25; P = 0.016], and the odds ratio for urinary sucrose/fructose ratio was highly significant (trend per quintile, 1.264; 95% CI, 1.142-1.401; P < 0.001). No associations for sugars intake and obesity were found using a food frequency questionnaire, and dietary vitamin C was apparently associated with increased risk (P < 0.001) despite an inverse association for plasma vitamin C. Nutritional biomarkers of consumption can complement existing methods for assessing cancer risk from diet in epidemiologic studies. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1651-4).
PubMed Accession Number :: 17684141.

Anderssen, S. A.; Cooper, A. R.; Riddoch, C.; Sardinha, L. B.; Harro, M.; Brage, S.; Andersen, L. B. (2007) Low cardiorespiratory fitness is a strong predictor for clustering of cardiovascular disease risk factors in children independent of country, age and sex Eur J Cardiovasc Prev Rehabil, 14 (4),526-531 [Journal Article] Online
Abstract: BACKGROUND AND DESIGN: Few studies have investigated the association between maximal cardiorespiratory capacity (fitness) and the clustered cardiovascular disease (CVD) risk in children and youth from culturally diverse countries. This cross-sectional study examined the association between fitness and clustered CVD risk in children and adolescents from three European countries. METHODS: Participants were 2845 randomly selected school children aged 9 or 15 years from Portugal (n=944), Denmark (n=849) and Estonia (n=1052). Cardiorespiratory fitness was determined during a maximal test on a cycle ergometer. CVD risk factors selected to assess the degree of clustering were the total cholesterol/high-density lipoprotein cholesterol ratio, plasma triglycerides, insulin resistance (homeostasis model assessment), sum of four skinfolds, and systolic blood pressure. RESULTS: There was a strong association between cardiorespiratory fitness and the clustering of CVD risk factors. The odds ratios for clustering in each quartile of fitness, using the quartile with the highest fitness as reference, were 13.0 [95% confidence interval (CI) 8.8-19.1]; 4.8 (95% CI 3.2-7.1) and 2.5 (95% CI 1.6-3.8), respectively, after adjusting for country, age, sex, socio-economic status, pubertal stage, family history of CVD and diabetes. In stratified analyses by age group, sex and country, similar strong patterns were observed. CONCLUSION: Low cardiorespiratory fitness is strongly associated with the clustering of CVD risk factors in children independent of country, age and sex.
PubMed Accession Number :: 17667643.

Thoolen, B.; De Ridder, D.; Bensing, J.; Maas, C.; Griffin, S.; Gorter, K.; Rutten, G. (2007) The effectiveness of a self-management intervention in patients with screen-detected type-2 diabetes Diabetes Care, , [Journal Article] Online
Abstract: Objective: to examine the effectiveness of a theory-driven self-management course in reducing cardiovascular risk in patients with screen-detected type-2 diabetes, taking ongoing medical treatment into account. Methods: 196 screen-detected patients, receiving either intensive pharmacological or usual-care treatment since diagnosis (3-33 months previously), were subsequently randomized to a control or intervention condition (self-management course). A 2x2 factorial design evaluated the behavioral intervention (self-management course versus control) nested within the medical treatment (intensive versus usual-care), using multilevel regression modelling to analyse changes in patients' BMI, Hba1c%, blood pressure (BP) and lipid profiles over 12 months, from the start of the 3-month course to 9-month follow-up Results: The self-management course significantly reduced BMI (-0.77 kg/m(2)) and systolic BP (-6.2 mmHg) up till 9-month follow-up, regardless of medical treatment. However, intensive medical treatment was also independently associated with lower BP, Hba1c%, total cholesterol and LDL before the course and further improvements in systolic BP (-4.7 mmHG). Patients receiving both intensive medical treatment and the self-management course therefore had the best outcomes Conclusion: This self-management course was effective in achieving sustained reductions in weight and BP, independent of medical treatment. A combination of behavioral and medical interventions is particularly effective in reducing cardiovascular risk in newly diagnosed patients. ClinicalTrials.gov-Identifier: NCT00237549.
PubMed Accession Number :: 17666461.

Ekelund, U.; Anderssen, S. A.; Froberg, K.; Sardinha, L. B.; Andersen, L. B.; Brage, S. (2007) Independent associations of physical activity and cardiorespiratory fitness with metabolic risk factors in children: the European youth heart study Diabetologia, 50 (9),1832-40 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: High levels of cardiorespiratory fitness (CRF) and physical activity (PA) are associated with a favourable metabolic risk profile. However, there has been no thorough exploration of the independent contributions of cardiorespiratory fitness and subcomponents of activity (total PA, time spent sedentary, and time spent in light, moderate and vigorous intensity PA) to metabolic risk factors in children and the relative importance of these factors. METHODS: We performed a population-based, cross-sectional study in 9- to 10- and 15- to 16-year-old boys and girls from three regions of Europe (n = 1709). We examined the independent associations of subcomponents of PA and CRF with metabolic risk factors (waist circumference, BP, fasting glucose, insulin, triacylglycerol and HDL-cholesterol levels). Clustered metabolic risk was expressed as a continuously distributed score calculated as the average of the standardised values of the six subcomponents. RESULTS: CRF (standardised beta = -0.09, 95% CI -0.12, -0.06), total PA (standardised beta = -0.08, 95% CI -0.10, -0.05) and all other subcomponents of PA were significantly associated with clustered metabolic risk. After excluding waist circumference from the summary score and further adjustment for waist circumference as a confounding factor, the magnitude of the association between CRF and clustered metabolic risk was attenuated (standardised beta = -0.05, 95% CI -0.08, -0.02), whereas the association with total PA was unchanged (standardised beta = -0.08 95% CI -0.10, -0.05). CONCLUSIONS/INTERPRETATION: PA and CRF are separately and independently associated with individual and clustered metabolic risk factors in children. The association between CRF and clustered risk is partly mediated or confounded by adiposity, whereas the association between activity and clustered risk is independent of adiposity. Our results suggest that fitness and activity affect metabolic risk through different pathways.
PubMed Accession Number :: 17641870.

Dunger, D. B.; Salgin, B.; Ong, K. K. (2007) Early developmental pathways of obesity and diabetes risk Proc Nutr Soc, 66 (3),451-7 [Journal Article] Online
Abstract: Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the beta-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of beta-cell mass, as demonstrated by recent studies of pancreatic beta-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of beta-cell mass may ultimately be the most important determinants of an individual's ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.
PubMed Accession Number :: 17637098.

Wareham, N. J. (2007) Epidemiological studies of physical activity and diabetes risk, and implications for diabetes prevention Appl Physiol Nutr Metab, 32 (4),778-82 [Journal Article] Online
Abstract: The evidence linking physical inactivity to the future risk of type 2 diabetes is strong, and modification of behaviour is a critical and effective element of strategies aimed at the prevention of this increasingly prevalent disorder. Two key unresolved epidemiologic issues relate to the type of activity that is likely to be maximally effective in preventing diabetes and the amount of activity that is required. Resolution of both these issues is likely to require a change in the way activity is measured, with a move away from self-report instruments, toward objective assessment of activity and the pattern and overall level of energy expenditure. It is also unclear whether the impact of physical activity on metabolic risk is homogenous across the population. Subgroups that might respond differently could be defined on the basis of characteristics such as age, degree of obesity, family history, ethnicity, and genetic risk, but the literature on effect modification is limited by study design issues. The identification of such subgroups could aid in the targeting of preventive interventions. An appropriate balance between individually tailored approaches aimed at those at high risk and interventions aimed at trying to shift physical activity levels in entire populations remains to be determined.
PubMed Accession Number :: 17622293.

Meuwese, M. C.; Stroes, E. S.; Hazen, S. L.; van Miert, J. N.; Kuivenhoven, J. A.; Schaub, R. G.; Wareham, N. J.; Luben, R.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2007) Serum Myeloperoxidase Levels Are Associated With the Future Risk of Coronary Artery Disease in Apparently Healthy Individuals The EPIC-Norfolk Prospective Population Study J Am Coll Cardiol, 50 (2),159-65 [Journal Article] Online
Abstract: OBJECTIVES: We evaluated whether serum myeloperoxidase (MPO) levels are associated with the risk of future development of coronary artery disease (CAD) in apparently healthy individuals. BACKGROUND: An enzyme of the innate immune system, MPO exhibits a wide array of proatherogenic effects. These include induction of oxidative damage to low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and promotion of plaque vulnerability. Recent studies revealed that MPO independently predicts adverse outcomes in patients with chest pain or suspected acute coronary syndrome. METHODS: Myeloperoxidase was measured in baseline samples of a case-control study nested in the prospective EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk population study. Case subjects (n = 1,138) were apparently healthy men and women who developed CAD during 8-year follow-up. Control subjects (n = 2,237), matched for age, gender, and enrollment time, remained free of CAD. RESULTS: The MPO levels were significantly higher in case subjects than in control subjects and correlated with C-reactive protein (CRP) (rho = 0.25; p < 0.001) and white blood cell count (rho = 0.33; p < 0.001). Risk of future CAD increased in consecutive quartiles of MPO concentration, with an odds ratio (OR) of 1.49 in the top versus bottom quartile (95% confidence interval [CI] 1.20 to 1.84; p < 0.001). After adjustment for traditional risk factors, the OR in the top quartile remained significant at 1.36 (95% CI 1.07 to 1.73). Elevated MPO levels (>728 pmol/l) similarly predicted increased risk of future CAD among participants with either LDL-cholesterol <130 mg/dl, HDL-cholesterol >50 mg/dl, or CRP <2.0 mg/l (OR 1.52 [95% CI 1.21 to 1.91], 1.59 [95% CI 1.24 to 2.05], and 1.42 [95% CI 1.14 to 1.77)], respectively). CONCLUSION: Elevated MPO levels predict future risk of CAD in apparently healthy individuals. This study suggests that inflammatory activation precedes the onset of overt CAD by many years.
PubMed Accession Number :: 17616301.

Ong, K.; de Zegher, F.; Valls, C.; Dunger, D. B.; Ibanez, L. (2007) Persisting benefits 12-18 months after discontinuation of pubertal metformin therapy in low birthweight girls Clin Endocrinol (Oxf), 67 ,468-471 [Journal Article] Online
Abstract: Background Discontinuation of metformin therapy, if started beyond menarche in adolescents or young women with hyperinsulinaemia following low birthweight, is rapidly followed by rebound deteriorations in body fat, insulin resistance and blood lipid profile. Objective We hypothesized that early commencement of metformin and its continuation throughout puberty might have more persisting benefits. Patients and measurements We followed up on a previously reported randomized study cohort at 12 months and 18 months after treatment discontinuation, including body composition by absorptiometry, fasting insulin, glucose and blood lipids. In that open-labelled, prospective study, 22 low birthweight girls with early normal puberty (Stage 2 breast development at age 8-9 years) were randomized to remain untreated (N = 12] or to receive metformin (850 mg/day; N = 10) for 36 months (between time -36 months to 0 month). Results The significant improvements previously reported at the end of the 36-month active treatment period in per cent body fat, abdominal fat mass, fasting insulin sensitivity, high density lipoprotein (HDL) cholesterol and triglyceride levels all persisted at follow-up 12 months after treatment discontinuation. Further anthropometry at 18 months off therapy confirmed the persistence of benefits in height, body mass index (BMI) and waist circumference in the previously metformin-exposed girls. Conclusion In low birth weight girls with early normal onset of puberty, metformin treatment for 3 years across puberty resulted in auxological, endocrine and metabolic benefits that persisted for at least 1 year after metformin withdrawal. Further follow-up and longer-term studies are needed to explore the possibility that insulin sensitization therapy during puberty might reprogramme predisposition to metabolic disease.
PubMed Accession Number :: 17608755.

Sandhu, M. S.; Weedon, M. N.; Fawcett, K. A.; Wasson, J.; Debenham, S. L.; Daly, A.; Lango, H.; Frayling, T. M.; Neumann, R. J.; Sherva, R.; Blech, I.; Pharoah, P. D.; Palmer, C. N.; Kimber, C.; Tavendale, R.; Morris, A. D.; McCarthy, M. I.; Walker, M.; Hitman, G.; Glaser, B.; Permutt, M. A.; Hattersley, A. T.; Wareham, N. J.; Barroso, I. (2007) Common variants in WFS1 confer risk of type 2 diabetes Nat Genet, 39 (8),951-953 [Journal Article] Online
Abstract: We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.
PubMed Accession Number :: 17603484.

Tammelin, T.; Ekelund, U.; Remes, J.; Nayha, S. (2007) Physical Activity and Sedentary Behaviors among Finnish Youth Med Sci Sports Exerc, 39 (7),1067-74 [Journal Article] Online
Abstract: PURPOSE:: There is general concern about the low level of physical activity and the high amount of time devoted to sedentary behavior among adolescents. This study aimed to determine the proportion of young Finns meeting the current guidelines for youth physical activity (>/= 60 min of moderate- to vigorous-intensity physical activity per day) and TV viewing (< 2 h.d) and to examine associations between physical activity and different sedentary behaviors. METHODS:: The study population consisted of 6928 boys and girls, members of the northern Finland birth cohort 1986 who, in 2001-2002, at age 15-16 yr, responded to a mailed questionnaire inquiring about their time spent in moderate to vigorous (MVPA), light (LPA), and commuting (CPA) physical activity, and different sedentary behaviors. RESULTS:: Fifty-nine percent of the boys and 50% of the girls reported 60 min or more of total physical activity per day. Only 23% of boys and 10% of girls reported 60 min of MVPA per day. Forty-eight percent of boys and 44% of girls reported more than 2 h of daily TV viewing. High amounts of TV viewing and computer use were associated with lower levels of physical activity in both genders. CONCLUSION:: Many adolescents exceeded the recommended level of TV viewing and did not meet current recommendations for health-related physical activity. The inverse associations of physical activity with TV viewing and computer use suggest that measures aimed to reduce sedentary behaviors may, at least partly, increase physical activity among youth.
PubMed Accession Number :: 17596773.

Kiens, B.; Beyer, N.; Brage, S.; Hyldstrup, L.; Ottesen, L. S.; Overgaard, K.; Pedersen, B. K.; Puggaard, L.; Aagaard, P. G. (2007) [Physical inactivity--consequences and correlations] Ugeskr Laeger, 169 (25),2442-5 [Journal Article] Online
Abstract: The Danish Fitness and Nutrition Council has examined the scientific literature to evaluate the effects of a physically inactive lifestyle on health in the adult population. Physical inactivity is defined as less than 2.5 hours of moderately intense activity per week. 30-40% of the adult Danish population is defined as physically inactive. A physically inactive lifestyle has a negative impact on metabolic and cardio-vascular functions and increases the risk of developing lifestyle diseases. Furthermore, physical inactivity increases the risk of disability among the elderly.
Keywords: Adult *Exercise *Health Status Humans *Life Style *Public Health Risk Factors Socioeconomic Factors
PubMed Accession Number :: 17594841.

Myint, P. K.; Luben, R. N.; Surtees, P. G.; Wainwright, N. W.; Welch, A. A.; Bingham, S. A.; Wareham, N. J.; Smith, R. D.; Harvey, I. M.; Khaw, K. T. (2007) Self-reported mental health-related quality of life and mortality in men and women in the European Prospective Investigation into Cancer (EPIC-Norfolk): a prospective population study Psychosom Med, 69 (5),410-4 [Journal Article] Online
Abstract: OBJECTIVE: To explore the relationship between self-reported mental functional health and mortality. METHODS: Participants included 17,777 men and women aged 40 to 79 years at baseline who lived in Norfolk, UK, and had no known cardiovascular disease or cancer, and completed the anglicized Short Form 36-item questionnaire (UK SF-36) during 1996 to 2000 in the European Prospective Investigation into Cancer-Norfolk prospective population study. We examined the relationship between mental functional health derived from the mental component summary scores of the SF-36 and mortality from all causes, cardiovascular disease, cancer, and other causes during an average 6.5-year follow-up. RESULTS: There were 1065 deaths during a total of 115,550 person-years of follow-up. Impaired mental health-related quality of life was associated with increased risk of all-cause mortality in men and women. A decrease of 1 SD (10 points) in SF-36 mental component summary scores was associated with a 14% increase in all-cause mortality (hazards ratio = 1.14; 95% Confidence Interval: 1.07, 1.21) after controlling for age, gender, body mass index, systolic blood pressure, cholesterol, alcohol consumption, diabetes, smoking, social class, and physical functional health. CONCLUSION: Poor self-reported mental functional health is related to increased risk of all-cause mortality in men and women. Interpretation of this association requires further investigation.
Keywords: Adult Aged Cardiovascular Diseases/*mortality/psychology England/epidemiology Female Humans Male *Mental Health Middle Aged Mortality/trends Neoplasms/*mortality/psychology Prospective Studies *Quality of Life
PubMed Accession Number :: 17585062.

Petry, C. J.; Ong, K. K.; Wingate, D. L.; de Zegher, F.; Ibanez, L.; Dunger, D. B. (2007) Lack of association between common polymorphisms in the 17beta-hydroxysteroid dehydrogenase type V gene (HSD17B5) and precocious pubarche J Steroid Biochem Mol Biol, 105 ,176-180 [Journal Article] Online
Abstract: BACKGROUND: 17beta-Hydroxysteroid dehydrogenase (type V; HSD17B5) is a key enzyme involved in testosterone production in females. A single nucleotide polymorphism (SNP) in the promoter region of its gene was recently found to be associated with polycystic ovary syndrome (PCOS) and its related hyperandrogenaemia. Precocious pubarche (PP) is a clinical entity pointing to adrenal androgen excess from mid-childhood onward and is associated with ovarian androgen excess from puberty onward. It is therefore a strong risk factor for PCOS. METHODS: To investigate associations between this promoter SNP along with three exonic SNPs (one non-synonymous and two synonymous) from the same gene, and PP, a case-control study was performed in 190 girls with PP (84 of which were also tested for functional ovarian hyperandrogenism) from Barcelona, Spain and 71 healthy controls. Clinical features and hormone concentrations relevant to hyperandrogenism were compared by HSD17B5 genotype and haplotype. RESULTS: Neither HSD17B5 genotypes nor haplotype were associated with PP, or subsequent androgen excess in girls from Barcelona (all P>0.05). CONCLUSIONS: HSD17B5 SNPs predicted to have functional effects do not appear to be a risk factor for PP in girls from Barcelona, despite these girls being at high risk of developing androgen excess in adulthood.
PubMed Accession Number :: 17583494.

Ekelund, U.; Franks, P. W.; Sharp, S.; Brage, S.; Wareham, N. J. (2007) Increase in physical activity energy expenditure is associated with reduced metabolic risk independent of change in fatness and fitness Diabetes Care, 30 ,2101-2106 [Journal Article] Online
Abstract: Objective: To examine whether change in physical activity energy expenditure (PAEE) is associated with change in metabolic risk factors and whether this association is independent of change in fat mass and aerobic fitness. Research Design and Methods: In a population-based sample of 176 men and 217 women followed prospectively (5.6 years), we measured PAEE by individually calibrated heart rate monitoring, aerobic fitness, total body fat (FM), and metabolic risk factors (blood pressure, fasting triglycerides, HDL-cholesterol, insulin and 2-hour glucose) at baseline and follow-up. Results: A 100 J/kgFFM/min increase in PAEE from baseline to follow-up reduced triglycerides by 3.5% (95% CI 0.03% to 5.7%) in men and 3.2% (95% CI 0.02% to 5.4%) in women, fasting insulin [reduced by 5.3% (95% CI 1.0% to 7.5%) in men and women], and 2 hour glucose [reduced by 3.2% (95% CI 0.3% to 5.3%) in men and 3.1% (0.3% to 5.2%) in women] at follow-up, after adjustment for sex, age, smoking status, aerobic fitness, baseline phenotype and change in fat mass. In general, the magnitudes of association for change in fat mass with metabolic risk factors were 2 to 3 times stronger than for PAEE. Conclusions: Increasing levels of physical activity may protect against metabolic disease even in the absence of improved aerobic fitness and reduced body fatness. Therefore, the combination of increasing levels of physical activity and avoidance of gain in fat mass is likely to be the most successful approach for preventing cardiovascular and metabolic disease.
PubMed Accession Number :: 17536069.

Holt, H. B.; Wild, S. H.; Wareham, N.; Ekelund, U.; Umpleby, M.; Shojaee-Moradie, F.; Holt, R. I.; Phillips, D. I.; Byrne, C. D. (2007) Differential effects of fatness, fitness and physical activity energy expenditure on whole-body, liver and fat insulin sensitivity Diabetologia, 50 ,1698-706 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The relative contributions of fitness (maximal oxygen uptake), physical activity energy expenditure (PAEE) and fatness to whole-body, liver and fat insulin sensitivity is uncertain. The aim of this study was to determine whether fitness and PAEE are associated with whole-body, liver and fat insulin sensitivity independently of body fat. MATERIALS AND METHODS: We recruited 25 men (mean [SD] age 53 [6] years). Whole-body (M value) and liver (percentage suppression of endogenous glucose output) insulin sensitivity were estimated using a hyperinsulinaemic-euglycaemic clamp. Insulin sensitivity in fat (insulin sensitivity index for NEFA) was estimated during an OGTT. Total and truncal fat were measured by dual-energy X-ray absorptiometry, fitness by treadmill, and PAEE (n = 21) by 3 day heart rate monitoring and Baecke questionnaire. RESULTS: In univariate analyses, fatness was strongly associated with insulin sensitivity (whole-body, liver and fat). Fitness was associated with whole-body (r = 0.53, p < 0.007) and liver (0.42, p = 0.04) insulin sensitivity, while PAEE was associated with liver insulin sensitivity (r = 0.55, p = 0.01). Regression models were established to describe associations between fatness, fitness and physical activity and measures of insulin sensitivity (whole-body, fat and liver) as outcomes. Only fatness was independently associated with whole-body insulin sensitivity (B coefficient -0.01, p = 0.001). Fitness was not associated with any outcome. Only PAEE was independently associated with liver insulin sensitivity (B coefficient 13.5, p = 0.02). CONCLUSIONS/INTERPRETATION: Fatness explains most of the variance in whole-body insulin sensitivity. In contrast, PAEE explains most of the variance in liver insulin sensitivity.
PubMed Accession Number :: 17534596.

Easton, D. F.; Pooley, K. A.; Dunning, A. M.; Pharoah, P. D.; Thompson, D.; Ballinger, D. G.; Struewing, J. P.; Morrison, J.; Field, H.; Luben, R.; Wareham, N.; Ahmed, S.; Healey, C. S.; Bowman, R.; Luccarini, C.; Conroy, D.; Shah, M.; Munday, H.; Jordan, C.; Perkins, B.; West, J.; Redman, K.; Meyer, K. B.; Haiman, C. A.; Kolonel, L. K.; Henderson, B. E.; Le Marchand, L.; Brennan, P.; Sangrajrang, S.; Gaborieau, V.; Odefrey, F.; Shen, C. Y.; Wu, P. E.; Wang, H. C.; Eccles, D.; Evans, D. G.; Peto, J.; Fletcher, O.; Johnson, N.; Seal, S.; Stratton, M. R.; Rahman, N.; Chenevix-Trench, G.; Bojesen, S. E.; Nordestgaard, B. G.; Axelsson, C. K.; Garcia-Closas, M.; Brinton, L.; Chanock, S.; Lissowska, J.; Peplonska, B.; Nevanlinna, H.; Fagerholm, R.; Eerola, H.; Kang, D.; Yoo, K. Y.; Noh, D. Y.; Ahn, S. H.; Hunter, D. J.; Hankinson, S. E.; Cox, D. G.; Hall, P.; Wedren, S.; Liu, J.; Low, Y. L.; Bogdanova, N.; Schurmann, P.; Dork, T.; Tollenaar, R. A.; Jacobi, C. E.; Devilee, P.; Klijn, J. G.; Sigurdson, A. J.; Doody, M. M.; Alexander, B. H.; Zhang, J.; Cox, A.; Brock, I. W.; Macpherson, G.; Reed, M. W.; Couch, F. J.; Goode, E. L.; Olson, J. E.; Meijers-Heijboer, H.; van den Ouweland, A.; Uitterlinden, A.; Rivadeneira, F.; Milne, R. L.; Ribas, G.; Gonzalez-Neira, A.; Benitez, J.; Hopper, J. L.; McCredie, M.; Southey, M.; Giles, G. G.; Schroen, C.; Justenhoven, C.; Brauch, H.; Hamann, U.; Ko, Y. D.; Spurdle, A. B.; Beesley, J.; Chen, X.; Aghmesheh, M.; Amor, D.; Andrews, L.; Antill, Y.; Armes, J.; Armitage, S.; Arnold, L.; Balleine, R.; Begley, G.; Beilby, J.; Bennett, I.; Bennett, B.; Berry, G.; Blackburn, A.; Brennan, M.; Brown, M.; Buckley, M.; Burke, J.; Butow, P.; Byron, K.; Callen, D.; Campbell, I.; Clarke, C.; Colley, A.; Cotton, D.; Cui, J.; Culling, B.; Cummings, M.; Dawson, S. J.; Dixon, J.; Dobrovic, A.; Dudding, T.; Edkins, T.; Eisenbruch, M.; Farshid, G.; Fawcett, S.; Field, M.; Firgaira, F.; Fleming, J.; Forbes, J.; Friedlander, M.; Gaff, C.; Gardner, M.; Gattas, M.; George, P.; Giles, G.; Gill, G.; Goldblatt, J.; Greening, S.; Grist, S.; Haan, E.; Harris, M.; Hart, S.; Hayward, N.; Hopper, J.; Humphrey, E.; Jenkins, M.; Jones, A.; Kefford, R.; Kirk, J.; Kollias, J.; Kovalenko, S.; Lakhani, S.; Leary, J.; Lim, J.; Lindeman, G.; Lipton, L.; Lobb, L.; Maclurcan, M.; Mann, G.; Marsh, D.; McKay, M.; Anne McLachlan, S.; Meiser, B.; Milne, R.; Mitchell, G.; Newman, B.; O'Loughlin, I.; Osborne, R.; Peters, L.; Phillips, K.; Price, M.; Reeve, J.; Reeve, T.; Richards, R.; Rinehart, G.; Robinson, B.; Rudzki, B.; Salisbury, E.; Sambrook, J.; Saunders, C.; Scott, C.; Scott, E.; Scott, R.; Seshadri, R.; Shelling, A.; Spurdle, A.; Suthers, G.; Taylor, D.; Tennant, C.; Thorne, H.; Townshend, S.; Tucker, K.; Tyler, J.; Venter, D.; Visvader, J.; Walpole, I.; Ward, R.; Waring, P.; Warner, B.; Warren, G.; Watson, E.; Williams, R.; Wilson, J.; Winship, I.; Young, M. A.; Bowtell, D.; Green, A.; Defazio, A.; Gertig, D.; Webb, P.; Mannermaa, A.; Kosma, V. M.; Kataja, V.; Hartikainen, J.; Day, N. E.; Cox, D. R.; Ponder, B. A. (2007) Genome-wide association study identifies novel breast cancer susceptibility loci Nature, 447 ,1087-93 [Journal Article] Online
Abstract: Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r(2) > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
PubMed Accession Number :: 17529967.

Ong, K. K.; Forouhi, N. (2007) Communicating the benefits of breast feeding Arch Dis Child, 92 (6),471-2 [Journal Article] Online
PubMed Accession Number :: 17515614.

Low, Y. L.; Dunning, A. M.; Dowsett, M.; Folkerd, E.; Doody, D.; Taylor, J.; Bhaniani, A.; Luben, R.; Khaw, K. T.; Wareham, N. J.; Bingham, S. A. (2007) Phytoestrogen Exposure Is Associated with Circulating Sex Hormone Levels in Postmenopausal Women and Interact with ESR1 and NR1I2 Gene Variants Cancer Epidemiol Biomarkers Prev, 16 (5),1009-16 [Journal Article] Online
Abstract: In this large cross-sectional study, we investigated the relationship between phytoestrogen exposure and circulating sex hormones and sex hormone-binding globulin (SHBG) levels in 1988 healthy postmenopausal women and their interactions with polymorphisms in genes involved in estrogen signaling. Plasma estradiol, testosterone, androstenedione, estrone, and SHBG were measured. Urinary levels of five isoflavones (daidzein, genistein, glycitein, O-desmethylangolensin, and equol) and two lignans (enterodiol and enterolactone) were measured and used as biomarkers for dietary intakes. Eighteen polymorphisms in ESR1, ESR2, and NR1I2 genes were genotyped. Results showed that lignans were positively associated with plasma SHBG levels (eta(p)(2) = 1.2%; P < 0.001) and negatively associated with plasma testosterone (eta(p)(2) = 0.2%; P = 0.042). Equol was negatively associated with plasma estradiol levels (eta(p)(2) = 0.3%; P = 0.028), whereas O-desmethylangolensin was positively associated with plasma estradiol level (eta(p)(2) = 0.3%; P = 0.010). There were significant phytoestrogen interactions with polymorphisms in ESR1 and NR1I2 genes in affecting estrone levels. We conclude that phytoestrogens modulate sex hormone and SHBG levels in postmenopausal women and interact with gene variants involved in estrogen signaling. Such phytoestrogen-gene interactions may explain the conflicting literature on the hormonal effects of phytoestrogens. (Cancer Epidemiol Biomarkers Prev 2007;16(5):1009-16).
PubMed Accession Number :: 17507630.

Chan, M. F.; Dowsett, M.; Folkerd, E.; Bingham, S.; Wareham, N.; Luben, R.; Welch, A.; Khaw, K. T. (2007) Usual physical activity and endogenous sex hormones in postmenopausal women: the European prospective investigation into cancer-norfolk population study Cancer Epidemiol Biomarkers Prev, 16 (5),900-5 [Journal Article] Online
Abstract: BACKGROUND: Short-term trials indicate that intensive physical activity may influence endogenous sex hormone concentrations. However, the relationship between usual daily physical activity and endogenous hormones in postmenopausal women in the general population is still uncertain. Objective and METHODS: To determine the relationship between usual physical activity and endogenous sex hormones in postmenopausal women. A cross-sectional population-based study of 2,082 postmenopausal women ages 55 to 81 years, residing in the general community of Norfolk, United Kingdom, and not currently using hormone replacement therapy were chosen to participate. Physical activity in the past 1 year was assessed using a validated questionnaire, and endogenous sex hormone and sex hormone-binding globulin (SHBG) concentrations were determined. RESULTS: Usual physical activity levels were inversely associated with circulating concentrations of testosterone and estradiol, testosterone/SHBG ratio, and positively associated with SHBG. These associations were only slightly attenuated after adjusting for potential covariates including body mass index, smoking status, alcohol intake, and reproductive variables. Testosterone concentrations and testosterone/SHBG ratios were 19% [95% confidence interval (95% CI), 9-27%, P < 0.001] and 24.0% (95% CI, 13-34% P < 0.001) lower, respectively, whereas estradiol concentrations were 6% (95% CI, 0-12%; P < 0.05) lower in the highest compared with lowest activity levels, respectively. A decreasing trend for the estradiol/SHBG ratio and 17alpha-hydroxyprogesterone concentrations was also observed. Androstenedione levels did not differ significantly according to physical activity. CONCLUSIONS: Higher usual physical activity levels among postmenopausal women seem to be related to lower endogenous testosterone and estradiol concentrations. This may be one mechanism that could partly explain the reported inverse relationship between physical activity and breast cancer risk in some studies. (Cancer Epidemiol Biomarkers Prev 2007;16(5):900-905).
PubMed Accession Number :: 17507613.

Simmons, R. K.; Harding, A. H.; Wareham, N. J.; Griffin, S. J. (2007) Do simple questions about diet and physical activity help to identify those at risk of Type 2 diabetes? Diabet Med, 24 (8),830-5 [Journal Article] Online
Abstract: Aims Diet and physical activity interventions can prevent diabetes in those at high risk due to impaired glucose tolerance. We determined whether simple measures of physical activity and diet predicted incident diabetes and enhanced prediction by known risk factors including age, body mass index and family history. Methods This was a population-based prospective cohort study (EPIC-Norfolk). Participants aged 40-79 years (n = 25 633) attended a health check between 1993 and 1998 and completed diet and activity questionnaires. We assessed the association between simple behavioural indices of physical activity and diet derived from the questionnaires as well as known risk score variables with incident diabetes at follow-up (mean 4.6 years). We developed a new diabetes risk score incorporating simple behavioural indices in a randomly selected half of the EPIC dataset using forward step-wise multivariate logistic regression, and tested this score in the remaining half. We compared existing and new scores using receiver-operating characteristic (ROC) curves. Results There were 417 incident cases of diabetes during 115 137 years of follow-up. A simple physical activity index independently predicted risk of diabetes. Eating one or more daily portion of vegetables, fresh fruit and wholemeal bread was associated with reduced risk; whilst eating meat products was associated with increased risk. The area under the ROC curves for the new and original score was the same (76.3%). Conclusions Simple indices of diet and activity are feasible to collect, predict future diabetes risk and might enhance routine data collection in primary care. However, they do not improve the prediction of risk scores based on known risk factors.
PubMed Accession Number :: 17490419.

Heude, B.; Ong, K. K.; Luben, R.; Wareham, N. J.; Sandhu, M. S. (2007) Study of Association between Common Variation in the Insulin-Like Growth Factor 2 Gene and Indices of Obesity and Body Size in Middle-Aged Men and Women J Clin Endocrinol Metab, 92 (7),2734-8 [Journal Article] Online
Abstract: Context: The IGF2 gene (IGF2) plays a key role in growth and is a candidate for association with obesity. Previous studies have reported that polymorphisms in IGF2 are associated with body weight and body mass index (BMI), but the results have been inconsistent. Objectives: The aim of this study was primarily to confirm the association with BMI and, secondarily, to study the associations with other indices of body size. Methods: In a sample of 2797 women and 2203 men aged 39-79 participating in the Norfolk arm of the European Prospective Investigation of Cancer, we genotyped three single nucleotide polymorphisms (SNPs) in the IGF2 gene that were previously associated with BMI [6815 A/T, 1156 T/C (G/A), and 820 G/A (ApaI)]. Results: No significant associations were observed between these SNPs and BMI. However, all three SNPs were significantly associated with height (P = 0.03 to 0.001). In a backward elimination regression analysis, two SNPs, 1156 T/C (G/A) and 820 G/A, remained independently associated with height (P = 0.003 and P = 0.038, respectively). Haplotype analysis of these two SNPs showed that carriers of the GA haplotype were shorter than carriers of each of the other three haplotypes (P < 0.001 for all comparisons). Conclusions: We did not confirm the previously reported associations between IGF2 polymorphisms and BMI. However, our results suggest that common variation in the IGF2 gene may be associated with adult height. IGF2 could be considered as a candidate gene for future research on mechanisms for the association between height and chronic diseases, such as cancer, diabetes, and coronary heart disease.
PubMed Accession Number :: 17488802.

Gielen, M.; Lindsey, P. J.; Derom, C.; Loos, R. J.; Derom, R.; Nijhuis, J. G.; Vlietinck, R. (2007) Twin Birth Weight Standards Neonatology, 92 (3),164-173 [Journal Article] Online
Abstract: Objective: The aim of this study was to present customized twin-specific birth weight standards. The relative contribution of gestational age, maternal factors, twin factors and placental factors to the birth weight was evaluated in a multivariate approach. Subjects and Methods: Perinatal data were obtained from 10,177 live-born twins from the East Flanders Prospective Twin Survey. Of 8,454 twins (4,227 pairs), of whom all data were available, the birth weights at different gestational ages were analyzed using a non-linear multivariate gaussian regression. Results: All considered covariates influenced birth weight of twins significantly, with the exception of sex of the co-twin and mode of conception and delivery. At 37 weeks of gestation, a difference of >1 kg existed between favourable and adverse prenatal environment. Up to 40 weeks, sex, site of the umbilical cord, parity, and birth order had a greater influence on birth weight than zygosity, chorionicity and fusion of the placentas. From 34 weeks on, the birth weight of the second-born twin deviated and after 40 weeks, birth weight of monozygotic monochorionic twins dropped, while the other twins continued to grow. Conclusion: Customized twin-specific birth weight standards, which take these covariates into account, offer the opportunity for a better assessment of the influence of birth weight of the twin on neonatal health in future research. Already the Developmental Origins of Health and Disease hypothesis showed that these prenatal conditions might also be important for the follow-up of the twin. Copyright (c) 2007 S. Karger AG, Basel.
PubMed Accession Number :: 17476117.

van der Steeg, W. A.; Boekholdt, S. M.; Stein, E. A.; El-Harchaoui, K.; Stroes, E. S.; Sandhu, M. S.; Wareham, N. J.; Jukema, J. W.; Luben, R.; Zwinderman, A. H.; Kastelein, J. J.; Khaw, K. T. (2007) Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk Ann Intern Med, 146 (9),640-8 [Journal Article] Online
Abstract: BACKGROUND: An elevated apolipoprotein B-apolipoprotein A-I (apo B-apo A-I) ratio is a risk factor for future coronary artery disease (CAD). It is not known whether this ratio is better than traditional lipid values for risk assessment and prediction and whether it adds predictive value to the Framingham risk score. OBJECTIVE: To evaluate whether the apo B-apo A-I ratio is associated with future CAD events independent of traditional lipid measurements and the Framingham risk score and to evaluate the ability of this ratio to predict occurrence of future CAD. DESIGN: Prospective, nested case-control study. SETTING: Norfolk, United Kingdom. PARTICIPANTS: Apparently healthy men and women (45 to 79 years of age) in the European Prospective Investigation into Cancer and Nutrition-Norfolk. Cases (n = 869) were persons who developed fatal or nonfatal CAD. Controls (n = 1511) were persons without CAD who were matched for age, sex, and enrollment period. MEASUREMENTS: Total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein, and C-reactive protein levels were measured directly. Low-density lipoprotein (LDL) cholesterol values were calculated by using the Friedewald formula. RESULTS: The apo B-apo A-I ratio was associated with future CAD events, independent of traditional lipid values (adjusted odds ratio, 1.85 [95% CI, 1.15 to 2.98]), including the total cholesterol-HDL cholesterol ratio, and independent of the Framingham risk score (adjusted odds ratio, 1.77 [CI, 1.31 to 2.39]). However, it did no better than lipid values at discriminating between CAD cases and controls (area under the receiver-operating characteristic curve, 0.670 for total cholesterol-HDL cholesterol ratio vs. 0.673 for apo B-apo A-I ratio [P = 0.38]) and added little to the predictive value of the Framingham risk score (area under the receiver-operating characteristic curve, 0.594 for Framingham risk score alone vs. 0.613 for Framingham risk score plus apo B-apo A-I ratio [P < 0.001]). In addition, it incorrectly classified 41.1% of cases and 50.4% of controls. LIMITATIONS: No participant was taking lipid-lowering medication, and diabetes was uncommon. CONCLUSIONS: The apo B-apo A-I ratio is independently associated with, but adds little to, existing measures for CAD risk assessment and discrimination in the general population. Other characteristics of the test, such as the ability to perform it on nonfasting samples, may still make it useful in some settings.
Keywords: Aged Apolipoprotein A-I/*blood Apolipoproteins B/*blood Case-Control Studies Coronary Artery Disease/*blood Female Humans Lipids/blood Male Middle Aged Prospective Studies ROC Curve Risk Assessment
PubMed Accession Number :: 17470832.

Brage, S.; Ekelund, U.; Brage, N.; Hennings, M. A.; Froberg, K.; Franks, P. W.; Wareham, N. J. (2007) Hierarchy of individual calibration levels for heart rate and accelerometry to measure physical activity J Appl Physiol, 103 (2),682-692 [Journal Article] Online
Abstract: Combining accelerometry with heart rate (HR) monitoring may improve precision of physical activity measurement. Considerable variation exists in the relationships between physical activity intensity (PAI) and HR and accelerometry, which may be reduced by individual calibration. However, individual calibration limits feasibility of these techniques in population studies and less burdensome, yet valid, methods of calibration are required. We aimed to evaluate the precision of different individual calibration procedures against a reference calibration procedure; a ramped treadmill walking-running test with continuous measurement of PAI by indirect calorimetry, in 26 women and 25 men [mean(SD): 35(9)yrs; 1.69(0.10)m; 70(14)kg]. Acceleration (along the longitudinal axis of the trunk) and HR were measured simultaneously. Alternative calibration procedures included treadmill testing without calorimetry, sub-maximal step and walk tests with and without calorimetry, and non-exercise calibration using sleeping HR and gender. Reference accelerometry and HR models explained >95% of the between-individual variance in PAI (p<0.001). This fraction dropped to 73 and 81%, respectively, for accelerometry and HR models calibrated with treadmill test without calorimetry. Step test calibration captured 62-64% (accelerometry) and 68% (HR) of the variance between individuals. Corresponding values were 63-76% and 59-61% for walk test calibration. There was only little benefit of including calorimetry during step and walk calibration for HR models. Non-exercise calibration procedures explained 54% (accelerometry) and 30% (HR) of the between-individual variance. In conclusion, a substantial proportion of the between-individual variance in relationships between PAI, accelerometry and HR is captured with simple calibration procedures, feasible for use in epidemiological studies. Key words: Energy expenditure, movement sensor, accelerometry, heart rate monitoring, individual calibration.
PubMed Accession Number :: 17463305.

Ong, K. K.; Northstone, K.; Wells, J. C.; Rubin, C.; Ness, A. R.; Golding, J.; Dunger, D. B. (2007) Earlier mother's age at menarche predicts rapid infancy growth and childhood obesity PLoS Med, 4 (4),e132 [Journal Article] Online
Abstract: BACKGROUND: Early menarche tends to be preceded by rapid infancy weight gain and is associated with increased childhood and adult obesity risk. As age at menarche is a heritable trait, we hypothesised that age at menarche in the mother may in turn predict her children's early growth and obesity risk. METHODS AND FINDINGS: We tested associations between mother's age at menarche, mother's adult body size and obesity risk, and her children's growth and obesity risk in 6,009 children from the UK population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort who had growth and fat mass at age 9 y measured by dual-energy X-ray absorptiometry. A subgroup of 914 children also had detailed infancy and childhood growth data. In the mothers, earlier menarche was associated with shorter adult height (by 0.64 cm/y), increased weight (0.92 kg/y), and body mass index (BMI, 0.51 kg/m2/y; all p < 0.001). In contrast, in her children, earlier mother's menarche predicted taller height at 9 y (by 0.41 cm/y) and greater weight (0.80 kg/y), BMI (0.29 kg/m2/y), and fat mass index (0.22 kg/m2/year; all p < 0.001). Children in the earliest mother's menarche quintile (< or =11 y) were more obese than the oldest quintile (> or =15 y) (OR, 2.15, 95% CI 1.46 to 3.17; p < 0.001, adjusted for mother's education and BMI). In the subgroup, children in the earliest quintile showed faster gains in weight (p < 0.001) and height (p < 0.001) only from birth to 2 y, but not from 2 to 9 y (p = 0.3-0.8). CONCLUSIONS: Earlier age at menarche may be a transgenerational marker of a faster growth tempo, characterised by rapid weight gain and growth, particularly during infancy, and leading to taller childhood stature, but likely earlier maturation and therefore shorter adult stature. This growth pattern confers increased childhood and adult obesity risks.
Keywords: Adolescent Age Factors Birth Weight/physiology Body Mass Index Child Child Development/*physiology Child, Preschool Cohort Studies Female Humans Male Menarche/*physiology Obesity/*epidemiology/etiology/*physiopathology Predictive Value of Tests Prospective Studies Risk Factors
PubMed Accession Number :: 17455989.

Duval, S.; Vazquez, G.; Baker, W. L.; Jacobs, D. R., Jr. (2007) The Collaborative Study of Obesity and Diabetes in Adults (CODA) project: meta-analysis design and description of participating studies Obes Rev, 8 (3),263-76 [Journal Article] Online
Abstract: The Collaborative Study of Obesity and Diabetes in Adults (CODA) project was formed to establish an international database of studies of abdominal obesity and type 2 diabetes mellitus (T2DM), and to provide analyses of these associations using individual participant data (IPD) meta-analytic techniques. The collaboration involves obtaining raw data from existing studies. The main objectives of the collaboration are to assess which simple anthropometric indices most closely predict the risk of T2DM in adults, and to investigate ethnicity and other factors that potentially modify that prediction. A second task related to primary prevention of diabetes subsequently evolved, the CODA-2 project, and is concerned with population-based methods to identify people most likely to benefit from diabetes interventions. This article describes the meta-analysis design and the studies involved. The collaboration currently has 37 studies enrolled, providing data on 260,000 participants. The proposed IPD meta-analyses will help resolve several outstanding issues in diabetes.
Keywords: Abdominal Fat/*metabolism Diabetes Mellitus, Type 2/*epidemiology/prevention & control Humans Meta-Analysis Obesity/*epidemiology/prevention & control Primary Prevention
PubMed Accession Number :: 17444967.

Wainwright, N. W.; Surtees, P. G.; Wareham, N. J.; Harrison, B. D. (2007) Psychosocial factors and incident asthma hospital admissions in the EPIC-Norfolk cohort study Allergy, 62 (5),554-60 [Journal Article] Online
Abstract: Background: Case series and case-control studies have shown high rates of psychosocial and behavioural risk factors amongst patients admitted to hospital with severe asthma. General population studies have shown associations between psychosocial factors and prevalent asthma but few have investigated incident asthma outcomes. Methods: Data on psychosocial factors and asthma hospital admissions were available for 20 854 participants, aged 41-80 years, in the Norfolk cohort of the European Prospective Investigation into Cancer study. Postal assessments included details of physical functioning, mood disorder history, social adversity and social support. Results: A total of 686 asthma hospital admissions were recorded. Psychosocial factors present at baseline, including current mood disorders, adverse circumstances in childhood, the impact of life events experienced during adulthood and negative perceived support from a close confidant, were associated with increased rates of hospital admission independent of age, sex, indicators of socio-economic status, physical functional health, and obesity. Restricted to those participants who reported lifetime doctor-diagnosed asthma at baseline, the reported impact of adverse life events experienced in adulthood, and both confiding and negative aspects of support quality, were associated with asthma hospital admission. The magnitude of these associations was comparable to those involving indicators of socio-economic status and physical health. Conclusions: These results show that psychosocial factors are associated with incident asthma hospital admissions and highlight the potential importance of taking account of psychosocial factors, including availability and quality of support networks, in guiding long-term asthma management.
PubMed Accession Number :: 17441796.

Frayling, T. M.; Timpson, N. J.; Weedon, M. N.; Zeggini, E.; Freathy, R. M.; Lindgren, C. M.; Perry, J. R.; Elliott, K. S.; Lango, H.; Rayner, N. W.; Shields, B.; Harries, L. W.; Barrett, J. C.; Ellard, S.; Groves, C. J.; Knight, B.; Patch, A. M.; Ness, A. R.; Ebrahim, S.; Lawlor, D. A.; Ring, S. M.; Ben-Shlomo, Y.; Jarvelin, M. R.; Sovio, U.; Bennett, A. J.; Melzer, D.; Ferrucci, L.; Loos, R. J.; Barroso, I.; Wareham, N. J.; Karpe, F.; Owen, K. R.; Cardon, L. R.; Walker, M.; Hitman, G. A.; Palmer, C. N.; Doney, A. S.; Morris, A. D.; Davey-Smith, G.; Hattersley, A. T.; McCarthy, M. I. (2007) A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity Science, 316 (5826),889-94 [Journal Article] Online
Abstract: Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes susceptibility genes identified a common variant in the FTO gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had a 1.67-fold increased risk of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
PubMed Accession Number :: 17434869.

Loos, R. J.; Franks, P. W.; Francis, R. W.; Barroso, I.; Gribble, F. M.; Savage, D. B.; Ong, K. K.; O'Rahilly, S.; Wareham, N. J. (2007) TCF7L2 polymorphisms modulate proinsulin levels and {beta}-cell function in a British Europid population Diabetes, 56 ,1943-7 [Journal Article] Online
Abstract: Objective and methods: Rapidly accumulating evidence shows that common TCF7L2 polymorphisms confer risk of type 2 diabetes (T2DM) through unknown mechanisms. We examined the association between four TCF7L2 single nucleotide polymorphisms (SNPs), including rs7903146, and measures of insulin sensitivity and insulin secretion in 1697 Europid men and women of the population-based MRC-Ely study. Results: The T-(minor) allele of rs7903146 was strongly and positively associated with fasting proinsulin (p=4.55x10(-9)) and 32,33 split proinsulin (p=1.72x10(-4)) relative to total insulin levels; i.e. differences between T/T- and A/A-homozygotes amounted to 21.9% and 18.4% respectively. Notably the insulin-to-glucose ratio (IGR) at 30min OGTT, a frequently used surrogate of first-phase insulin secretion, was not associated with the TCF7L2 SNP (p>0.7). However, the insulin response (IGR) at 60min OGTT, was significantly lower in T-allele carriers (p=3.5x10(-3)). The T-allele was also associated with higher HbA1c concentrations (p=1.2x10(-2)) and reduced beta-cell function, assessed by HOMA-B (p=2.8x10(-2)). Similar results were obtained for the other TCF7L2 SNPs. Of note, both major genes involved in proinsulin processing (PC1, PC2) contain TCF-binding sites in their promoters. Conclusions: Our findings suggest that the TCF7L2 risk allele may predispose to T2DM by impairing beta-cell proinsulin processing. The risk-allele increases proinsulin levels and diminishes the 60min, but not 30min insulin response during OGTT. The strong association between the TCF7L2 risk-allele and fasting proinsulin, but not insulin levels is notable as in this unselected and largely normoglycaemic population external influences on beta-cell stress are unlikely to be major factors influencing the efficiency of proinsulin processing.
PubMed Accession Number :: 17416797.

Meirhaeghe, A.; Sandhu, M. S.; McCarthy, M. I.; de Groote, P.; Cottel, D.; Arveiler, D.; Ferrieres, J.; Groves, C. J.; Hattersley, A. T.; Hitman, G. A.; Walker, M.; Wareham, N. J.; Amouyel, P. (2007) Association between the T-381C polymorphism of the Brain Natriuretic Peptide gene and risk of type 2 diabetes in human populations Hum Mol Genet, 16 ,1343-50 [Journal Article] Online
Abstract: Brain natriuretic peptide (BNP/NPPB) is a member of the natriuretic family involved in the regulation of blood pressure and blood volume as well as lipolysis control in human fat cells. Thus BNP may play a role in energy metabolism and metabolic diseases. We therefore assessed the association between the BNP promoter T-381C polymorphism and risk of type 2 diabetes and metabolic and BNP expression traits in several population samples. In French population-based samples (n=3216), we found that individuals bearing the -381CC genotype had lower (p=0.005) fasting glucose levels than -381TC or -381TT individuals. Moreover, the -381CC genotype was less frequent in individuals with type 2 diabetes (n=280, 13.6%) or with impaired fasting glucose (n=248, 12.9%) compared with normoglycaemic individuals (n=2485, 17.8%). The adjusted odds ratio [95% CI] of type 2 diabetes for -381CC individuals was 0.69 [0.47-1.00], p=0.05 when compared with -381T allele bearers. We replicated this association in 4 additional case-control studies for type 2 diabetes. The overall odds ratio [95% CI] of type 2 diabetes was 0.85 [0.76-0.96], p=0.008 (under a recessive model) (3,593 cases and 6,646 controls in total). We also found that the -381C allele was associated with higher plasma BNP concentrations (p=0.015) (n=634) and higher BNP promoter activity in reporter gene assays. Collectively, these data suggest that relatively high BNP expression may protect against type 2 diabetes in humans.
PubMed Accession Number :: 17412758.

Sattar, N.; McConnachie, A.; Ford, I.; Gaw, A.; Cleland, S. J.; Forouhi, N. G.; McFarlane, P.; Shepherd, J.; Cobbe, S.; Packard, C. (2007) Serial metabolic measurements and conversion to type 2 diabetes in the west of Scotland coronary prevention study: specific elevations in alanine aminotransferase and triglycerides suggest hepatic fat accumulation as a potential contributing factor Diabetes, 56 (4),984-91 [Journal Article] Online
Abstract: To examine metabolic changes (lipids, liver enzymes, blood pressure, and weight) potentially associated with conversion to diabetes, we analyzed serial glucose and other metabolic measures obtained every 6 months within the West of Scotland Coronary Prevention Study trial. Changes in parameters for 86 men who converted to new-onset diabetes ("converters": two consecutive glucose levels >/=7 mmol/l) were compared with 860 "nonconverters" matched for age and treatment allocation. Eighteen months before the diagnosis, converters to diabetes had elevated (P < 0.01) fasting glucose, weight, triglyceride, alanine aminotransferase (ALT), blood pressure, and white cell count and lower HDL cholesterol compared with nonconverters. The mean (SD) increase in fasting glucose over 18 months in converters was 1.80 (1.52) mmol/l, compared with 0.10 (0.57) in nonconverters. Of parameters measured, only ALT (P = 0.0005) and triglyceride (P = 0.030) increased significantly more over the 18 months in converters compared with nonconverters, but neither parameter increased significantly in nonconverters with high baseline glucose concentrations (>6.1 mmol/l). Finally, only sustained increases in ALT predicted a higher risk for diabetes. We conclude that a relatively rapid rise in fasting glucose levels is frequent in converters to diabetes and that associated increases over time in ALT and potentially triglyceride suggest hepatic fat accumulation as a contributing factor for conversion to diabetes in men at risk.
PubMed Accession Number :: 17395744.

Wild, S. H.; Forouhi, N. G. (2007) What is the scale of the future diabetes epidemic, and how certain are we about it? Diabetologia, 50 (5),903-905 [Journal Article] Online
PubMed Accession Number :: 17375282.

Surtees, P. G.; Wainwright, N. W.; Luben, R. L.; Wareham, N. J.; Bingham, S. A.; Khaw, K. T. (2007) Adaptation to Social Adversity Is Associated With Stroke Incidence. Evidence From the EPIC-Norfolk Prospective Cohort Study Stroke, 38 (5),1447-53 [Journal Article] Online
Abstract: BACKGROUND AND PURPOSE: Laboratory-based studies have suggested that individual differences in cardiovascular reactivity and stress adaptive capacity are associated with stroke incidence. We test the hypothesis that sense of coherence (SOC), a marker of social stress adaptive capacity, is associated with incident stroke in a population-based prospective cohort study. METHODS: A total of 20 629 participants, aged 41 to 80 years, in the UK European Prospective Investigation into Cancer (EPIC)-Norfolk study, who had not previously experienced a stroke, completed assessments that included SOC and details of their experience of life events during adulthood. An index of adaptation was constructed from responses to questions concerning over 80 000 adverse life events. RESULTS: During 145 000 person-years of follow-up (mean 7.1 years), 452 participants experienced either a fatal or nonfatal stroke event. A strong (as opposed to a weak) SOC was associated with a reduced rate of stroke incidence (rate ratio 0.76; 95% CI, 0.60 to 0.96) after adjustment for age, sex, pre-existing myocardial infarction, diabetes, hypertension treatment, family history of stroke, cigarette smoking, systolic blood pressure, obesity, social class, education, hostility and depression. No sex difference in this association was observed. Measures of social adversity occurrence and impact were not associated with stroke incidence, whereas faster reported adaptation to adverse event exposure was associated with a reduced rate of stroke incidence (rate ratio 0.89; 95% CI, 0.81 to 0.98; per standard deviation change in adaptation score, adjusted for age and sex). CONCLUSIONS: Stress adaptive capacity is a potentially important candidate risk factor for stroke.
PubMed Accession Number :: 17363725.

Young, E. H.; Wareham, N. J.; Farooqi, S.; Hinney, A.; Hebebrand, J.; Scherag, A.; O'Rahilly, S.; Barroso, I.; Sandhu, M. S. (2007) The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals Int J Obes (Lond), 31 ,1437-1441 [Journal Article] Online
Abstract: Background:Previous studies have suggested that a variant in the melanocortin-4 receptor (MC4R) gene is important in protecting against common obesity. Larger studies are needed, however, to confirm this relation.Methods:We assessed the association between the V103I polymorphism in the MC4R gene and obesity in three UK population based cohort studies, totalling 8304 individuals. We also did a meta-analysis of relevant studies, involving 10 975 cases and 18 588 controls, to place our findings in context.Finding:In an analysis of all studies, individuals carrying the isoleucine allele had an 18% (95% confidence interval 4-30%, P=0.015) lower risk of obesity compared with non-carriers. There was no heterogeneity among studies and no apparent publication bias.Interpretation:This study confirms that the V103I polymorphism protects against human obesity at a population level. As such it provides proof of principle that specific gene variants may, at least in part, explain susceptibility and resistance to common forms of human obesity. A better understanding of the mechanisms underlying this association will help determine whether changes in MC4R activity have therapeutic potential.International Journal of Obesity advance online publication, 13 March 2007; doi:10.1038/sj.ijo.0803609.
PubMed Accession Number :: 17356525.

Peeters, M. W.; Thomis, M. A.; Loos, R. J.; Derom, C. A.; Fagard, R.; Claessens, A. L.; Vlietinck, R. F.; Beunen, G. P. (2007) Heritability of somatotype components: a multivariate analysis Int J Obes (Lond), 31 (8),1295-1301 [Journal Article] Online
Abstract: Objective:To study the genetic and environmental determination of variation in Heath-Carter somatotype (ST) components (endomorphy, mesomorphy and ectomorphy).Design:Multivariate path analysis on twin data.Subjects:Eight hundred and three members of 424 adult Flemish twin pairs (18-34 years of age).Results:The results indicate the significance of sex differences and the significance of the covariation between the three ST components. After age-regression, variation of the population in ST components and their covariation is explained by additive genetic sources of variance (A), shared (familial) environment (C) and unique environment (E). In men, additive genetic sources of variance explain 28.0% (CI 8.7-50.8%), 86.3% (71.6-90.2%) and 66.5% (37.4-85.1%) for endomorphy, mesomorphy and ectomorphy, respectively. For women, corresponding values are 32.3% (8.9-55.6%), 82.0% (67.7-87.7%) and 70.1% (48.9-81.8%). For all components in men and women, more than 70% of the total variation was explained by sources of variance shared between the three components, emphasising the importance of analysing the ST in a multivariate way.Conclusions:The findings suggest that the high heritabilities for mesomorphy and ectomorphy reported in earlier twin studies in adolescence are maintained in adulthood. For endomorphy, which represents a relative measure of subcutaneous adipose tissue, however, the results suggest heritability may be considerably lower than most values reported in earlier studies on adolescent twins. The heritability is also lower than values reported for, for example, body mass index (BMI), which next to the weight of organs and adipose tissue also includes muscle and bone tissue. Considering the differences in heritability between musculoskeletal robustness (mesomorphy) and subcutaneous adipose tissue (endomorphy) it may be questioned whether studying the genetics of BMI will eventually lead to a better understanding of the genetics of fatness, obesity and overweight.International Journal of Obesity advance online publication, 6 March 2007; doi:10.1038/sj.ijo.0803575.
PubMed Accession Number :: 17342076.

Forouhi, N. G.; Harding, A. H.; Allison, M.; Sandhu, M. S.; Welch, A.; Luben, R.; Bingham, S.; Khaw, K. T.; Wareham, N. J. (2007) Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study Diabetologia, 50 (5),949-956 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The aim of this study was to examine the association between baseline body iron stores and new-onset diabetes. SUBJECTS AND METHODS: We studied the association between baseline serum ferritin concentration and type 2 diabetes in 360 clinically incident diabetes cases and 758 controls nested within the EPIC (European Prospective Investigation of Cancer)-Norfolk Cohort Study. Serum ferritin levels were categorised into five groups: sex-specific quartiles of the normal range of ferritin and a group with clinically raised ferritin below levels indicative of haemochromatosis. RESULTS: Baseline serum ferritin was higher among cases than control participants (geometric mean: men 96.6 vs 67.8 ng/ml, respectively, p < 0.001; women 45.9 vs 34.8 ng/ml, respectively, p = 0.005). In analyses adjusted for known risk factors (age, BMI, sex, family history, physical activity, smoking habit) and dietary factors measured by 7-day food diary, the risk of diabetes was markedly elevated in participants with clinically raised ferritin compared with the lowest quartile (odds ratio [OR] 7.4, 95% CI 3.5-15.4). Further adjustment for potential confounding by inflammation (C-reactive protein, IL-6 and fibrinogen) had no material impact on the observed association, while adjustment for hepatic enzymes (alanine aminotransferase and gamma glutamyl transferase) and adiponectin attenuated the magnitude of association, but it remained statistically significant (OR 3.2 [1.3-7.6]). CONCLUSIONS/INTERPRETATION: Serum ferritin is an important and independent predictor of the development of diabetes. This finding may have important implications for understanding the aetiology of diabetes.
PubMed Accession Number :: 17333112.

Mesa, J. L.; Loos, R. J.; Franks, P. W.; Ong, K. K.; Luan, J.; O'Rahilly, S.; Wareham, N. J.; Barroso, I. (2007) Lamin a/c polymorphisms, type 2 diabetes, and the metabolic syndrome: case-control and quantitative trait studies Diabetes, 56 (3),884-9 [Journal Article] Online
Abstract: Mutations in the LMNA gene, encoding the nuclear envelope protein lamin A/C, are responsible for a number of distinct disease entities including Dunnigan-type familial partial lipodystrophy. Dunningan-type lipodystrophy is characterized by loss of subcutaneous adipose tissue, insulin resistance, dyslipidemia, and type 2 diabetes and shares many of the features of the metabolic syndrome. Furthermore, several genome-wide linkage scans for type 2 diabetes have found evidence of linkage at chromosome 1q21.2, the region that harbors the LMNA gene. Therefore, LMNA is a biological and positional candidate for type 2 diabetes susceptibility. Previous studies have reported association between a common LMNA variant (1908C>T; rs4641) and adverse metabolic traits in ethnically diverse populations from Asia and North America. In the present study, we characterized the common variation across the LMNA gene (including rs4641) and tested for association with type 2 diabetes in two large case-control studies (n = 2,052) and with features of the metabolic syndrome in a separate cohort study (n = 1,572). Despite our study being sufficiently powered to detect effects similar and even smaller in magnitude than those previously reported, none of the LMNA single nucleotide polymorphisms were statistically significantly associated with type 2 diabetes or the metabolic syndrome. Thus, it appears unlikely that variation at LMNA substantially increases the risk of type 2 diabetes or related traits in U.K. Europids.
PubMed Accession Number :: 17327461.

Tan, K.; Kimber, W. A.; Luan, J.; Soos, M. A.; Semple, R. K.; Wareham, N. J.; O'Rahilly, S.; Barroso, I. (2007) Analysis of Genetic Variation in Akt2/PKB-{beta} in Severe Insulin Resistance, Lipodystrophy, Type 2 Diabetes, and Related Metabolic Phenotypes Diabetes, 56 (3),714-9 [Journal Article] Online
Abstract: We previously reported a family in which a heterozygous missense mutation in Akt2 led to a dominantly inherited syndrome of insulin-resistant diabetes and partial lipodystrophy. To determine whether genetic variation in AKT2 plays a broader role in human metabolic disease, we sequenced the entire coding region and splice junctions of AKT2 in 94 unrelated patients with severe insulin resistance, 35 of whom had partial lipodystrophy. Two rare missense mutations (R208K and R467W) were identified in single individuals. However, insulin-stimulated kinase activities of these variants were indistinguishable from wild type. In two large case-control studies (total number of participants 2,200), 0 of 11 common single nucleotide polymorphism (SNPs) in AKT2 showed significant association with type 2 diabetes. In a quantitative trait study of 1,721 extensively phenotyped individuals from the U.K., no association was found with any relevant intermediate metabolic trait. In summary, although heterozygous loss-of- function mutations in AKT2 can cause a syndrome of severe insulin resistance and lipodystrophy in humans, such mutations are uncommon causes of these syndromes. Furthermore, genetic variation in and around the AKT2 locus is unlikely to contribute significantly to the risk of type 2 diabetes or related intermediate metabolic traits in U.K. populations.
PubMed Accession Number :: 17327441.

Semple, R. K.; Halberg, N. H.; Burling, K.; Soos, M. A.; Schraw, T.; Luan, J.; Cochran, E. K.; Dunger, D. B.; Wareham, N. J.; Scherer, P. E.; Gorden, P.; O'Rahilly, S. (2007) Paradoxical elevation of high molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies Diabetes, 56 ,1712-7 [Journal Article] Online
Abstract: Objective: Total plasma adiponectin and high molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. However we have recently reported paradoxical hyperadiponectinemia in patients with severe insulin resistance due to genetically defective insulin receptors. This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance, or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction, and to refine the previous observations by determining adiponectin complex distribution. Research Design and Methods: Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or of undefined cause. Results: Despite extreme insulin resistance, patients with type B insulin resistance (all female; mean age 42 years (range 12-54)) had dramatically elevated total plasma adiponectin compared to the general population (mean 43.0 mg/l (range 31.3-54.2) vs mean 8.9 mg/l (range 1.5-28.5 for B.M.I.<25 kg/m2)), which was accounted for largely by HMW polymers. Hyperadiponectinaemia resolved in parallel with reduction of insulin receptor antibodies and clinical resolution of insulin resistance. Conclusions: While the well established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated.
PubMed Accession Number :: 17325257.

Wainwright, N. W.; Surtees, P. G.; Wareham, N. J.; Harrison, B. D. (2007) Psychosocial factors and asthma in a community sample of older adults J Psychosom Res, 62 (3),357-61 [Journal Article] Online
Abstract: OBJECTIVE: The objective of this study was to investigate the associations between psychosocial factors and asthma in a population-based cohort study of older adults. METHODS: A total of 20,888 participants in the Norfolk cohort of the European Prospective Investigation into Cancer study completed assessments that included details of lifetime self-reported doctor-diagnosed asthma, mood disorder history, social adversity experience, and social support. RESULTS: Doctor-diagnosed asthma was reported by 1699 (8.1%) participants. After adjusting for age, sex, preexisting myocardial infarction, stroke, diabetes, cancer, cigarette smoking, social class, and area deprivation, the psychosocial factors most strongly (and independently) associated with asthma were major depressive disorder (P=.0001), adverse childhood circumstances (P=.005), reported impact of life events experienced in adulthood (P=.003), long-term difficulties in adulthood (P=.04), and negative aspects of confidant support (P=.002). CONCLUSION: These results demonstrate that adverse psychosocial factors cluster among older adults with asthma. These findings may have implications for guiding improvements in asthma management.
PubMed Accession Number :: 17324687.

Stamatakis, E.; Ekelund, U.; Wareham, N. J. (2007) Temporal trends in physical activity in England: The Health Survey for England 1991 to 2004 Prev Med, 45 ,416-23 [Journal Article] Online
Abstract: OBJECTIVES.: Physical activity is an established risk factor for chronic disease but very little is known about its temporal trends in England. Such information is crucial for planning public health interventions. METHODS.: We explored temporal trends in occupational activity, walking, domestic activity, and sports using Health Survey for England data in 95,342 adults aged 16 and over. Data were collected annually in 1991-4, 1997-9, and 2003-04. Multivariate logistic regression and multiple linear regression models assessed trends in physical activity for dichotomous and continuous outcomes, respectively. Analyses were adjusted for age and social class. RESULTS.: Physical activity levels at work declined over time but there was a consistent and significant upward trend in regular sports participation among all age groups. Changes in questions in 1997 and 1999 confounded trends in walking and heavy domestic activity and total physical activity. Between 1999 and 2004 (when physical activity questions remained unchanged), there were significant increases in average time spent in all activity types and the percentage of adults meeting the current physical activity recommendations. These short-term increases were more marked among adults aged 35 to 64. CONCLUSION.: The common perception that overall physical activity levels are declining may be over-simplistic as despite the decreases in occupational physical activity, there is a clear upward trend in sports participation. Changes in the measuring methodology over time preclude the presentation of a clear picture of the total temporal trends in physical activity in England.
PubMed Accession Number :: 17316777.

Wareham, N. (2007) Physical activity and obesity prevention Obes Rev, 8 Suppl 1 ,109-14 [Journal Article] Online
PubMed Accession Number :: 17316312.

Mallat, Z.; Simon, T.; Benessiano, J.; Ederhy, S.; Sebella-Arguelles, C.; Cohen, A.; Huart, V.; Wareham, N. J.; Luben, R.; Khaw, K. T.; Tedgui, A.; Boekholdt, S. M. (2007) Circulating Secretory Phospholipase A2 Activity and Risk of Incident Coronary Events in Healthy Men and Women. The EPIC-NORFOLK Study Arterioscler Thromb Vasc Biol, 27 ,1177-83 [Journal Article] Online
Abstract: OBJECTIVE: To assess the association between secretory phospholipase A2 (sPLA2) activity, which encompasses several types of sPLA2, and cardiovascular disease (CAD) in healthy individuals. METHODS AND RESULTS: We investigated this association in a nested case-control study among the 25 663 participants in EPIC-Norfolk cohort. Cases (n=991) were subjects in whom CAD developed during the 6 years of mean follow-up. Controls (n=1806) matched by age, sex, and enrollment time remained free of any CAD during follow-up. The risk of incident CAD was associated with increasing quartiles of sPLA2 activity (P<0.001). After adjustment for risk factors, C-reactive protein and sPLA2 type IIA concentration, the odds ratios of incident CAD in the second, third, and fourth quartiles of sPLA2 activity were 1.41, 1.33, and 1.56 (P=0.003), compared with the lowest quartile. sPLA2 activity and CRP were poorly correlated (r=0.15), and their combined values were more informative for incident risk of CAD than either biomarker alone. Subjects in the highest quartiles of sPLA2 activity and CRP had an adjusted odds ratio of 2.89 (95% confidence interval, 1.78 to 4.68; P<0.001) for CAD compared with those with the lowest quartiles of both markers. CONCLUSIONS: Measurement of serum sPLA2 activity provides additive prognostic value to traditional risk factors, C-reactive protein concentrations, and identifies a subgroup of individuals at high risk for incident CAD. Measurement of sPLA2 type II concentration had little added prognostic utility.
PubMed Accession Number :: 17303774.

Danesh, J.; Saracci, R.; Berglund, G.; Feskens, E.; Overvad, K.; Panico, S.; Thompson, S.; Fournier, A.; Clavel-Chapelon, F.; Canonico, M.; Kaaks, R.; Linseisen, J.; Boeing, H.; Pischon, T.; Weikert, C.; Olsen, A.; Tjonneland, A.; Johnsen, S. P.; Jensen, M. K.; Quiros, J. R.; Svatetz, C. A.; Perez, M. J.; Larranaga, N.; Sanchez, C. N.; Iribas, C. M.; Bingham, S.; Khaw, K. T.; Wareham, N.; Key, T.; Roddam, A.; Trichopoulou, A.; Benetou, V.; Trichopoulos, D.; Masala, G.; Sieri, S.; Tumino, R.; Sacerdote, C.; Mattiello, A.; Verschuren, W. M.; Bueno-de-Mesquita, H. B.; Grobbee, D. E.; van der Schouw, Y. T.; Melander, O.; Hallmans, G.; Wennberg, P.; Lund, E.; Kumle, M.; Skeie, G.; Ferrari, P.; Slimani, N.; Norat, T.; Riboli, E. (2007) EPIC-Heart: The cardiovascular component of a prospective study of nutritional, lifestyle and biological factors in 520,000 middle-aged participants from 10 European countries Eur J Epidemiol, 22 (2),129-41 [Journal Article] Online
Abstract: EPIC-Heart is the cardiovascular component of the European Prospective Investigation into Cancer and Nutrition (EPIC), a multi-centre prospective cohort study investigating the relationship between nutrition and major chronic disease outcomes. Its objective is to advance understanding about the separate and combined influences of lifestyle (especially dietary), environmental, metabolic and genetic factors in the development of cardiovascular diseases by making best possible use of the unusually informative database and biological samples in EPIC. Between 1992 and 2000, 519,978 participants (366,521 women and 153,457 men, mostly aged 35-70 years) in 23 centres in 10 European countries commenced follow-up for cause- specific mortality, cancer incidence and major cardiovascular morbidity. Dietary information was collected with quantitative questionnaires or semi-quantitative food frequency questionnaires, including a 24-h dietary recall sub-study to help calibrate the dietary measurements. Information was collected on physical activity, tobacco smoking, alcohol consumption, occupational history, socio-economic status, and history of previous illnesses. Anthropometric measurements and blood pressure recordings were made in the majority of participants. Blood samples were taken from 385,747 individuals, from which plasma, serum, red cells, and buffy coat fractions were separated and aliquoted for long-term storage. By 2004, an estimated 10,000 incident fatal and non-fatal coronary and stroke events had been recorded. The first cycle of EPIC-Heart analyses will assess associations of coronary mortality with several prominent dietary hypotheses and with established cardiovascular risk factors. Subsequent analyses will extend this approach to non-fatal cardiovascular outcomes and to further dietary, biochemical and genetic factors.
PubMed Accession Number :: 17295097.

Parsian, A. J.; Racette, B. A.; Zhao, J. H.; Sinha, R.; Patra, B.; Perlmutter, J. S.; Parsian, A. (2007) Association of alpha-synuclein gene haplotypes with Parkinson's disease Parkinsonism Relat Disord, 13 ,343-7 [Journal Article] Online
Abstract: In a previous study, we detected an association between a dinucleotide repeat (Rep1) in the alpha-Synuclein (SNCA) gene and sporadic Parkinson's disease (PD). To extend our previous finding in a larger sample and further determine the role of SNCA in the development of PD, we screened a sample of 194 familial PD (FPD), 327 sporadic PD (SPD), and 215 controls with the Rep1 marker and 2 single nucleotide polymorphisms (SNPs) (770 and int4) in the SNCA gene. There was significant difference in allele frequency between African American and American Indian groups for Rep1 marker (p=0.03). These two samples were excluded from further analysis because of sample size. Comparison of allele frequency differences between PD and controls for the single-locus was significant only for Rep1 and SPD (p=0.017). The global case control association was highly significant for the three loci haplotypes comparisons. Our results indicate that Rep1 locus may be in linkage disequilibrium (LD) with a mutation in the gene or itself could be a risk factor for SPD.
PubMed Accession Number :: 17292657.

Anyama, N.; Bracebridge, S.; Black, C.; Niggebrugge, A.; Griffin, S. J. (2007) What happens to people diagnosed with tuberculosis? A population-based cohort Epidemiol Infect, 135 (7),1069-76 [Journal Article] Online
Abstract: We examined different patient outcomes following diagnosis of tuberculosis (TB). Incident cases were reported to the enhanced surveillance system in the East of England, between 2000 and 2003. For the 575 cases reported in 2001 and 2002, outcomes were assessed 1 year after initiating treatment. The crude clinical incidence rate of TB was 6.0 cases/100000 person-years (pyr) [95% confidence interval (CI) 5.7-6.4], highest in the 25-29 years age group (14.9, 95% CI 12.9-17.1 cases/100000 pyr) and among Black Africans (328.6, 95% CI 286.9-374.6 cases/100000 pyr). Patients born abroad were 2.35 (95% CI 1.03-5.32) times more likely to be lost to follow-up than those born in the United Kingdom. Age at diagnosis (OR 1.05, 95% CI 1.04-1.07) and pulmonary disease (OR 2.73, 95% CI 1.21-6.15) were independently associated with mortality. Elderly patients and those with pulmonary TB appear to have worse outcomes despite treatment. Foreign-born patients may need closer follow-up to ensure favourable outcomes.
PubMed Accession Number :: 17288641.

El Harchaoui, K.; van der Steeg, W. A.; Stroes, E. S.; Kuivenhoven, J. A.; Otvos, J. D.; Wareham, N. J.; Hutten, B. A.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2007) Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study J Am Coll Cardiol, 49 (5),547-53 [Journal Article] Online
Abstract: OBJECTIVES: We assessed relations of low-density lipoprotein (LDL) particle number (LDL-P) and LDL particle size as measured by nuclear magnetic resonance spectroscopy with LDL cholesterol (LDL-C) and the risk of future coronary artery disease (CAD). BACKGROUND: Whereas LDL-C is an established risk factor for CAD, its discriminative power is limited. Measuring LDL-P and size may have stronger associations with CAD than LDL-C. METHODS: A nested case-control study was performed in the prospective EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study, which comprises 25,663 subjects. Cases (n = 1,003) were individuals who developed CAD during 6 year follow-up. Control subjects (n = 1,885) were matched for age, gender, and enrollment time. Odds ratios (ORs) for future CAD were calculated, and we also evaluated whether LDL-P could improve the Framingham risk score (FRS) to predict CAD. RESULTS: In univariate analyses, LDL-P (OR 2.00, 95% confidence interval [CI] 1.58 to 2.59) and non-high-density lipoprotein cholesterol (non-HDL-C) (OR 2.14, 95% CI 1.69 to 2.69) were more closely associated with CAD than LDL-C (OR 1.73, 95% CI 1.37 to 2.18). The additional value of LDL-P was lost after adjustment for HDL-C and triglyceride levels. Whereas LDL size was inversely related to CAD (OR 0.60, 95% CI 0.47 to 0.76), this relation was abolished upon adjustment for LDL-P. In a model adjusted for the FRS, LDL-P retained its association with CAD (p for trend 0.02). CONCLUSIONS: In this large study of individuals with moderately elevated LDL-C, LDL-P was related to CAD on top of FRS as well as after adjusting for LDL-C. The additional value of LDL-P was comparable to non-HDL-C, and it was abolished after adjusting for triglycerides and HDL-C.
PubMed Accession Number :: 17276177.

Ekelund, U.; Griffin, S. J.; Wareham, N. J. (2007) Physical activity and metabolic risk in individuals with a family history of type 2 diabetes Diabetes Care, 30 (2),337-42 [Journal Article] Online
Abstract: OBJECTIVE: We sought to examine the independent associations between different dimensions of physical activity with intermediary and clustered metabolic risk factors in overweight individuals with an increased risk of type 2 diabetes to inform future preventive action. RESEARCH DESIGN AND METHODS: We measured total body movement and five other subcomponents of physical activity by accelerometry in 258 adults (aged 30-50 years) with a family history of type 2 diabetes. We estimated aerobic fitness from an incremental treadmill exercise test. We measured body composition by bioimpedance and waist circumference, blood pressure, fasting triglycerides, HDL cholesterol, glucose, and insulin with standard methods. We constructed a standardized continuously distributed variable for clustered risk. RESULTS: Total body movement (counts . day(-1)) was significantly and independently associated with three of six risk factors (fasting triglycerides, insulin, and HDL) and with clustered metabolic risk (P = 0.004) after adjustment for age, sex, and obesity. Time spent at moderate- and vigorous-intensity physical activity (MPVA) was independently associated with clustered metabolic risk (P = 0.03). Five- and 10-min bouts of MVPA, time spent sedentary, time spent at light-intensity activity, and aerobic fitness were not significantly related with clustered risk after adjustment for confounding factors. CONCLUSIONS: Total body movement is associated with intermediary phenotypic risk factors for cardiovascular disease and metabolic disease and with clustered metabolic risk independent of aerobic fitness and obesity. Increasing the total amount of physical activity in sedentary and overweight individuals may have beneficial effects on metabolic risk factors.
PubMed Accession Number :: 17259504.

Forouhi, N. G.; Luan, J.; Hennings, S.; Wareham, N. J. (2007) Incidence of Type 2 diabetes in England and its association with baseline impaired fasting glucose: The Ely study 1990-2000 Diabet Med, 24 (2),200-7 [Journal Article] Online
Abstract: Aim To determine the incidence of Type 2 diabetes and to examine the effect of different cut-points for impaired fasting glucose (IFG) on diabetes incidence. Methods Population-based longitudinal study (1990-2000) with clinical, anthropometric and biochemical measurements, including an oral glucose tolerance test (OGTT), in 1040 non-diabetic adults aged 40-69 years at baseline. Baseline glucose status was defined as normoglycaemia < 5.6, IFG-lower 5.6-6.0 and IFG-original 6.1-6.9 mmol/l. The all-IFG group included fasting glucose values of 5.6-6.9 mmol/l. Results The 10-year cumulative incidence of diabetes was 7.3 per 1000 person-years. Diabetes incidence was 2.4 [95% confidence interval (CI) 1.2, 4.8], 6.2 (4.0, 9.8) and 17.5 (12.5, 24.5) per 1000 person-years in those with normoglycaemia, IFG-lower and IFG-original, respectively. Compared with normoglycaemia, the age/sex-adjusted risk [hazard ratio (HR) and 95% CI] for incident diabetes was greatest in the IFG-original category (HR 6.9; 3.1, 15.2) and increased to a lesser degree in the IFG-lower (HR 2.5; 1.1, 5.7) and all-IFG categories (HR 4.1; 1.9, 8.7). When adjusted for confounding factors, the magnitude and direction of associations persisted, with HR 1.9, 4.4 and 2.9, for the categories IFG-lower, IFG-original and all-IFG, respectively. Conclusions Diabetes incidence is more strongly related to IFG defined as fasting glucose between 6.1 and 6.9 mmol/l than to the lower category of 5.6-6.0 mmol/l, or entire range of 5.6-6.9 mmol/l. Future studies should examine the association of IFG with cardiovascular outcomes, but for diabetes risk our study supports the use of the IFG cut-point at 6.1 mmol/l. Diabet. Med. 24, 200 -207 (2007).
PubMed Accession Number :: 17257284.

Franks, P. W.; Loos, R. J.; Brage, S.; O'Rahilly, S.; Wareham, N. J.; Ekelund, U. (2007) Physical activity energy expenditure may mediate the relationship between plasma leptin levels and worsening insulin resistance independently of adiposity J Appl Physiol, 102 (5),1921-6 [Journal Article] Online
Abstract: Background: Leptin regulates a constellation of neuroendocrine processes that control energy homeostasis. The infusion of leptin in rodents lacking endogenous leptin promotes physical activity energy expenditure (PAEE) and improves insulin signalling, whereas hyperleptinemia is associated with physical inactivity and insulin resistance (IR). Methods & Results: We tested whether baseline leptin levels predict changes in PAEE and IR over time, independently of obesity. We also assessed whether the relationship between leptin and change in IR is mediated by PAEE. The population consisted of 288 non-diabetic UK Caucasian adults (mean age: 49.4 SD: 0.7 yrs), in whom leptin, insulin, glucose, PAEE (via HR monitoring with individual calibration by indirect calorimetry), and anthropometric characteristics had been measured at baseline and 5yrs later. In linear regression models, baseline leptin levels inversely predicted follow-up PAEE (p=0.033). On average, individuals with low leptin levels (below sex-specific median) increased their daily activity 35% more during the 5yr follow-up period than those with above median leptin levels. Baseline leptin level also predicted worsening IR (fasting, 30-min and 2hr insulins, and HOMA-IR: all p<0.01). Associations were independent of potential confounders such as adiposity, age and sex. Including baseline PAEE as a cofactor in the leptin-insulin models reduced the strength (1-4% reduction) and significance of the associations, suggesting that PAEE mediates the leptin-insulin relationships. Conclusions: Hyperleptinemia predicts a relative decline in PAEE and worsening insulin resistance, possibly via shared molecular pathways. Key words: Leptin, Physical activity, Insulin resistance, Adiposity, Epidemiology.
PubMed Accession Number :: 17234803.

Loos, R. J.; Barroso, I.; O'Rahilly, S.; Wareham, N. J. (2007) Comment on "A common genetic variant is associated with adult and childhood obesity" Science, 315 (5809),187; author reply 187 [Journal Article] Online
Abstract: Herbert et al. (Reports, 14 April 2006, p. 279) found that the rs7566605 genetic variant, located upstream of the INSIG2 gene, was consistently associated with increased body mass index. However, we found no evidence of association between rs7566605 and body mass index in two large ethnically homogeneous population-based cohorts. On the contrary, an opposite tendency was observed.
PubMed Accession Number :: 17218509.

Collins, S. C.; Luan, J.; Thompson, A. J.; Daly, A.; Semple, R. K.; O'Rahilly, S.; Wareham, N. J.; Barroso, I. (2007) Adiponectin receptor genes: mutation screening in syndromes of insulin resistance and association studies for type 2 diabetes and metabolic traits in UK populations Diabetologia, 50 (3),555-62 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic properties. Several reports suggest that genetic variants in the adiponectin gene are associated with circulating levels of adiponectin, insulin sensitivity and type 2 diabetes risk. Recently two receptors for adiponectin have been cloned. Genetic studies have yielded conflicting results on the role of these genes and type 2 diabetes predisposition. In this study we aimed to evaluate the potential role of genetic variation in these genes in syndromes of severe insulin resistance, type 2 diabetes and in related metabolic traits in UK Europid populations. MATERIALS AND METHODS: Exons and splice junctions of the adiponectin receptor 1 and 2 genes (ADIPOR1; ADIPOR2) were sequenced in patients from our severe insulin resistance cohort (n=129). Subsequently, 24 polymorphisms were tested for association with type 2 diabetes in population-based type 2 diabetes case-control studies (n=2,127) and with quantitative traits in a population-based longitudinal study (n=1,721). RESULTS: No missense or nonsense mutations in ADIPOR1 and ADIPOR2 were detected in the cohort of patients with severe insulin resistance. None of the 24 polymorphisms (allele frequency 2.3-48.3%) tested was associated with type 2 diabetes in the case-control study. Similarly, none of the polymorphisms was associated with fasting plasma insulin, fasting and 2-h post-load plasma glucose, 30-min insulin increment or BMI. CONCLUSIONS/INTERPRETATION: Genetic variation in ADIPOR1 and ADIPOR2 is not a major cause of extreme insulin resistance in humans, nor does it contribute in a significant manner to type 2 diabetes risk and related traits in UK Europid populations.
PubMed Accession Number :: 17216283.

Franks, P. W.; Ekelund, U.; Brage, S.; Luan, J.; Schafer, A. J.; O'Rahilly, S.; Barroso, I.; Wareham, N. J. (2007) PPARGC1A coding variation may initiate impaired NEFA clearance during glucose challenge Diabetologia, 50 (3),569-73 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein, encoded by the PPARGC1A gene, transcriptionally activates a complex pathway of lipid and glucose metabolism and is expressed primarily in tissues of high metabolic activity such as liver, heart and exercising oxidative skeletal muscle fibre. Ppargc1a-null mice develop systemic dyslipidaemia and hepatic steatosis. In humans, NEFAs downregulate PPARGC1A expression in skeletal muscle. Furthermore, a common non-synonymous coding variant at PPARGC1A (Gly482Ser, rs8192678) is associated with decreased PPARGC1A mRNA levels and increased type 2 diabetes risk. MATERIALS AND METHODS: In a population-based sample of 691 healthy middle-aged Europids we assessed whether Gly482Ser is associated with levels of NEFA when fasting and in response to an oral glucose challenge. We also assessed the potential effect-modifying role of adipose tissue mass on these phenotypes. RESULTS: After adjustment for age, sex, fat mass and fat-free mass, the Ser482 allele associated with higher NEFA at 30 min and 2 h and with NEFA AUC (all values p </= 0.02). Furthermore, suggestive evidence of interaction between fat mass and Gly482Ser was observed for fasting NEFA (p = 0.059). After stratification by level of obesity, genotype associations were observed in the obese for fasting NEFA (p = 0.028) and NEFA at 30 min (p = 0.013) and 2 h (p = 0.002), and with NEFA AUC (p = 0.005), but no significant associations were observed in lean individuals (all values p > 0.6). CONCLUSIONS/INTERPRETATION: Our observations indicate that NEFA clearance is blunted following a glucose load in carriers of the PPARCG1A Ser482 allele. This association is augmented by obesity.
PubMed Accession Number :: 17216277.

Myint, P. K.; Welch, A.A.; Bingham, S.A.; Surtees, P. G.; Wainwright, N. W.J.; Luben, R.N.; Wareham, N.J.; Smith, R. D.; Harvey, I. M.; Day, N.E.; Khaw, K. T. (2007) Fruit and vegetable consumption and self-reported functional health in men and women in the European Prospective Investigation into Cancer - Norfolk (EPIC-Norfolk): a population-based cross-sectional study Public Health Nutr, 10 (1),34-41 [Journal Article]
PubMed Accession Number :: 17212840 .

Myint, P. K.; Sinha, S.; Wareham, N. J.; Bingham, S. A.; Luben, R. N.; Welch, A. A.; Khaw, K. T. (2007) Glycated Hemoglobin and Risk of Stroke in People Without Known Diabetes in the European Prospective Investigation Into Cancer (EPIC)-Norfolk Prospective Population Study. A Threshold Relationship? Stroke, 38 ,271-5 [Journal Article] Online
Abstract: BACKGROUND AND PURPOSE: Diabetes is a well-recognized risk factor for cardiovascular diseases. Evidence suggests a linear relationship between blood glucose and myocardial infarction, even at blood glucose concentrations below the threshold for diabetes. The relationship between blood glucose concentration and stroke in people without established diabetes has been studied less extensively. METHODS: We examined the prospective relationship between usual blood glucose level measured by glycohemoglobin (HbA1c) concentrations and incident stroke risk in a general population without diabetes and stroke at baseline assessment in the European Prospective Investigation Into Cancer (EPIC)-Norfolk. RESULTS: A total of 10 489 men and women aged 40 to 79 years at baseline were followed up (mean=8.5 years). Mean age, systolic and diastolic blood pressure, body mass index, total cholesterol, triglycerides, and proportion of current smokers increased and mean high-density lipoprotein cholesterol decreased with increasing HbA1c concentrations. There were 164 incident strokes identified over 88 652 person-years. After adjustment for age, sex, and cardiovascular risk factors, the relative risks (95% CI) for stroke for participants with HbA1c concentrations 5% to 5.4%, 5.5% to 6.9%, and >/=7% were 0.78 (0.50 to 1.22), 0.83 (0.54 to 1.27), and 2.83 (1.40 to 5.74), respectively, compared with those with HbA1c <5%. CONCLUSIONS: In contrast to the continuous linear relationship observed between blood glucose level and coronary heart disease risk, the association between blood glucose level and stroke risk appears to be more consistent with a threshold relationship. These observations may give insights into the differing pathogenesis of different vascular diseases.
PubMed Accession Number :: 17204684.

Sarwar, N.; Danesh, J.; Eiriksdottir, G.; Sigurdsson, G.; Wareham, N.; Bingham, S.; Boekholdt, S. M.; Khaw, K. T.; Gudnason, V. (2007) Triglycerides and the Risk of Coronary Heart Disease. 10 158 Incident Cases Among 262 525 Participants in 29 Western Prospective Studies Circulation, 115 (4),450-8 [Journal Article] Online
Abstract: BACKGROUND: Many epidemiological studies have reported on associations between serum triglyceride concentrations and the risk of coronary heart disease, but this association has not been reliably quantified. In the present study, we report 2 separate nested case-control comparisons in 2 different prospective, population-based cohorts, plus an updated meta-analysis of 27 additional prospective studies in general Western populations. METHODS AND RESULTS: Measurements were made in a total of 3582 incident cases of fatal and nonfatal coronary heart disease and 6175 controls selected from among the 44 237 men and women screened in the Reykjavik and the European Prospective Investigation of Cancer (EPIC)-Norfolk studies. Repeat measurements were obtained an average of 4 years apart in 1933 participants in the EPIC-Norfolk Study and an average of 12 years apart in 379 participants in the Reykjavik study. The long-term stability of log-triglyceride values (within-person correlation coefficients of 0.64 [95% CI, 0.60 to 0.68] over 4 years and 0.63 [95% CI, 0.57 to 0.70] over 12 years) was similar to those of blood pressure and total serum cholesterol. After adjustment for baseline values of several established risk factors, the strength of the association was substantially attenuated, and the adjusted odds ratio for coronary heart disease was 1.76 (95% CI, 1.39 to 2.21) in the Reykjavik study and 1.57 (95% CI, 1.10 to 2.24) in the EPIC-Norfolk study in a comparison of individuals in the top third with those in the bottom third of usual log-triglyceride values. Similar overall findings (adjusted odds ratio, 1.72; 95% CI, 1.56 to 1.90) were observed in an updated meta-analysis involving a total of 10 158 incident coronary heart disease cases from 262 525 participants in 29 studies. CONCLUSIONS: Available prospective studies in Western populations consistently indicate moderate and highly significant associations between triglyceride values and coronary heart disease risk. Because these associations depend considerably on levels of established risk factors, however, further studies are needed to help assess the nature of any independent associations.
PubMed Accession Number :: 17190864.

Seminara, D.; Khoury, M. J.; O'Brien, T. R.; Manolio, T.; Gwinn, M. L.; Little, J.; Higgins, J. P.; Bernstein, J. L.; Boffetta, P.; Bondy, M.; Bray, M. S.; Brenchley, P. E.; Buffler, P. A.; Casas, J. P.; Chokkalingam, A. P.; Danesh, J.; Davey Smith, G.; Dolan, S.; Duncan, R.; Gruis, N. A.; Hashibe, M.; Hunter, D.; Jarvelin, M. R.; Malmer, B.; Maraganore, D. M.; Newton-Bishop, J. A.; Riboli, E.; Salanti, G.; Taioli, E.; Timpson, N.; Uitterlinden, A. G.; Vineis, P.; Wareham, N.; Winn, D. M.; Zimmern, R.; Ioannidis, J. P. (2007) The emergence of networks in human genome epidemiology: challenges and opportunities Epidemiology, 18 (1),1-8 [Journal Article] Online
PubMed Accession Number :: 17179752.

Kaptoge, S.; Jakes, R. W.; Dalzell, N.; Wareham, N.; Khaw, K. T.; Loveridge, N.; Beck, T. J.; Reeve, J. (2007) Effects of physical activity on evolution of proximal femur structure in a younger elderly population Bone, 40 ,506-15 [Journal Article] Online
Abstract: INTRODUCTION:: For a fixed weight, a wider bone of standardised length is stiffer. But moving the cortices away from the centre of mass risks creating structural (elastic) instability, and hip fractures have been postulated to occur as a consequence of buckling of the thinned supero-lateral femoral neck cortex during a fall. We hypothesised that stereotyped physical activity (e.g., walking) may help conserve bending resistance (section modulus, Z) through redistribution of bone tissue, but it might be at the expense of supero-lateral cortical stability. METHODS:: Hip structural analysis (HSA) software applied to DXA scans was used to derive measurements of section modulus and distances of a cross-section's centre of mass from the supero-lateral cortical margin (lateral distance, in cm). DXA scans were obtained on 1361 men and women in the EPIC-Norfolk population-based prospective cohort study. Up to 4 repeat DXA scans were done in 8 years of follow-up. Weight, height and activities of daily living were assessed on each occasion. A detailed physical activity and lifestyle questionnaire was administered at baseline. The lateral distance was measured on three narrow cross-sections with good precision: narrow neck (NN, coefficient of variation 2.6%), intertrochanter (IT) and shaft (S). A linear mixed model was used to assess associations with predictors. RESULTS:: Ageing was associated with medial shifting of the centre of mass, so that lateral distance increased. Both greater weight and height were associated with greater lateral distance (P<0.0001). Among physical activity-related variables, walking/cycling for >1 h/day (P=0.025), weekly time spent on moderate impact activity (P=0.003), forced expiratory volume in 1 s (NN and IT, P<0.026) and lifetime physical activity (IT, P<0.0001) were associated with higher lateral distance. However, after adjusting for these variables, activities of daily living scores (NN, P<0.0001) and weekly time spent on low impact hip flexing activities were associated with shorter lateral distance (P=0.001). Greater baseline lateral distance was significantly associated with increased risk of subsequent hip fracture (n=26) in females (P<0.05, all regions) independently of age, height and bone mineral content. CONCLUSION:: The age-related shift medially of the centre of mass of the femoral neck and trochanter may have adverse effects on fracture resistance in the event of a fall, so compromising the beneficial effects of walking on fitness, strength and risk of falling. The role of more diverse physical activity patterns in old age that impose loading on the supero-lateral cortex of the femur, involving for example hip flexion and stretching, needs investigation for their ability to correct this medial shifting of the centre of mass.
PubMed Accession Number :: 17098489.

Pinedo, S.; Vissers, M. N.; Bergmann, K.; Elharchaoui, K.; Lutjohann, D.; Luben, R.; Wareham, N. J.; Kastelein, J. J.; Khaw, K. T.; Boekholdt, S. M. (2007) Plasma levels of plant sterols and the risk of coronary artery disease: the prospective EPIC-Norfolk Population Study J Lipid Res, 48 (1),139-44 [Journal Article] Online
Abstract: Some studies have suggested that a modest increase of plant sterol levels is a risk factor for coronary artery disease (CAD). We studied the relationship between plant sterol levels and CAD risk in a prospective nested case-control study consisting of 373 cases and 758 controls. Sitosterol and campesterol concentrations did not differ between cases and controls [sitosterol, 0.21 vs. 0.21 mg/dl (P = 0.1); campesterol, 0.31 vs. 0.32 mg/dl (P = 0.5)]. The sitosterol-to-cholesterol ratio was significantly lower in cases than in controls (1.19 vs. 1.29 mug/mg; P = 0.008), whereas the campesterol-to-cholesterol ratio did not differ significantly (1.78 vs. 1.88 mug/mg; P = 0.1). Plant sterol concentrations correlated positively with cholesterol levels and inversely with body mass index and triglyceride and lathosterol concentrations. Among individuals in the highest tertile of the sitosterol concentration, the unadjusted odds ratio (OR) for future CAD was 0.75 [95% confidence interval (CI) = 0.56-1.01]. After adjustment for traditional risk factors, the OR was 0.79 (95% CI = 0.56-1.13). For the campesterol concentration, the unadjusted OR was 0.95 (95% CI = 0.71-1.29) and the adjusted OR was 0.97 (95% CI = 0.68-1.39). In this large prospective study, higher levels of plant sterols, at least in the physiological range, do not appear to be adversely related to CAD in apparently healthy individuals.
PubMed Accession Number :: 17074925.

Myint, P. K.; Surtees, P. G.; Wainwright, N. W.; Wareham, N. J.; Bingham, S. A.; Luben, R. N.; Welch, A. A.; Smith, R. D.; Harvey, I. M.; Khaw, K. T. (2007) Modifiable lifestyle behaviors and functional health in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study Prev Med, 44 ,109-116 [Journal Article] Online
Abstract: OBJECTIVE.: To examine the association between modifiable lifestyle behaviors and functional health. METHOD.: Population-based cross-sectional study in 16,678 men and women aged 40-79 years at baseline in 1993-1997 participating in the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. RESULTS.: Smoking and physical inactivity were associated with poorer physical functional health, equivalent to being 7 years and 10-13 years older, respectively, and poorer mental functional health compared to non-smoking or being physically active. After adjusting for age, body mass index, social class, education, prevalent illness, and other lifestyles; men and women who currently smoke were more likely to report poor physical functional health compared to non-smokers {Odds Ratio (OR)=1.85 (95% confidence interval (CI): 1.49, 2.30) and 1.56 (1.30, 1.87)} and poor mental functional health {1.38 (1.12, 1.70); 1.77 (1.51, 2.07)}, respectively. The OR for good physical function in those who were physically active compared to inactive was 1.67 (1.41, 1.97) in men and 1.63 (1.39, 1.91) in women. Moderate alcohol consumption was positively associated with good physical and mental functional health. CONCLUSION.: Modifiable behavioral factors are associated with substantial differences in the observed age-related decline in physical functional health and the prevalence of those in good and poor functional health in the community.
PubMed Accession Number :: 17069879.

Ekelund, U.; Ong, K. K.; Linne, Y.; Neovius, M.; Brage, S.; Dunger, D. B.; Wareham, N. J.; Rossner, S. (2007) Association of weight gain in infancy and early childhood with metabolic risk in young adults J Clin Endocrinol Metab, 92 (1),98-103 [Journal Article] Online
Abstract: Context: Early postnatal life has been suggested as an important window during which risks for long-term health may be influenced. Objective: The aim of this study was to examine the independent associations between weight gain during infancy (0-6 months) and early childhood (3-6 yr) with components of the metabolic syndrome in young adults. Design: This was a prospective cohort study (The Stockholm Weight Development Study). Setting: The study was conducted in a general community. Participants: Subjects included 128 (54 males) singletons, followed from birth to 17 yr. Main Outcome Measure: None of these young adults met the full criteria for the metabolic syndrome. We therefore calculated a continuous clustered metabolic risk score by averaging the standardized values of the following components: waist circumference, blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, glucose, and insulin level. Results: Clustered metabolic risk at age 17 yr was predicted by weight gain during infancy (standardized beta = 0.16; P < 0.0001) but not during early childhood (standardized beta = 0.10; P = 0.23), adjusted for birth weight, gestational age, current height, maternal fat mass, and socioeconomic status at age 17 yr. Further adjustment for current fat mass and weight gain during childhood did not alter the significant association between infancy weight gain with the metabolic risk score (standardized beta = 0.20; P = 0.007). Conclusions: Rapid weight gain during infancy (0-6 months) but not during early childhood (3-6 yr) predicted clustered metabolic risk at age 17 yr. Early interventions to moderate rapid weight gain even at very young ages may help to reduce adult cardiovascular disease risks.
PubMed Accession Number :: 17032722.

Franks, P. W.; Mesa, J. L.; Harding, A. H.; Wareham, N. J. (2007) Gene-lifestyle interaction on risk of type 2 diabetes Nutr Metab Cardiovasc Dis, 17 ,104-124 [Journal Article] Online
Abstract: The descriptive epidemiology of type 2 diabetes suggests that gene-lifestyle interactions are critical to the development of the condition. However, unravelling the molecular detail of these interactions is a complex task. The existing literature is based on small intervention studies or cross-sectional observational quantitative trait studies. Our systematic review of the literature identified some evidence of interactions, most notably for a common variant in the PPAR-gamma gene which appears to interact with the nature of dietary fat intake. Other interactions have been reported for adrenoceptors, uncoupling proteins, fatty acid binding proteins, apolipoproteins and lipoprotein lipase. There are, to date, no reports based on the ideal study design which is a case-control study nested within a cohort. To limit the likelihood of false discovery, such studies would need to be large and the search for interaction should be restricted to a priori biologically driven hypotheses. Additional study designs that examine differential response to lifestyle change or test interaction in the context of quantitative trait studies would complement the nested case-control approach, but the emphasis here should be on precision of measurement of both phenotype and lifestyle behaviour.
PubMed Accession Number :: 17011759.

Hemmingsson, E.; Ekelund, U. (2007) Is the association between physical activity and body mass index obesity dependent? Int J Obes (Lond), 31 (4),663-8 [Journal Article] Online
Abstract: Background:Most studies indicate an inverse relationship between physical activity (PA) and body mass index (BMI). However, the impact of obesity on this relationship is unclear.Objective:To scrutinize the BMI/PA relationship by analysing multiple categories of PA from a sample with a wide BMI range.Design:PA was measured with accelerometry for 7 consecutive days during free-living conditions in 85 severely obese outpatients (mean BMI 42.7 kg/m(2) (s.d. 6.1); age 43.0 year (12.6)) and 193 control subjects (24.0 kg/m(2) (3.5); 41.6 year (13.0)). Six categories of PA were calculated from the accelerometer data (min/day of sedentary time, min/day of light PA, min/day of moderate PA, min/day of vigorous PA, activity counts/day and steps/day). Participants were stratified in obese and non-obese subgroups (BMI=30 kg/m(2) as cutoff). Associations between BMI and PA were examined in the total sample, and in subgroups. The impact of sex and age on the BMI/PA association was tested.Results:In the total sample, the association between BMI and PA was significant in all PA categories except for time spent sedentary (P=0.68). However, in subgroup analyses, the association between BMI and PA in non-obese was only significant for activity counts/day (r=-0.16, P<0.05) and vigorous intensity PA (r=-0.15, P=0.05). After adjustment for age, vigorous PA remained significantly associated with BMI in the non-obese (r=-0.17, P<0.05). In obese individuals, significant associations between BMI and PA were found for all six PA categories (age adjusted), sedentary time (r=0.26, P=0.05), light PA (r=-0.30, P<0.01), moderate PA (r=-0.35, P<0.01), vigorous PA (r=-0.39, P<0.001), activity counts/day (r=-0.50, P<0.001) and steps/day (r=-0.54, P<0.001).Conclusion:The association between PA and BMI was weak in non-obese individuals. In contrast, BMI was highly significantly associated with PA in obese individuals. Longitudinal studies are needed to tease out the direction of association between PA and BMI across BMI categories, as the cross-sectional associations seem to be dependent on obesity status.International Journal of Obesity advance online publication, 5 September 2006; doi:10.1038/sj.ijo.0803458.
PubMed Accession Number :: 16953254.

Fernandez-Twinn, D. S.; Ekizoglou, S.; Gusterson, B. A.; Luan, J.; Ozanne, S. E. (2007) Compensatory mammary growth following protein restriction during pregnancy and lactation increases early-onset mammary tumor incidence in rats Carcinogenesis, 28 ,545-52 [Journal Article] Online
Abstract: Breast cancer incidence is increased in women with both high and low birth weight. The latter is also associated with hyperglycaemia, insulin resistance and type-2 diabetes, each of which independently increases breast cancer risk. We showed previously in our model of poor early growth that pregnancy estradiol levels were raised while offspring developed type-2 diabetes. We hypothesised that nutritionally-induced poor early growth influences breast cancer risk and investigated this in our model. Wistar rat dams were given either a control diet (20% casein) or an isocaloric low-protein diet (8% casein) throughout pregnancy and lactation. Offspring postnatal mammary gland development was assessed by morphometry. To identify potential growth mechanisms, we measured protein expression of receptors involved in insulin and hormone signalling, both in cleared mammary gland lysates and isolated epithelial cells. Mammary tumor incidence and latency (n=96) was monitored after three weekly intraperitoneal nitrosomethylurea injections (50 mg/kg bodyweight). Low-protein offspring displayed reduced postnatal ductal branching and epithelial invasion at 3 weeks, followed by compensatory mammary growth 1 week later coinciding with increased protein expression of receptors to insulin, IGF-1 and estrogen. Significantly, early mammary tumor incidence (0-16 weeks post-treatment) was doubled in low-protein offspring [RR 2.13 (1.02, 4.45); p=0.046]. The data suggest that poor early nutrition has an important influence on the mammary primordium, and increases future susceptibility to breast cancer. Up-regulated growth factor and hormone signaling during compensatory mammary growth may mediate this increased susceptibility and present potential targets for intervention.
PubMed Accession Number :: 16952910.

Hung, C. C.; Luan, J.; Sims, M.; Keogh, J. M.; Hall, C.; Wareham, N. J.; O'Rahilly, S.; Farooqi, I. S. (2007) Studies of the SIM1 gene in relation to human obesity and obesity-related traits Int J Obes (Lond), 31 ,429-434 [Journal Article] Online
Abstract: Objective:The single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor, which plays a critical role in the development of the paraventricular nucleus (PVN) of the hypothalamus. SIM1-deficient mice have a hypocellular PVN and are severely obese with increased food intake.Design:We examined whether variants in the SIM1 gene might be associated with severe early-onset obesity in humans. Two hundred and seventy-seven subjects with hyperphagia and severe, early-onset obesity were screened. Association studies with common single-nucleotide polymorphisms (SNPs) in the SIM1 gene were performed in two population-based cohorts.Results:One novel missense mutation, I128T, was found in one obese subject and not in 192 controls. However, the variant did not co-segregate with obesity in the family. Four SNPs, IVS4+83GA, P352T, A371V and T653T, were also identified. The two common SNPs, P352T and A371V, which are in complete linkage disequilibrium, were genotyped in 981 subjects from a population-based cohort, the Ely Study. An allele frequency of 0.13 was observed. Male subjects carrying the P352T/A371V haplotype were found to have a slightly higher body mass index (BMI; P=0.038). Female subjects homozygous for the haplotype gained more weight over a period of 4.5 and 10 years (P=0.003 and P=0.02, respectively). The association studies were repeated in another population-based cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC) - Norfolk Study with 4869 subjects successfully genotyped. Male subjects homozygous for the P352T/A371V haplotype had slightly higher BMI (P=0.04).Conclusion:Mutations in SIM1 are not commonly found in humans with severe early-onset obesity. The relationship between the common variants in SIM1 with BMI and body weight gain deserves further exploration in other populations.International Journal of Obesity advance online publication, 22 August 2006; doi:10.1038/sj.ijo.0803443.
PubMed Accession Number :: 16924270.

Hu, S. P.; Luan, J. A.; Li, B.; Chen, J. X.; Cai, K. L.; Huang, L. Q.; Xu, X. Y. (2007) Genetic link between Chaoshan and other Chinese Han populations: Evidence from HLA-A and HLA-B allele frequency distribution Am J Phys Anthropol, 132 ,140-50 [Journal Article] Online
Abstract: The genetic polymorphism of HLA-A and HLA-B loci was investigated in 505 Chaoshanese using PCR-SSP method. Among the HLA-A alleles detected, A*11 (35.64%) was most frequent, followed by A*02 (31.78%). Of 34 HLA-B alleles tested, 30 were observed, in which B*60 (21.68%), B*46 (14.46%), and B*58 (10.69%) were highly predominant. Comparison was made with other nine Chinese Han ethnic groups covering the Mainland China, Taiwan, Hong Kong, and Singapore. The high frequent alleles found in Chaoshanese were also common in other Chinese groups compared though the frequency levels varied from group to group. The phylogenic tree analysis based on the HLA-A and -B allele frequencies of all the 10 Chinese ethnic groups revealed that Chaoshanese, while clustering in general with the southern China-related Han Chinese, had the highest affinity to the Mainland Minnanese, but separated distinctively from the northern Han Chinese. The study, however, was yet to confirm the hypothesis of the Central Plains Han origin of Chaoshanese. Interestingly, the alleles (B*46, B*38, and B*58) and the related haplotypes (A*02-B*46 and A*33-B*58) that are positively associated with nasopharyngeal carcinoma (NPC), a disease prevailing predominantly among southern Chinese, were always at much higher frequencies among southern Chinese than among northern Chinese, whereas A*31 and B*13, the two alleles with highly protective effects for NPC, and the associated haplotype A*30-B*13 were predominantly high in northern Chinese. The different genetic background between northern and southern China may explain, at least partially, the prevalence of NPC among southern Chinese. Am J Phys Anthropol, 2006. (c) 2006 Wiley-Liss, Inc.
PubMed Accession Number :: 16883565.

Ekelund, U.; Sarnblad, S.; Brage, S.; Ryberg, J.; Wareham, N. J.; Aman, J. (2007) Does physical activity equally predict gain in fat mass among obese and nonobese young adults? Int J Obes (Lond), 31 (1),65-71 [Journal Article] Online
Abstract: Background:Differences in energy metabolism and physical activity (PA) may contribute to the long-term regulation of body weight (BW).Objective:To examine the associations between metabolic determinants, energy expenditure and objectively measured components of PA with change in BW and fat mass (FM).Design:Prospective (4 years.), case-control study in obese (n=13) and normal weight (n=15) young adults.Measurements:At baseline, we measured resting metabolic rate, substrate oxidation, movement economy (ml O(2) kg(-1) min(-1)), aerobic fitness (VO(2max)), total and PA energy expenditure by doubly labelled water, and PA by accelerometry. Fat mass was measured by DXA. At follow-up we repeated our measurements of PA and FM.Results:Fat mass increased significantly (P<0.001) in both groups. Physical activity did not change between baseline and 'follow up'. Change in overall PA (counts per minute) was inversely associated with change in BW and (beta=-0.0124, P=0.054) and FM (beta=-0.008, P=0.04). Post hoc analyses suggested that this association was explained by changes in the normal weight group only (beta=-0.01; P=0.008; and beta=-0.0097; P=0.009, for BW and FM, respectively). Metabolic determinants, energy expenditure estimates and subcomponents of PA (i.e. time spent at different intensity levels) were not significantly associated with change in BW or FM.Conclusion:Our results suggest an independent association between PA and FM. However, this association may differ depending on obesity status. The gain in FM, without any change in PA, may suggest that dietary intake is the major contributor to the positive energy balance.International Journal of Obesity (2007) 31, 65-71. doi:10.1038/sj.ijo.0803361; published online 2 May 2006.
PubMed Accession Number :: 16652123.

Zhao, J. H. (2007) gap: Genetic Analysis Package Journal of Statistical Software, 23 (8),1-18 [Journal Article]

Zhao, J. H.; Luan, J.A.; Baksh, M.F.; Tan, Q. (2007) Mining gene networks with applicatiojn to GAW15 Problem 1 BMC Proceedings, 1(Suppl 1):S52 , [Journal Article]

Dunger, D. B.; Salgin, B.; Ong, K. (2006) Muscle mass and insulin sensitivity in children and adolescents Horm Res, 66 Suppl 1 ,79-84 [Journal Article] Online
Abstract: Muscle is the major target for insulin-stimulated glucose uptake, the key determinant of total body insulin sensitivity. Muscle-specific insulin resistance with compensatory hyperinsulinaemia is a feature of normal puberty, and contributes to the variation in growth and protein anabolism. Low insulin levels will tend to delay pubertal growth and development, whereas high insulin levels will accelerate the process, reflecting the nutritional regulation of the tempo of development during puberty. Abnormal levels of insulin resistance during childhood, as seen in children born small-for-gestational-age (SGA) who demonstrate rapid post-natal catch-up growth, are associated with excess gains in visceral fat mass and reduced lean body mass. Thus, early developmental changes, as well as genetic variation, may predispose the children to gains in visceral and ectopic fat, which are important determinants of insulin sensitivity and disease risk in children with obesity. The mechanisms that relate fat deposition to risk of diabetes mellitus are still speculative, but insulin sensitization with thiazolidinediones or metformin can reverse nutrient disposal in fat in favour of increases in lean body mass. Such treatment with metformin, which reduces circulating insulin levels, will slow the pubertal tempo of growth and may increase gains in final height in individuals born SGA. Copyright (c) 2006 S. Karger AG, Basel.
PubMed Accession Number :: 17259725.

Ekelund, U.; Brage, S.; Froberg, K.; Harro, M.; Anderssen, S. A.; Sardinha, L. B.; Riddoch, C.; Andersen, L. B. (2006) TV viewing and physical activity are independently associated with metabolic risk in children: the European Youth Heart Study PLoS Med, 3 (12),e488 [Journal Article] Online
Abstract: BACKGROUND: TV viewing has been linked to metabolic-risk factors in youth. However, it is unclear whether this association is independent of physical activity (PA) and obesity. METHODS AND FINDINGS: We did a population-based, cross-sectional study in 9- to 10-y-old and 15- to 16-y-old boys and girls from three regions in Europe (n = 1,921). We examined the independent associations between TV viewing, PA measured by accelerometry, and metabolic-risk factors (body fatness, blood pressure, fasting triglycerides, inverted high-density lipoprotein (HDL) cholesterol, glucose, and insulin levels). Clustered metabolic risk was expressed as a continuously distributed score calculated as the average of the standardized values of the six subcomponents. There was a positive association between TV viewing and adiposity (p = 0.021). However, after adjustment for PA, gender, age group, study location, sexual maturity, smoking status, birth weight, and parental socio-economic status, the association of TV viewing with clustered metabolic risk was no longer significant (p = 0.053). PA was independently and inversely associated with systolic and diastolic blood pressure, fasting glucose, insulin (all p < 0.01), and triglycerides (p = 0.02). PA was also significantly and inversely associated with the clustered risk score (p < 0.0001), independently of obesity and other confounding factors. CONCLUSIONS: TV viewing and PA may be separate entities and differently associated with adiposity and metabolic risk. The association between TV viewing and clustered metabolic risk is mediated by adiposity, whereas PA is associated with individual and clustered metabolic-risk indicators independently of obesity. Thus, preventive action against metabolic risk in children may need to target TV viewing and PA separately.
Keywords: Adolescent Child Confounding Factors (Epidemiology) Cross-Sectional Studies Denmark Estonia Female Humans Male *Motor Activity Obesity/*epidemiology Portugal Risk Management *Television Time Factors
PubMed Accession Number :: 17194189.

Finucane, F. M. (2006) Cerebral aneurysms N Engl J Med, 355 (25),2703; author reply 2705 [Journal Article] Online
Keywords: Aneurysm, Ruptured/complications Humans Hyponatremia/*etiology Intracranial Aneurysm/*complications Subarachnoid Hemorrhage/*complications
PubMed Accession Number :: 17183002.

Low, Y. L.; Taylor, J. I.; Grace, P. B.; Mulligan, A. A.; Welch, A. A.; Scollen, S.; Dunning, A. M.; Luben, R. N.; Khaw, K. T.; Day, N. E.; Wareham, N. J.; Bingham, S. A. (2006) Phytoestrogen Exposure, Polymorphisms in COMT, CYP19, ESR1, and SHBG Genes, and Their Associations With Prostate Cancer Risk Nutr Cancer, 56 (1),31-9 [Journal Article] Online
Abstract: Abstract: Prospective phytoestrogen exposure was assessed using both biomarkers and estimates of intake in 89 British men recruited into the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition study, men who subsequently developed prostate cancer. Results were compared with those from 178 healthy men matched by age and date of recruitment. Levels of seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in spot urine and serum samples. Five single-nucleotide polymorphisms in COMT, CYP19, ESR1, and SHBG genes were genotyped. Urinary levels of all phytoestrogens correlated strongly with serum levels. Correlation coefficients ranged from 0.63 (glycitein) to 0.88 (daidzein) (P < 0.001). Urinary and serum levels correlated significantly with isoflavone intake assessed from food diaries (R = 0.15-0.20; P < 0.05) but not with that from a food-frequency questionnaire. Odds ratios for phytoestrogen exposure, as assessed using the four methods, were not significantly associated with prostate cancer risk (P = 0.15-0.94). Men with the CC genotype for the ESRI PvuII polymorphism had significantly higher risk for prostate cancer compared with men with the TT genotype [adjusted odds ratio = 4.65 (1.60-13.49); P = 0.005]. Our results utilizing a combined prospective exposure provide no evidence that phytoestrogens alter prostate cancer risk in British men, whereas the C allele for the PvuII polymorphism may be associated with increased risk.
PubMed Accession Number :: 17176215.

Matthijs Boekholdt, S.; Sandhu, M. S.; Day, N. E.; Luben, R.; Bingham, S. A.; Peters, R. J.; Wareham, N. J.; Khaw, K. T. (2006) Physical activity, C-reactive protein levels and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study Eur J Cardiovasc Prev Rehabil, 13 (6),970-976 [Journal Article] Online
Abstract: BACKGROUND: Physical activity is inversely associated with the risk of future coronary artery disease. Whether this relationship is in part mediated by lower levels of systemic inflammation, as indicated by C-reactive protein concentrations, is unknown. METHODS: We performed a nested case-control study among apparently healthy men and women enrolled in the European Prospective Investigation into Cancer and Nutrition-Norfolk prospective population study, to investigate the relationship among habitual (work-related and leisure time) physical activity, cardiovascular risk factors and the risk of future coronary artery disease. RESULTS: Among men, those with an active lifestyle had a significantly lower risk of future coronary artery disease than those with an inactive lifestyle [odds ratio (OR) 0.65; 95% confidence interval (CI) 0.47-0.90; P for linearity, 0.008], after adjustment for smoking, systolic blood pressure, diabetes, body mass index and low-density lipoprotein and high-density lipoprotein cholesterol. Additional adjustment for C-reactive protein levels attenuated this relationship only slightly (OR 0.68; 95%CI 0.49-0.93; P for linearity, 0.02). Similarly, active women had an adjusted odds ratio of 0.48 (0.28-0.82; P for linearity <0.001) for future coronary artery disease compared with inactive women. Additional adjustment for C-reactive protein levels attenuated this relationship slightly (OR 0.51; 0.30-0.87; P for linearity, 0.003). CONCLUSIONS: We observed that people with an active lifestyle had a substantially lower risk of future coronary artery disease than people with an inactive lifestyle, and that this relationship was partly mediated through lower levels of established cardiovascular risk factors and in addition, C-reactive protein. This observation suggests that reduced systemic inflammation may be one of the mechanisms through which physical activity leads to reduced cardiovascular risk.
PubMed Accession Number :: 17143130.

Andersen, L. B.; Anderssen, S. A.; Brage, S.; Ekelund, U.; Froberg, K. (2006) [Physical activity and clustering of CVD risk factors--secondary publication] Ugeskr Laeger, 168 (47),4101-3 [Journal Article] Online
Abstract: This study aimed to derive guidelines on physical activity. We did a cross-sectional study of 1732 9-year-old and 15-year-old children. Objectively measured physical activity was associated to clustered CVD risk with an OR for the least active of 3.29 compared with the most active quintile. The time spent in moderate activity in children where risk was elevated was less than 116 min per day in 9-year-old and less than 88 min per day in 15-year-old children. Physical activity levels should be higher than the current international guidelines of at least 1 h per day to prevent clustering of CVD risk factors.
PubMed Accession Number :: 17134609.

Khaw, K. T.; Wareham, N. (2006) Glycated hemoglobin as a marker of cardiovascular risk Curr Opin Lipidol, 17 (6),637-43 [Journal Article] Online
Abstract: PURPOSE OF REVIEW: Diabetes mellitus is an established risk factor for cardiovascular disease. This review examines glycated hemoglobin, an indicator of long-term average blood glucose concentrations, in risk prediction for cardiovascular disease. RECENT FINDINGS: Glycated hemoglobin concentrations predict cardiovascular disease risk in people with diabetes, and trial data suggest that good blood glucose control is associated with reduction in cardiovascular disease. Elevated glycated hemoglobin levels below the thresholds accepted for diabetes are also associated with increasing cardiovascular disease risk independent of classical risk factors in a continuous relationship across the whole normal distribution. A 1% increase in absolute concentrations of glycated hemoglobin is associated with about 10-20% increase in cardiovascular disease risk. The continuous relationship is most evident for coronary heart disease in men; the shape of the risk curve is less clear for women and for other cardiovascular endpoints such as stroke or peripheral vascular disease. SUMMARY: Glycated hemoglobin concentration predicts cardiovascular risk both in people with diabetes and in the general population, and may help identify individuals at higher risk of cardiovascular disease for targeted interventions, including blood pressure or cholesterol reduction. Understanding the nature of this relationship may inform new preventive and therapeutic interventions.
PubMed Accession Number :: 17095908.

Ekelund, U.; Ong, K. K.; Linne, Y.; Neovius, M.; Brage, S.; Dunger, D. B.; Wareham, N. J.; Rossner, S. (2006) Association of Weight Gain in Infancy and Early Childhood with Metabolic Risk in Young Adults J Clin Endocrinol Metab, , [Journal Article] Online
Abstract: Context: Early postnatal life has been suggested as an important window during which risks for long-term health may be influenced. Objective: To examine the independent associations between weight gain during infancy (0-6 months) and early childhood (3-6 yr) with the components of the metabolic syndrome in young adults. Design: Prospective cohort study (The Stockholm Weight Development Study). Setting: General community. Participants: 128 (54 males) singletons, followed from birth to 17 yr. Main outcome measure: None of these young adults met the full criteria for the metabolic syndrome. We therefore calculated a continuous clustered metabolic risk score by averaging the standardized values of the following components (i.e. waist circumference [WC], blood pressure, fasting triglycerides, HDL cholesterol, glucose and insulin levels). Results: Clustered metabolic risk at age 17 yr was predicted by weight gain during infancy (standardized beta = 0.16; P < 0.0001) but not during early childhood (standardized beta = 0.10; P = 0.23), adjusted for birth weight, gestational age, current height, maternal fat mass and socio-economic status at age 17 yr. Further adjustment for current fat mass and weight gain during childhood, did not alter the significant association between infancy weight gain with the metabolic risk score (Standardized beta = 0.20; P = 0.007). Conclusions: Rapid weight gain during infancy (0-6 months) but not during early childhood (3-6 yr) predicted clustered metabolic risk at age 17 yr. Early interventions to moderate rapid weight gain even at very young ages may help to reduce adult cardiovascular disease risks.
PubMed Accession Number :: 17032722.

Franks, P. W.; Loos, R. J. (2006) PGC-1alpha gene and physical activity in type 2 diabetes mellitus Exerc Sport Sci Rev, 34 (4),171-5 [Journal Article] Online
Abstract: Exercise stimulates PGC-1alpha gene expression and increases V O2max, the latter of which relates inversely with type 2 diabetes risk. Consistently, low levels of PGC-1alpha mRNA and nucleotide sequence variation at PGC-1alpha associate with lower level of V O2max and increased diabetes risk. Thus, PGC-1alpha sequence variation may interact with physical activity to modify diabetes risk via changes in oxidative energy metabolism.
PubMed Accession Number :: 17031255.

Fawcett, K. A.; Wareham, N. J.; Luan, J.; Syddall, H.; Cooper, C.; O'Rahilly, S.; Day, I. N.; Sandhu, M. S.; Barroso, I. (2006) PARL Leu262Val is not associated with fasting insulin levels in UK populations Diabetologia, 49 (11),2649-52 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: PARL, the gene encoding presenilins-associated rhomboid-like protein, maps to chromosome 3q27 within a quantitative trait locus that influences components of the metabolic syndrome. Recently, an amino acid substitution (Leu262Val, rs3732581) in PARL was associated with fasting plasma insulin levels in a US white population (N=1031). This variant was also found to modify the positive association between age and fasting insulin. The aim of this study was to test whether these findings could be replicated in two UK population-based cohorts. METHODS: Participants from the Medical Research Council Ely and Hertfordshire cohort studies were genotyped for this variant using a SNaPshot primer extension assay and Taqman assay respectively. Full phenotypic and genotypic data were available for 3,666 study participants. RESULTS: Based on a dominant model, we found no association between the Leu262Val polymorphism and fasting insulin levels (p=0.79) or BMI (p=0.98). We did not observe the previously reported interaction between age and genotype on fasting insulin (p=0.14). CONCLUSIONS/INTERPRETATION: Despite having greater statistical power, our data do not support the previously reported association between PARL Leu262Val and fasting plasma insulin levels, a measure of insulin resistance. Our findings indicate that this variant is unlikely to be an important contributor to insulin resistance in UK populations.
PubMed Accession Number :: 17019603.

Harding, A. H.; Loos, R. J.; Luan, J.; O'Rahilly, S.; Wareham, N. J.; Barroso, I. (2006) Polymorphisms in the gene encoding sterol regulatory element-binding factor-1c are associated with type 2 diabetes Diabetologia, 49 (11),2642-8 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The sterol regulatory element-binding factor (SREBF)-1c is a transcription factor involved in the regulation of lipid and glucose metabolism. We have previously found evidence that a common SREBF1c single-nucleotide polymorphism (SNP), located between exons 18c and 19c, is associated with an increased risk of type 2 diabetes. The present study aimed to replicate our previously reported association in a larger case-control study and to examine an additional five SREBF1c SNPs for their association with diabetes risk and plasma glucose concentrations. METHODS: We genotyped six SREBF1c SNPs in two case-control studies (n=1,938) and in a large cohort study (n=1,721) and tested for association with type 2 diabetes and with plasma glucose concentrations (fasting and 120-min post-glucose load), respectively. RESULTS: In the case-control studies, carriers of the minor allele of the previously reported SNP (rs11868035) had a significantly increased diabetes risk (odds ratio [OR]=1.20 [95% CI 1.04-1.38], p=0.015). Also, three other SNPs (rs2236513, rs6502618 and rs1889018), located in the 5' region, were significantly associated with diabetes risk (OR >/=1.21, p</=0.006). Furthermore, two SNPs (rs2236513 and rs1889018) in the 5' region were weakly (p<0.09) associated with plasma glucose concentrations in the cohort study. Rare homozygotes had increased (p</=0.05) 120-min post-load glucose concentrations compared with carriers of the wild-type allele. Haplotype analyses showed significant (p=0.04) association with diabetes risk and confirmed the single SNP analyses. CONCLUSIONS/INTERPRETATION: In summary, we replicated our previous finding and found evidence for SNPs in the 5' region of the SREBF1c gene to be associated with the risk of type 2 diabetes and plasma glucose concentration.
PubMed Accession Number :: 17019602.

Agostini, M.; Schoenmakers, E.; Mitchell, C.; Szatmari, I.; Savage, D.; Smith, A.; Rajanayagam, O.; Semple, R.; Luan, J.; Bath, L.; Zalin, A.; Labib, M.; Kumar, S.; Simpson, H.; Blom, D.; Marais, D.; Schwabe, J.; Barroso, I.; Trembath, R.; Wareham, N.; Nagy, L.; Gurnell, M.; O'Rahilly, S.; Chatterjee, K. (2006) Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance Cell Metab, 4 (4),303-11 [Journal Article] Online
Abstract: PPARgamma is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARgamma in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARgamma coactivators and inhibit coexpressed wild-type receptor. Expression of PPARgamma target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARgamma action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.
PubMed Accession Number :: 17011503.

Myint, P. K.; Welch, A. A.; Bingham, S. A.; Luben, R. N.; Wareham, N. J.; Day, N. E.; Khaw, K. T. (2006) Habitual fish consumption and risk of incident stroke: the European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study Public Health Nutr, 9 (7),882-8 [Journal Article] Online
Abstract: OBJECTIVES: To examine the association between fish consumption and stroke risk. DESIGN: Prospective population cohort study.Setting: Norfolk, UK cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk). SUBJECTS: Subjects were 24 312 men and women aged 40-79 years who had no previous history of stroke at baseline.Methods: Fish consumption was assessed using a food-frequency questionnaire at baseline in 1993-1997 and stroke incidence ascertained to 2004. RESULTS: A total of 421 incident strokes were identified (mean follow-up=8.5 years, total person-years=209 238). There were no significant relationships between total fish, shellfish or fish roe consumption and risk of stroke in men and women after adjusting for age, systolic blood pressure, body mass index, smoking, cholesterol, diabetes, physical activity, alcohol consumption, fish oil supplement use and total energy intake using Cox regression analyses. Oily fish consumption was significantly lower in women who subsequently had a stroke (odds ratio (OR) for consumers vs. non-consumers=0.69, 95% confidence interval (CI) 0.51-0.94, P=0.02). The trend in men was similar but not significant (OR for consumers vs. non-consumers=0.88, 95% CI 0.65-1.19, P=0.41). CONCLUSIONS: There was no consistent relationship between fish consumption and stroke in this British population. Inconsistencies in the observed health effects of fish consumption in different populations may reflect different patterns and type of fish consumed and preparation methods.
PubMed Accession Number :: 17010254.

Low, Y. L.; Dunning, A. M.; Dowsett, M.; Luben, R. N.; Khaw, K. T.; Wareham, N. J.; Bingham, S. A. (2006) Implications of Gene-Environment Interaction in Studies of Gene Variants in Breast Cancer: An Example of Dietary Isoflavones and the D356N Polymorphism in the Sex Hormone-Binding Globulin Gene Cancer Res, 66 (18),8980-8983 [Journal Article] Online
Abstract: Studies to identify common genetic variants contributing to breast cancer risk often yield inconsistent results. Breast cancer is a complex disease involving both genetic and environmental determinants. Dietary isoflavones are thought to reduce breast cancer risk by stimulating circulating sex hormone-binding globulin (SHBG) levels. The SHBG gene contains a D356N polymorphism and the N variant is associated with reduced SHBG clearance compared with the D variant. In this study, we show a significant gene-environment interaction between SHBG D356N polymorphism and dietary isoflavone exposure on circulating SHBG levels in 1,988 postmenopausal women. SHBG levels were positively associated with isoflavones in women carrying the N variant (eta(p)(2) = 1.9%; P = 0.006) but not in women carrying only the D variant (eta(p)(2) = 0.0%; P = 0.999; P(interaction) = 0.019). This finding shows that the subtle effects of some genetic variants may be magnified and only become detectable in the presence of certain exposures. This gene-environment interaction might explain heterogeneity in studies associating SHBG gene variants and soy consumption with breast cancer risk in Far East population exposed to high isoflavone levels compared with populations with lower levels. (Cancer Res 2006; 66(18): 8980-3).
PubMed Accession Number :: 16982738.

Forouhi, N. G.; Sattar, N.; Tillin, T.; McKeigue, P. M.; Chaturvedi, N. (2006) Do known risk factors explain the higher coronary heart disease mortality in South Asian compared with European men? Prospective follow-up of the Southall and Brent studies, UK Diabetologia, 49 (11),2580-8 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: We examined prospectively whether measured risk factors can explain the higher CHD mortality in South Asians compared with Europeans. MATERIALS AND METHODS: Conventional CHD risk factors and those associated with insulin resistance were measured in 1,787 European and 1,420 South Asian men aged 40 to 69 years at baseline in the population-based Southall and Brent studies (London) between 1988 and 1990. Participants were followed up for mortality. RESULTS: By February 2006, there were 202 CHD deaths (108 Asian, 94 European). South Asian men had double the CHD mortality of European men in Cox regression analyses adjusted for age, smoking, and cholesterol (hazard ratio [HR] 2.14, 95% CI 1.56-2.94, p<0.001). Nearly half of all South Asian CHD deaths versus 13% of deaths among Europeans were among persons with diabetes. Asian men had greater CHD mortality than Europeans, both in the with- and the without-diabetes categories at baseline. CHD mortality remained significantly higher in South Asian men in multivariable models that adjusted for conventional risk factors and diabetes and/or impaired glucose regulation, features of insulin resistance, or the metabolic syndrome (HR 1.6-1.9). Accounting for co-morbidity and socio-economic status did not materially alter the findings. CONCLUSIONS/INTERPRETATION: These data confirm that South Asian men have significantly higher CHD mortality than their European counterparts, while indicating that neither conventional risk factors, nor insulin resistance parameters or metabolic syndrome criteria as currently defined can account for this excess risk. The contribution of unmeasured factors to the elevated vascular risk in South Asians should be addressed in future studies.
PubMed Accession Number :: 16972045.

Myint, P. K.; Luben, R. N.; Wareham, N. J.; Welch, A. A.; Bingham, S. A.; Day, N. E.; Khaw, K. T. (2006) Combined Work and Leisure Physical Activity and Risk of Stroke in Men and Women in the European Prospective Investigation into Cancer-Norfolk Prospective Population Study Neuroepidemiology, 27 (3),122-129 [Journal Article] Online
Abstract: Most studies to date support a protective role of physical activity in reducing stroke risk. However, they were not able to take into account combined work and leisure activity. We prospectively followed up 22,602 men and women aged 40-79 years, who had no history of stroke and myocardial infarction at baseline, participating in the European Prospective Investigation into Cancer-Norfolk. Participants were categorized into four levels of physical activity based on a validated self-reported questionnaire, which assesses combined work and leisure activities, at baseline during the period from 1993 to 1997. Stroke incidence was ascertained by death certificate and hospital record linkage data up to 2004, average 8.6 years of follow-up. We used the Cox proportional hazards model. There were 361 incident strokes during follow-up (total person years = 195,092). After adjusting for age, sex, systolic blood pressure, body mass index, cholesterol, history of diabetes and smoking, men and women who were physically active were less likely to have a stroke (relative risk = 0.70, 95% CI: 0.49-0.99, p = 0.024) compared to those who were inactive. This highlights the fact that efforts to increase physical activity in both the work place and in leisure time should be encouraged. Copyright (c) 2006 S. Karger AG, Basel.
PubMed Accession Number :: 16946623.

Keller, T. T.; Nagel, C.; Te Velthuis, H.; Gerdes, V. E.; Wareham, N. J.; Bingham, S. A.; Luben, R.; Hack, C. E.; Reitsma, P. H.; Levi, M.; Khaw, K. T.; Boekholdt, S. M. (2006) Tissue factor serum levels and the risk of future coronary artery disease in apparently healthy men and women; the EPIC-Norfolk prospective population study J Thromb Haemost, 4 (11),2391-6 [Journal Article] Online
Abstract: Summary Introduction:Tissue factor (TF) has been implicated in coronary artery disease (CAD). High levels of circulating TF are found in patients with acute atherothrombotic events. Whether high serum TF levels predict risk of future CAD independent of known risk factors remains unknown. Methods: We conducted a prospective case-control study nested in the EPIC-Norfolk population study. Cases (n=1037) were apparently healthy men and women, aged 45-79 years, who developed fatal or non-fatal CAD during follow-up. Controls (n=2005) were matched by age, sex and enrolment time. Serum TF levels were measured using high-affinity antibodies. Results: In men, median TF levels were not significant higher in cases than in controls (59.0 pg/ml range: 16.7-370.4 versus 54.9 pg/ml range: 16.2-452.4). In women, median TF levels were not significant higher in controls than in cases (73.4 pg/ml range: 16.7-492.3 versus 50.5 pg/ml range: 16.5-376.7). The prevalence of smoking was about double in the lowest compared to the highest TF quartile. Correcting for sex, age, BMI, smoking, diabetes, systolic blood pressure, LDL-c, and HDL-c, and CRP levels, the risk of future CAD was 1.05 (95% CI: 0.81-1.36) for people in the highest TF quartile, compared to those in the lowest (P-value for linearity = 0.8). Conclusion: High levels of serum TF were not independently associated with an increased risk of future CAD in apparently healthy individuals.
PubMed Accession Number :: 16938131.

Tillin, T.; Forouhi, N. G.; McKeigue, P. M.; Chaturvedi, N. (2006) The Role of Diabetes and Components of the Metabolic Syndrome in Stroke and Coronary Heart Disease Mortality in U.K. White and African-Caribbean Populations Diabetes Care, 29 (9),2127-2129 [Journal Article] Online
PubMed Accession Number :: 16936166.

Boekholdt, S. M.; Meuwese, M. C.; Day, N. E.; Luben, R.; Welch, A.; Wareham, N. J.; Khaw, K. T. (2006) Plasma concentrations of ascorbic acid and C-reactive protein, and risk of future coronary artery disease, in apparently healthy men and women: the EPIC-Norfolk prospective population study Br J Nutr, 96 (3),516-22 [Journal Article] Online
Abstract: High plasma concentrations of ascorbic acid, a marker of fruit and vegetable intake, are associated with low risk of coronary artery disease. Whether this relationship is explained by a reduction in systemic inflammation is unclear. We investigated the relationship between ascorbic acid plasma concentration and coronary artery disease risk, and in addition whether this relationship depended on classical risk factors and C-reactive protein (CRP) concentration. We used a prospective nested case-control design. The study consisted of 979 cases and 1794 controls (1767 men and 1006 women). Increasing ascorbic acid quartiles were associated with lower age, BMI, systolic and diastolic blood pressure, and CRP concentration, but with higher HDL-cholesterol concentration. No associations existed between ascorbic acid concentration and total cholesterol concentration or LDL-cholesterol concentration. When data from men and women were pooled, the risk estimates decreased with increasing ascorbic acid quartiles such that people in the highest ascorbic acid quartile had an odds ratio for future coronary artery disease of 0.67 (95 % CI 0.52, 0.87) compared with those in the lowest quartile (P for linearity=0.001). This relationship was independent of sex, age, diabetes, smoking, BMI, LDL-cholesterol, HDL-cholesterol, systolic blood pressure and CRP level. These data suggest that the risk reduction associated with higher ascorbic acid plasma concentrations, a marker of fruit and vegetable intake, is independent of classical risk factors and also independent of CRP concentration.
PubMed Accession Number :: 16925857.

Heldgaard, P. E.; Griffin, S. J. (2006) Routinely collected general practice data aids identification of people with hyperglycaemia and metabolic syndrome Diabet Med, 23 (9),996-1002 [Journal Article] Online
Abstract: To assess the performance of a risk score comprising data routinely available in general practice records (age, gender, body mass index, family history of diabetes, smoking habits and prescribed anti-hypertensive drugs or steroids) in detecting diabetes, impaired glucose tolerance and metabolic syndrome. In a population-based, cross-sectional study in a semi-rural general practice in Jutland, Denmark, Cambridge Risk Scores were calculated for 1355 patients without known diabetes (69% response rate) who completed questionnaires and underwent anthropometric measurement and an oral glucose tolerance test. Prevalences of diabetes, impaired glucose tolerance and metabolic syndrome were 2.29% (95% CI: 1.56-3.23), 6.64% (95% CI: 5.38-8.10) and 13.4% (95% CI: 11.5-15.2), respectively. Area under the ROC curve for the risk score and diabetes was 83.8% (75.9-91.7) and for metabolic syndrome [European Group for the Study of Insulin Resistance (EGIR)] was 78.1% (74.6-81.6). Twenty per cent of the population had a risk score above 0.246; at this threshold the sensitivity to detect diabetes was 71.0% (53.4-83.9), the specificity 81.2% (79.0-83.2), positive predictive value 8.1% (6.6-10.0) and likelihood ratio 3.77 (2.94-4.85). For metabolic syndrome (EGIR) corresponding values for sensitivity were 50.3% (43.1-57.5), specificity 84.7% (82.5-85.6), positive predictive value 33.6% (28.2-39.4), and likelihood ratio 3.28 (2.69-4.00). Undiagnosed hyperglycaemia and metabolic syndrome are common. The Cambridge Risk Score is a practical first step in a screening procedure to identify individuals with these disorders who might benefit from diagnostic testing or to direct preventive interventions. Diabet. Med. 23, 996-1002 (2006).
PubMed Accession Number :: 16922706.

Iniguez, G.; Ong, K.; Bazaes, R.; Avila, A.; Salazar, T.; Dunger, D.; Mericq, V. (2006) Longitudinal Changes in IGF-I, Insulin Sensitivity and Secretion from Birth to Age Three Years in Small-for-Gestational-Age Children J Clin Endocrinol Metab, 91 (11),4645-9 [Journal Article] Online
Abstract: Introduction: Insulin resistance (IR) develops as early as age 1 to 3 yr in small-for-gestational-age (SGA) infants who show rapid "catch-up" postnatal weight gain. In contrast, greater insulin secretion is related to infancy height gains. We hypothesized that insulin-like growth factor I (IGF-I) levels could be differentially related to gains in length and weight, and also differentially related to IR and insulin secretion. Methods: We measured serum IGF-I levels in a prospective study of 50 SGA (birth weight <5(th) percentile) and 14 normal birth weight (AGA) newborns who had fasting bloods and auxology assessed at birth (48 h old), and IR (by HOMA), insulin secretion by short intra-venous glucose tolerance test (IVGTT), and IGF-I levels, at age 1 yr and 3 yr. Results: SGA infants had similar mean length and weight at 3 yr compared with AGA infants. SGA infants had lower IGF-I levels at birth (P < 0.0001), but conversely they had higher IGF-I levels at 3 yr (P = 0.003) than AGA infants. Within the SGA group, at 1 yr IGF-I was associated with length gain from birth and insulin secretion (P < 0.0001); in contrast at 3 yr IGF-I was positively related to weight, BMI and insulin resistance. Conclusions: IGF-I levels increased rapidly from birth in SGA, but not AGA children. During the key first year growth period IGF-I levels were related to beta-cell function and longitudinal growth. In contrast by 3 yr, when catch-up growth was completed, IGF-I levels were related to BMI and IR, and these higher IGF-I levels in SGA infants might indicate the presence of relative IGF-I resistance.
PubMed Accession Number :: 16912131.

Keller, T. T.; van Leuven, S. I.; Meuwese, M. C.; Wareham, N. J.; Luben, R.; Stroes, E. S.; Hack, C. E.; Levi, M.; Khaw, K. T.; Boekholdt, S. M. (2006) Serum Levels of Mannose-Binding Lectin and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women Arterioscler Thromb Vasc Biol, 26 ,2345-50 [Journal Article] Online
Abstract: OBJECTIVE: To determine the association between serum levels of mannose-binding lectin (MBL) and the risk of future coronary artery disease (CAD) in apparently healthy men and women. METHODS AND RESULTS: We performed a prospective case-control study among apparently healthy men and women nested in the EPIC-Norfolk cohort. Baseline concentrations of MBL were measured in serum samples of 946 patients who experienced a myocardial infarction or died of CAD during follow-up, and 1799 matched controls who remained free of CAD. Among men, median MBL levels were 1.63 ng/mL (interquartile range [IQR]: 0.59 to 3.80) in cases and 1.20 ng/mL (IQR: 0.48 to 3.37) in controls. Among women, median MBL levels were 1.02 ng/mL (IQR: 0.43 to 2.95) in cases and 1.01 ng/mL (IQR: 0.43 to 2.94) in controls. After adjustment, the odds ratio in men for future CAD was 1.59 (95% confidence interval [CI]: 1.09 to 2.32; P for linearity=0.01) for those in the highest quartile compared with those in the lowest quartile. In women no such relation was observed. CONCLUSIONS: Elevated levels of MBL are associated with an increased risk of future CAD in apparently healthy men but not in women. The sex difference merits further exploration.
PubMed Accession Number :: 16902159.

Proper, K. I.; Heymans, M. W.; Paw, M. J.; van Sluijs, E. M.; van Poppel, M. N.; van Mechelen, W. (2006) Promoting physical activity with people in different places-A Dutch perspective J Sci Med Sport, 9 ,371-377 [Journal Article] Online
Abstract: This paper describes five recent Dutch studies of the effectiveness of physical activity interventions carried out in diverse settings: general practice (GP), aged care facilities, and workplaces. The stage-based physical activity counselling carried out in the GP setting demonstrated a beneficial effect on the determinants of physical activity, but did not show any additional effect on physical activity behaviour, compared with standard physical activity advice. In contrast, the stage-based intervention through the workplace was effective in increasing physical activity, due mostly to an increase in vigorous-intensity activities. In the aged care setting, functional-skills training alone or in combination with resistance training showed functional improvement only in participants with high participation rates. Functional-skills training appeared to be more feasible than resistance training in this population of frail elderly. The two studies which aimed to promote earlier return-to-work among workers with sick leave due to non-specific low back pain also showed promising results. As a result, it was recommended that occupational physicians (OP) should refer workers with low back pain in the subacute phase of their sick leave to a low intensity intervention consisting of short meetings and exercises aimed at changing behaviour, and that the OPs contact other health care providers (GPs and physiotherapists) about the treatment strategy. Together, the results of these five Dutch studies suggest that it is feasible to successfully promote physical activity to groups of people in diverse places, with benefits in terms of both prevention and management of chronic disease and injury.
PubMed Accession Number :: 16901753.

Ong, K. K.; Loos, R. J. (2006) Rapid infancy weight gain and subsequent obesity: Systematic reviews and hopeful suggestions Acta Paediatr, 95 (8),904-8 [Journal Article] Online
Abstract: In a systematic review, we identified 21 separate studies with data on the association between rapid infancy weight gain, up to age 2 y, and subsequent obesity risk. Uniformly all studies reported significant positive associations. We transformed the reported effect sizes to a standard infancy weight gain exposure, and found that further differences in study design accounted for much of the variation in risk. An accompanying paper by Melinda Yeung reminds us that there are benefits of postnatal catch-up growth in certain populations, and suggests that genetic and nutritional factors could moderate the unhealthy translation of rapid infancy weight gain to visceral fat and insulin resistance. Further evidence is needed, and we will need to rigorously test the benefits and risks of any interventions. However, the concept of "healthy" rapid catch-up infancy growth is an attractive prospect.Conclusion: Rapid infancy weight gain is consistently associated with increased subsequent obesity risk, but the predictive ability of different weight gain cut-offs needs to be tested.
PubMed Accession Number :: 16882560.

Boekholdt, S. M.; Sandhu, M. S.; Wareham, N. J.; Luben, R.; Reitsma, P. H.; Khaw, K. T. (2006) Fibrinogen plasma levels modify the association between the factor XIII Val34Leu variant and risk of coronary artery disease; the EPIC-Norfolk prospective population study J Thromb Haemost, 4 ,2204-9 [Journal Article] Online
Abstract: The factor XIII Val34Leu variant has been implicated in coronary artery disease (CAD). In vitro evidence suggests an interaction between this variant and fibrinogen concentrations in determining thrombus structure. In an 8-year prospective population study of 25,663 men and women, we compared 898 apparently healthy men and women developing incident CAD with 1580 matched controls. Overall, the factor XIII Val34Leu variant was not associated with the risk of future CAD. However, a significant interaction existed between the Val34Leu variant and fibrinogen levels for the risk of future CAD (p=0.004). Among people in the lowest tertile of fibrinogen concentrations, LeuLeu carriers had an odds ratio (OR) of 2.88 (95%CI 1.24-6.74) compared to wild-type individuals (p for linearity = 0.003). By contrast, among those in the highest fibrinogen tertile, LeuLeu carriers were had a lower risk than wild-type individuals (OR 0.47, 95%CI 0.18-1.17, p for linearity = 0.1). Our results suggest that a significant gene-covariate interaction exists between the factor XIII Val34Leu variant and fibrinogen levels. Relationships between genotype and disease risk may be altered by biological covariates. Simplistic paradigms of gene or biomarker associations are unlikely to fully characterise disease risk in populations.
PubMed Accession Number :: 16881935.

Andersen, L. B.; Harro, M.; Sardinha, L. B.; Froberg, K.; Ekelund, U.; Brage, S.; Anderssen, S. A. (2006) Physical activity and clustered cardiovascular risk in children: a cross-sectional study (The European Youth Heart Study) Lancet, 368 (9532),299-304 [Journal Article] Online
Abstract: BACKGROUND: Atherosclerosis develops from early childhood; physical activity could positively affect this process. This study's aim was to assess the associations of objectively measured physical activity with clustering of cardiovascular disease risk factors in children and derive guidelines on the basis of this analysis. METHODS: We did a cross-sectional study of 1732 randomly selected 9-year-old and 15-year-old school children from Denmark, Estonia, and Portugal. Risk factors included in the composite risk factor score (mean of Z scores) were systolic blood pressure, triglyceride, total cholesterol/HDL ratio, insulin resistance, sum of four skinfolds, and aerobic fitness. Individuals with a risk score above 1 SD of the composite variable were defined as being at risk. Physical activity was assessed by accelerometry. FINDINGS: Odds ratios for having clustered risk for ascending quintiles of physical activity (counts per min; cpm) were 3.29 (95% CI 1.96-5.52), 3.13 (1.87-5.25), 2.51 (1.47-4.26), and 2.03 (1.18-3.50), respectively, compared with the most active quintile. The first to the third quintile of physical activity had a raised risk in all analyses. The mean time spent above 2000 cpm in the fourth quintile was 116 min per day in 9-year-old and 88 min per day in 15-year-old children. INTERPRETATION: Physical activity levels should be higher than the current international guidelines of at least 1 h per day of physical activity of at least moderate intensity to prevent clustering of cardiovascular disease risk factors.
PubMed Accession Number :: 16860699.

Franks, P. W. (2006) Obesity, inflammatory markers and cardiovascular disease: distinguishing causality from confounding J Hum Hypertens, 20 (11),837-40 [Journal Article] Online
PubMed Accession Number :: 16855628.

O'Rahilly, S.; Wareham, N. J. (2006) Genetic variants and common diseases--better late than never N Engl J Med, 355 (3),306-8 [Journal Article] Online
PubMed Accession Number :: 16855272.

Myint, P. K.; Welch, A. A.; Luben, R. N.; Wainwright, N. W.; Surtees, P. G.; Bingham, S. A.; Wareham, N. J.; Smith, R. D.; Harvey, I. M.; Khaw, K. T. (2006) Obesity Indices and Self-Reported Functional Health in Men and Women in the EPIC-Norfolk Obesity (Silver Spring), 14 (5),884-893 [Journal Article] Online
Abstract: OBJECTIVE: To investigate the association between two indices of obesity, BMI and waist-to-hip ratio (WHR), and self-reported physical and mental functional health. RESEARCH METHODS AND PROCEDURES: We examined the relationship between obesity indices and self-reported physical and mental functional health measured by the Anglicized version of the Short-Form 36-item questionnaire in a population-based cross sectional study of 16,806 men and women 40 to 79 years old living in the general community in Norfolk, United Kingdom. RESULTS: Higher BMI and WHR were both independently associated with poorer self-reported physical functional health in men and women. The effect of BMI was greater in women compared with men, and the effect of WHR was greater in men compared with women, for poor physical functional health. Higher WHR but not BMI was associated with lower mental functional health in men and women. DISCUSSION: High BMI and WHR seem to be adversely related to self-perceived functional health in both men and women, although their relative impacts seem to differ by sex. Our findings also highlight the importance of using WHR in addition to BMI in assessing the impact of obesity on health outcome.
PubMed Accession Number :: 16855198.

Edge, J. A.; Jakes, R. W.; Roy, Y.; Hawkins, M.; Winter, D.; Ford-Adams, M. E.; Murphy, N. P.; Bergomi, A.; Widmer, B.; Dunger, D. B. (2006) The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children Diabetologia, 49 (9),2002-9 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Cerebral oedema complicating diabetic ketoacidosis (DKA) remains the major cause of morbidity and mortality in children with type 1 diabetes, but its aetiology remains unknown. Our objective was to determine the impact of baseline biochemical factors and of treatment-related variables on risk of the development of cerebral oedema in children with DKA. MATERIALS AND METHODS: This was a national UK case-control study. Through the British Paediatric Surveillance Unit we identified 43 cases of cerebral oedema. Through a parallel reporting system, we also identified 2,940 episodes of DKA and selected 169 control subjects on the basis of comparable age, sex, numbers of new or known cases of diabetes and date of admission. Baseline biochemical data and treatment-related variables were extracted from the clinical notes of cases and control subjects. RESULTS: Allowing for differences in age, sex and new or known diabetes, cases were more acidotic at diagnosis of DKA (odds ratio [OR] for events in the least acidotic compared with the most acidotic tertile=0.02 [95% CI: 0.002-0.15], p<0.001). In addition, cases had higher potassium and urea levels at baseline. Calculated osmolality and baseline glucose were not significantly different. After allowing for severity of acidosis, insulin administration in the first hour (OR 12.7 [1.41-114.5], p=0.02) and volume of fluid administered over the first 4 h (OR 6.55 [1.38-30.97], p=0.01) were associated with risk. Low baseline plasma sodium and an elevated p(a)CO(2) also contributed to risk in the final regression model. Bicarbonate administration was not associated with increased risk of an event when corrected for acidosis. CONCLUSIONS/INTERPRETATION: In this case-control study of DKA, baseline acidosis and abnormalities of sodium, potassium and urea concentrations were important predictors of risk of cerebral oedema. Additional risk factors identified were early administration of insulin and high volumes of fluid. These observations should be taken into account when designing treatment protocols.
PubMed Accession Number :: 16847700.

Vaessen, S. F.; Schaap, F. G.; Kuivenhoven, J. A.; Groen, A. K.; Hutten, B. A.; Boekholdt, S. M.; Hattori, H.; Sandhu, M. S.; Bingham, S. A.; Luben, R.; Palmen, J. A.; Wareham, N. J.; Humphries, S. E.; Kastelein, J. J.; Talmud, P. J.; Khaw, K. T. (2006) Apolipoprotein av, triglycerides and risk of future coronary artery disease in apparently healthy men and women; the prospective epic-norfolk population study J Lipid Res, 47 (9),2064-70 [Journal Article] Online
Abstract: In mouse models apolipoprotein (apo) AV exhibits triglyceride-lowering effects. We investigated the apoAV: triglyceride relationship and the association of apoAV with coronary artery disease (CAD) risk by determining serum apoAV levels and genotypes in a nested case (n=1034): control (n=2031) study. In both univariate and multivariate analysis, apoAV levels showed no association with future CAD (p=0.4 and p=0.5, respectively). Unexpectedly there was a significant positive correlation between serum apoAV and TG, in men and women (r=0.36 and 0.28, respectively, p<0.001 each), but a negative correlation between apoAV and LPL mass (r=-0.14 and -0.12, for men and women respectively, p<0.001 each). The frequency of the c.56C>G polymorphism did not differ between cases and controls despite significant positive association of c.56G with both apoAV and TG levels. For -1131T>C, the minor allele was significantly associated with lower apoAV yet higher TG levels, and was overrepresented in cases (p=0.047). The association of -1131T>C with CAD risk was, however, independent of apoAV levels and likely acts through linkage disequilibrium with APOC3 variants. The positive correlation of apoAV levels with TG levels, negative correlation with LPL levels and lack of association with CAD risk highlights the need for further human studies to clarify the role of apoAV.
PubMed Accession Number :: 16769999.

Ong, K. K.; Ahmed, M. L.; Dunger, D. B. (2006) Lessons from large population studies on timing and tempo of puberty (secular trends and relation to body size): the European trend Mol Cell Endocrinol, 254-255 ,8-12 [Journal Article] Online
Abstract: Ever since the publication of the first textbook on human growth by Johann Augustin Stoeller in 1729, temporal changes (or secular trends) in growth and pubertal maturation have been observed throughout the world. Data covering the longest time span are often reported from European populations. For example, in Norway and Denmark the age at menarche has fallen rapidly since the 19th century, by up to 12 months per decade. These changes have broadly paralleled increases in adult height in most European countries over the last century, with rates of around 10-30mm per decade. These secular trends are influenced by background ethnic, geographical and socio-economic factors, and clearly nutritional changes have an important role as reflected by positive correlations between age at puberty onset or age at menarche and childhood body size. Changes in height, pubertal maturation, and childhood body size have all also been related to rate of weight gain in infancy, and there is growing evidence to suggest that this early postnatal period may represent an early window of susceptibility to long-term 'programming' of various outcomes in humans. There is debate as to whether the secular trends in pubertal maturation are continuing or have reached their limit. Even where temporal changes are overall clearly significant, they are most marked in the more nutritionally deprived sub-groups. Whether over-nutrition and increasing childhood obesity will continue to lead earlier puberty is uncertain. The confirmation of an estimated advance in the age at menarche of 6-12 months per 100 years will require a long-term perspective on behalf of current investigators, and new consideration of methodological approaches in an age of increasing recognition of children's rights for privacy.
PubMed Accession Number :: 16757103.

Glumer, C.; Yuyun, M.; Griffin, S.; Farewell, D.; Spiegelhalter, D.; Kinmonth, A. L.; Wareham, N. J. (2006) What determines the cost-effectiveness of diabetes screening? Diabetologia, 49 (7),1536-44 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The cost-effectiveness of screening for diabetes is unknown but has been modelled previously. None of these models has taken account of uncertainty. We aimed to describe these uncertainties in a model where the outcome was CHD risk. SUBJECTS AND METHODS: Our model used population data from the Danish Inter99 study, and simulations were run in a theoretical population of 1,000,000 individuals. CHD risk was estimated using the UK Prospective Diabetes Study (UKPDS) risk engine, and risk reduction from published randomised clinical trials. Probabilistic sensitivity analysis was used to provide confidence intervals for modelled outputs. Uncertain parameter values were independently simulated from distributions derived from existing literature and deterministic sensitivity analysis performed using multiple model runs under different strategy choices and using extreme parameter estimates. RESULTS: In the least conservative model (low costs and multiplicative risk reduction for combined treatments), the 95% confidence interval of the incremental cost-effectiveness ratio varied from pound23,300-82,000. The major contributors to this uncertainty were treatment risk reduction model parameters: the risk reduction for hypertension treatment and UKPDS risk model intercept. Overall cost-effectiveness ratio was not sensitive to decisions about which groups to screen, nor the costs of screening or treatment. It was strongly affected by assumptions about how treatments combine to reduce risk. CONCLUSIONS/INTERPRETATION: Our model suggests that there is considerable uncertainty about whether or not screening for diabetes would be cost-effective. The most important but uncertain parameter is the effect of treatment. In addition to directly influencing current policy decisions, health care modelling can identify important unknown or uncertain parameters that may be the target of future research.
PubMed Accession Number :: 16752172.

Sarnblad, S.; Ekelund, U.; Aman, J. (2006) Dietary Fat Intake Predicts 1-Year Change in Body Fat in Adolescent Girls With Type 1 Diabetes Diabetes Care, 29 (6),1227-1230 [Journal Article] Online
Abstract: OBJECTIVE: The purpose of this study was to determine whether objectively measured physical activity and dietary macronutrient intake differentially predict body fat in adolescent girls with type 1 diabetes and control girls. RESEARCH DESIGN AND METHODS: This study comprised 23 girls (12-19 years) with type 1 diabetes and 19 age-matched healthy control girls. At baseline, physical activity and energy intake were assessed for 7 consecutive days by accelerometry and a structured food diary, respectively. Body composition was measured by dual-energy X-ray absorptiometry at baseline and after 1 year. RESULTS: Fat intake was positively related to a 1-year change in percentage body fat (P = 0.006), after adjustment for total energy intake. No significant interaction was observed (case-control group x main exposure), indicating that the association between fat intake and gain in body fat was similar in both groups. Physical activity did not predict gain in body fat; however, total physical activity was positively associated with a gain in lean body mass (P < 0.01). Girls treated with six daily dosages of insulin increased their percentage of body fat significantly more than those treated with four daily injections (P < 0.05). CONCLUSIONS: In this prospective case-control study, we found that fat intake predicted gain in percentage of body fat in both adolescent girls with type 1 diabetes and healthy control girls. The number of daily insulin injections seems to influence the accumulation of body fat in girls with type 1 diabetes.
PubMed Accession Number :: 16732000.

Mosedale, D. E.; Sandhu, M. S.; Luan, J.; Goodall, M.; Grainger, D. J. (2006) A new sensitive and specific enzyme-linked immunosorbent assay for IgD J Immunol Methods, 313 (1-2),74-80 [Journal Article] Online
Abstract: We have developed a new highly specific ELISA for IgD, and then used it to measure levels of circulating IgD in the serum of 480 un-selected patients from the East Anglia region of UK. The assay is both extremely sensitive and specific, with a minimum detected IgD concentration of 30 pg/ml and more than 10,000-fold specificity for IgD over all other human immunoglobulins. The assay shows linear dilution characteristics with both purified IgD and human serum, and spiking of purified IgD into either purified immunoglobulins or human serum shows c. 100% recovery. Furthermore, intra-assay and inter-assay coefficients of variation for repeated measurements of the same samples are below 10% and 15% respectively. Measurement of IgD levels on the un-selected patient population showed levels to range from <300 pg/ml to over 100 mug/ml, with a geometric mean of 8 mug/ml. The distribution is approximately normal after log transformation. Levels of circulating IgD were higher in men than in women. There was a significant negative correlation between levels of IgD and age in women, but not in men. Moreover, after adjustment for age and sex, there were statistically significantly higher levels of circulating IgD in male (but not female) smokers, compared to their non-smoking counterparts. These results highlight the care that needs to be taken to control for age, sex and cigarette smoking when examining levels of circulating IgD in future studies.
PubMed Accession Number :: 16714033.

Khaw, K. T.; Jakes, R.; Bingham, S.; Welch, A.; Luben, R.; Day, N.; Wareham, N. (2006) Work and leisure time physical activity assessed using a simple, pragmatic, validated questionnaire and incident cardiovascular disease and all-cause mortality in men and women: The European Prospective Investigation into Cancer in Norfolk prospective population study Int J Epidemiol, 35 ,1034-43 [Journal Article] Online
Abstract: BACKGROUND: The health benefits of physical activity are well established, but the overall amount of physical activity associated with cardiovascular and other health outcomes, and whether the relationships are similar in men and women and at different ages is still debated. This may be partly related to different methods for assessing physical activity. Most studies have focused on leisure time physical activity. METHODS: We examined the prospective relationship between usual physical activity, taking into account both leisure and work activity, using a simple, pragmatic, four-point rating scale validated against heart rate monitoring, and cardiovascular disease incidence and total mortality after an average 8 years follow-up in 22 191 community living men and women aged 45-79 years with no known cardiovascular disease or cancer at baseline. RESULTS: The relative risks (95% confidence interval) for all-cause mortality (1553 deaths) for men and women who were moderately inactive, moderately active, and active compared with those who were inactive were 0.83 (0.73-0.95), 0.68 (0.58-0.80), and 0.68 (0.57-0.81), respectively, after adjusting for age, sex, systolic blood pressure, blood cholesterol, cigarette smoking, alcohol intake, diabetes, body mass index, and social class. The relationships were also consistent for cardiovascular disease incidence (3079 events), in subgroups stratified by age, sex, body mass index, smoking status and social class, and after excluding deaths in the first 2 years. The combined scale was more consistently associated with mortality than the individual work and leisure time components separately. CONCLUSIONS: When both work and leisure time physical activity patterns are taken into account, using a simple, pragmatic, validated questionnaire feasible for use in clinical and public health practice, even very moderate levels of usual physical activity are associated with significantly reduced risk of mortality and cardiovascular disease in men and women in the general population and potential population attributable impact of 14% for inactive compared with active levels. These findings may encourage efforts to increase physical activity levels not only in leisure time but also in usual daily working life.
PubMed Accession Number :: 16709620.

Semple, R. K.; Soos, M. A.; Luan, J.; Mitchell, C. S.; Wilson, J. C.; Gurnell, M.; Cochran, E. K.; Gorden, P.; Chatterjee, V. K.; Wareham, N. J.; O'Rahilly, S. (2006) Elevated plasma adiponectin in humans with genetically defective insulin receptors J Clin Endocrinol Metab, 91 (8),3219-23 [Journal Article] Online
Abstract: Context: Adiponectin has been suggested to play a role in the aetiopathogenesis of at least some forms of insulin resistance, in part based on a strong correlation between plasma levels of adiponectin and measures of insulin sensitivity. Objective: To establish whether this relationship is maintained at extreme levels of insulin resistance. Design/Setting: A cross sectional study in a University Teaching Hospital of subjects recruited from the UK and U.S.A. Participants: 75 subjects with a range of syndromes of severe insulin resistance and 872 non-diabetic controls. Outcome Measures: fasting plasma insulin, adiponectin, and leptin Results: Unexpectedly, subjects with mutations in the insulin receptor, despite having the most severe degree of insulin resistance, had elevated plasma adiponectin (median 24.4 mg/l; range 6.6-36.6 (Normal adult range at B.M.I. of 20 kg/m(2) = 3-19 mg/l)), while all other subjects had low adiponectin levels (median 2.0 mg/l; range 0.12-11.2). Plasma leptin in all but one subject with an insulin receptoropathy was low or undetectable (median 0.5 ng/ml; range 0-16: Normal adult range for B.M.I. of <25 kg/m(2) =2.4-24.4 (female) and 0.4-8.3 ng/ml (male)). Conclusions: We conclude a) that the relationship between plasma adiponectin and insulin sensitivity is complex and dependent on the precise etiology of defective insulin action and b) that the combination of high plasma adiponectin with low leptin may have clinical utility in patients with severe insulin resistance as a marker of the presence of a genetic defect in the insulin receptor.
PubMed Accession Number :: 16705075.

Ibanez, L.; Ong, K.; Valls, C.; Marcos, M. V.; Dunger, D. B.; de Zegher, F. (2006) Metformin Treatment to Prevent Early Puberty in Girls with Precocious Pubarche J Clin Endocrinol Metab, 91 (8),2888-91 [Journal Article] Online
Abstract: Context and Objective: Girls with precocious pubarche (PP, pubic hair < 8 yr) are at high risk for early onset and rapid progression of puberty, in particular if their prenatal growth was restrained (low birthweight, LBW) and followed by rapid postnatal catch-up of weight gain. We postulated that insulin resistance contributes to early onset and rapid progression of puberty in LBW-PP girls, and thus explored the puberty-delaying effects of insulin sensitization with metformin initiated shortly after PP diagnosis. Setting, Design, and Patients: The study population consisted of 38 prepubertal LBW girls with PP attributed to exaggerated adrenarche [mean BW 2.4 Kg; age 7.9 yr; body mass index (BMI) 18.4 Kg/m(2)]; these girls were randomly assigned to remain untreated (n = 19) or to receive metformin (n = 19; 425 mg/d) for 2 yr. Main outcome measures: Pubertal staging, age at menarche, body composition by absorptiometry, fasting insulin, glucose, lipids, leptin, insulin-like growth factor-1 (IGF-1), IGF-binding protein-1 (IGFBP-1), testosterone, dehydroepiandrosterone-sulfate (DHEAS), testosterone, sex hormone-binding globulin (SHBG). Results: Metformin treatment was associated with a less adipose body composition (and lower serum leptin levels) and with a 0.4 yr delay in the clinical onset of puberty (Tanner B2; 9.5 yr vs. 9.1 yr; P < 0.01). These findings were corroborated by a delay of at least 1 yr in the puberty-associated rise of circulating IGF-1 (P < 0.01). Available results also point to a metformin-associated delay of menarche (P < 0.02); so far, gain in height and lean mass was not divergent between study subgroups. Conclusion: The efficacy of early metformin treatment in PP girls is herewith extended to include not only a less adipose body composition after 2 yr, but also a less advanced onset of puberty, while height gain is maintained. These findings open the perspective that, ultimately, metformin treatment may also prove to heighten the short adult stature of LBW-PP girls.
PubMed Accession Number :: 16684823.

Ibanez, L.; Ong, K.; Dunger, D. B.; Zegher, F. (2006) Effects of growth hormone treatment on neutrophil count in children born small for gestational age Pediatrics, 117 (5),1868-9 [Journal Article] Online
PubMed Accession Number :: 16651363.

Kolbe-Alexander, T. L.; Lambert, E. V.; Harkins, J. B.; Ekelund, U. (2006) Comparison of two methods of measuring physical activity in South African older adults J Aging Phys Act, 14 (1),98-114 [Journal Article] Online
Abstract: The aim of this study was to assess the validity and reliability of the Yale Physical Activity Survey (YPAS) and the short version of the International Physical Activity Questionnaire (IPAQ) in older South African adults. The YPAS includes measures of weekly energy expenditure (EE) for housework, yard work, caregiving, exercise, and recreation. The IPAQ measures total time and EE during vigorous and moderate activity, walking, and sitting. The instruments were administered twice for test-retest reliability (men, n = 52, 68 +/- 5.4 years, and women, n = 70, 66 +/- 5.8 years). Data for criterion validity were obtained from accelerometers. YPAS reliability ranged from r = .44 to.80 for men and r = .59 to .99 for women (p < .0001). IPAQ reliability was lower for men (r = .29 to .76) than for women (r = .46 to .77). Criterion validity of the YPAS was .31 to .54 for men and .26 to .29 for women. The YPAS and short IPAQ had comparable results for reliability and criterion validity.
Keywords: Aged Comparative Study Data Interpretation, Statistical Female Humans Male *Motor Activity *Questionnaires Reproducibility of Results Research Support, Non-U.S. Gov't South Africa
PubMed Accession Number :: 16648654.

Ong, K. K.; Frystyk, J.; Flyvbjerg, A.; Petry, C. J.; Ness, A.; Dunger, D. B. (2006) Sex-Discordant Associations With Adiponectin Levels and Lipid Profiles in Children Diabetes, 55 (5),1337-1341 [Journal Article] Online
Abstract: In adults, lower circulating levels of the adipocyte-derived hormone adiponectin are associated with obesity, type 2 diabetes, and cardiovascular disease risks. Its use as a risk marker in children is less clear. In 839 children aged 8 years from a representative birth cohort, circulating adiponectin levels were associated with body weight, BMI, waist circumference, and fasting and 30-min insulin levels, but the associations were opposite in boys, with positive associations, and girls, with inverse associations (P = 0.008-0.00001 for interaction with sex). Girls had overall higher adiponectin, higher total cholesterol, lower HDL cholesterol, and higher triglyceride levels than boys, even after adjustment for BMI. With increasing BMI, girls showed steeper declines in HDL cholesterol (P = 0.01 for interaction) and adiponectin levels (P = 0.0005 for interaction) and a steeper increase in triglyceride levels (P = 0.009 for interaction) compared with boys. In conclusion, plasma adiponectin is not a simple marker of central fat and insulin sensitivity in children. With increasing BMI, decreasing adiponectin levels in girls could contribute to their faster deterioration in lipid profiles in comparison with boys. Our data suggest a complex age- and sex-related regulation of adiponectin secretion or clearance.
PubMed Accession Number :: 16644690.

Tingstrom, P. R.; Ekelund, U.; Kamwendo, K.; Bergdahl, B. (2006) Effects of a problem-based learning rehabilitation program on physical activity in patients with coronary artery disease J Cardiopulm Rehabil, 26 (1),32-8 [Journal Article] Online
Abstract: PURPOSE: To evaluate the effects of a problem-based learning (PBL) rehabilitation program on physical activity. METHODS: We randomized 207 consecutive patients younger than 70 years, with a recent event of coronary artery disease (CAD), to a PBL group (n = 104) or a control group (n = 103). In addition to standard treatment, the PBL patients participated in a 1-year program with 13 sessions in small groups, where learning needs and behavior change were focused upon. Physical activity was assessed by means of interviews with all patients and by an activity monitor in 69 patients at pretest and in 175 after 1 year. RESULTS: Only small differences between groups were found at posttest. Interview data revealed significantly less activity at low-intensity level in the control group, whereas the activity monitor showed no significant differences. No changes were found in total physical activity during the year within the 2 groups. The self-reported physical activity indicating a level of brisk walking was markedly higher than that measured by the activity monitor, the latter indicating that only 35% of the patients achieved a 10-minute period of continued physical activity per day on an adequate level. CONCLUSIONS: Our PBL program had no important impact on the physical activity pattern of patients with CAD. The activity monitor is a feasible way of measuring physical activity in these patients, indicating a lower level of physical activity than interview data.
PubMed Accession Number :: 16617225.

Ong, K. K. (2006) Size at birth, postnatal growth and risk of obesity Horm Res, 65 Suppl 3 ,65-9 [Journal Article] Online
Abstract: Epidemiological studies over the last 15 years have shown that size at birth, early postnatal catch-up growth and excess childhood weight gain are associated with an increased risk of adult cardiovascular disease and type 2 diabetes. At the same time, rising rates of obesity and overweight in children, even at pre-school ages, have shifted efforts towards the identification of very early factors that predict risk of subsequent obesity, which may allow early targeted interventions. Overall, higher birth weight is positively associated with subsequent greater body mass index in childhood and later life; however, the relationship is complex. Higher birth weight is associated with greater subsequent lean mass, rather than fat mass. In contrast, lower birth weight is associated with a subsequent higher ratio of fat mass to lean mass, and greater central fat and insulin resistance. This paradoxical effect of lower birth weight is at least partly explained by the observation that infants who have been growth restrained in utero tend to gain weight more rapidly, or 'catch up', during the early postnatal period, which leads to increased central fat deposition. There is still debate as to whether there are critical early periods for obesity: does excess weight gain during infancy, childhood or even very early neonatal life have a greater impact on long-term fat deposition and insulin resistance? Early identification of childhood obesity risk will be aided by identification of maternal and fetal genes that regulate fetal nutrition and growth, and postnatal genes that regulate appetite, energy expenditure and the partitioning of energy intake into fat or lean tissue growth.
PubMed Accession Number :: 16612116.

Heude, B.; Petry, C. J.; Pembrey, M.; Dunger, D. B.; Ong, K. K. (2006) The insulin gene variable number of tandem repeat: associations and interactions with childhood body fat mass and insulin secretion in normal children J Clin Endocrinol Metab, 91 (7),2770-5 [Journal Article] Online
Abstract: CONTEXT: Polymorphism at the insulin gene (INS) variable number of tandem repeat (VNTR) shows variable associations with childhood body mass index (BMI) in different populations. OBJECTIVE: The objective of this study was to observe INS VNTR associations with body composition and insulin secretion in children. DESIGN: The study was designed as a prospective birth cohort study. PARTICIPANTS: A total of 947 children genotyped for the INS VNTR participated. MAIN OUTCOME MEASURES: Main outcome measures were whole body dual x-ray emission absorptiometry at 9 yr to estimate height-corrected fat mass index (FMI), truncal FMI, and fat-free mass, and insulin secretion after oral glucose at 8 yr. RESULTS: Homozygous III/III children had higher BMI (P = 0.020), FMI (P = 0.015), and truncal FMI (P = 0.022) at 9 yr than class I bearers, but no difference in fat-free mass (P = 0.23). Gain in weight sd score between birth and 3 yr was associated positively with BMI, FMI, and truncal FMI in class I bearers, but not in III/III children (p-interaction with genotype = 0.009-0.066). INS VNTR genotype was not associated overall with insulin secretion at 8 yr (P = 0.64), but class I bearers showed a stronger positive correlation between insulin secretion and BMI at 8 yr (regression coefficient +/- se, 0.26 +/- 0.05; P < 0.0001) than III/III children (-0.10 +/- 0.07; P = 0.48) (p-interaction = 0.003). CONCLUSION: We clarified that the overall association between INS VNTR class III/III genotype and larger BMI in this population relates to fat mass, but not fat-free mass. In contrast, among the subgroup of children who showed rapid infancy weight gain, class I bearers tended to have larger BMI and fat mass than III/III children. This genetic interaction could relate to insulin secretion, which, in class I bearers, increased more rapidly with overweight and obesity.
Keywords: Body Composition *Body Mass Index Body Size Child Child, Preschool Cohort Studies Fasting Genetic Predisposition to Disease Genotype Homozygote Humans Infant, Newborn Insulin/blood/*genetics/*secretion Insulin Resistance Minisatellite Repeats/*genetics Obesity/genetics Prospective Studies Research Support, Non-U.S. Gov't Weight Gain
PubMed Accession Number :: 16608900.

Ibanez, L.; Ong, K.; Dunger, D. B.; de Zegher, F. (2006) Early Development of Adiposity and Insulin Resistance Following Catch-up Weight Gain in Small-for-Gestational-Age Children J Clin Endocrinol Metab, 91 (6),2153-8 [Journal Article] Online
Abstract: Context and Objective: Low birthweight followed by rapid postnatal weight gain is associated with long-term risks for central obesity and insulin resistance. However the timing of these changes is unclear. Setting, Design, and Patients: Longitudinal cohort study in low birthweight (SGA; birthweight < -2SD: n = 29) and normal birthweight (AGA: n = 22) children from Barcelona. Main outcome measures: Body composition, by DXA scan, and insulin sensitivity, assessed longitudinally at ages 2, 3 and 4 yr old. Results: Mean height, weight and BMI at ages 2, 3 and 4 yr were not different between SGA and AGA children. At age 2 yr SGA children had similar body composition, but were more insulin sensitive than AGA children and had lower serum IGF-1 levels and lower neutrophil counts. Between ages 2 to 4 yr, despite similar gains in weight and BMI, SGA children gained more abdominal fat and body adiposity, and less lean mass than AGA children; by age 4 yr SGA children had greater adiposity, insulin resistance and higher neutrophil counts than AGA children (P = 0.01 to 0.0004). In SGA children, total and abdominal fat mass at 4 yr was more closely related to rate of weight gain between 0-2 yr (P = 0.002 to 0.0003) than between 2-4 yr (P = 0.04 to 0.1). Conclusion: Consequent to catch-up weight gain between birth to 2 yr, SGA children showed a dramatic transition toward central adiposity and insulin resistance between ages 2 to 4 yr. Understanding the mechanisms underlying this predisposition to adverse future health could lead to specific preventive interventions during early childhood.
PubMed Accession Number :: 16537681.

Forouhi, N. G.; Balkau, B.; Borch-Johnsen, K.; Dekker, J.; Glumer, C.; Qiao, Q.; Spijkerman, A.; Stolk, R.; Tabac, A.; Wareham, N. J. (2006) The threshold for diagnosing impaired fasting glucose: a position statement by the European Diabetes Epidemiology Group Diabetologia, 49 (5),822-7 [Journal Article] Online
Abstract: The category of IFG was introduced in the late 1990s to denote a state of non-diabetic hyperglycaemia defined by a fasting plasma glucose (FPG) concentration between 6.1 and 6.9 mmol/l. In 2003 the American Diabetes Association recommended that this diagnostic threshold be lowered to 5.6 mmol/l. The justification for lowering the threshold has been questioned. This simple change in cut-off value creates a pandemic of IFG, with a two- to five-fold increase in the prevalence of IFG across the world. Such a change in threshold has far-reaching public health implications. The European Diabetes Epidemiology Group (EDEG) has reviewed the evidence for this lower cut-off point for the definition of IFG and concludes that the previous definition should not be altered. EDEG further recommends that the value of all categorical definitions of non-diabetic hyperglycaemia should be reconsidered.
PubMed Accession Number :: 16525842.

Ong, K. K.; Emmett, P. M.; Noble, S.; Ness, A.; Dunger, D. B. (2006) Dietary energy intake at the age of 4 months predicts postnatal weight gain and childhood body mass index Pediatrics, 117 (3),e503-8 [Journal Article] Online
Abstract: OBJECTIVE: Rapid infant weight gain has been shown to predict later obesity risk; however, it is unclear which factors influence infant diet and weight gain. The objective of this study was to determine whether different feeding patterns and energy intakes that are provided to infants affect body weight and BMI later in childhood. METHODS: This representative birth cohort study was conducted in the United Kingdom. Energy intake at age 4 months was estimated from 1-day unweighed dietary records in 881 infants and related to their childhood weight gain and BMI. RESULTS: Among formula- or mixed-fed infants (N = 582), energy intake was higher in first-born infants (mean +/- SE: 2730 +/- 29.4 kJ/day; n = 263) than in subsequent-born infants (2620.8 +/- 25.2 kJ/day; n = 296). Energy intake at 4 months was also higher in infants who were given solid foods earlier (1-2 months: 2805.6 +/- 50.4 kJ/day, n = 89; 2-3 months: 2658.6 +/- 25.2 kJ/day, n = 339; 4+ months: 2587.2 +/- 46.2 kJ/day, n = 111). Higher energy intake at 4 months predicted greater weight gain between birth to age 1, 2, or 3 years and larger body weight and BMI at ages 1 to 5 years. No significant associations were seen in breastfed infants (N = 299). CONCLUSIONS: Among formula- or mixed-fed infants, dietary energy intake at age 4 months predicted postnatal weight gain and childhood obesity risk. Both prenatal and postnatal factors may influence infant energy intake and postnatal weight gain.
PubMed Accession Number :: 16510629.

Simmons, R. K.; Harding, A. H.; Jakes, R. W.; Welch, A.; Wareham, N. J.; Griffin, S. J. (2006) How much might achievement of diabetes prevention behaviour goals reduce the incidence of diabetes if implemented at the population level? Diabetologia, 49 (5),905-11 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Randomised trials targeting high-risk people with impaired glucose tolerance have halved progression to diabetes using behavioural interventions aimed at achieving five goals related to weight, diet and physical activity. The number of people currently meeting these goals in the general population is unknown. The potential impact on the incidence of diabetes of increasing the proportion of people who meet these goals is also unclear. We quantified the association between the achievement of behavioural goals for the prevention of diabetes and the incidence of diabetes in a population-based cohort study. SUBJECTS AND METHODS: European Prospective Investigation into Cancer (EPIC)-Norfolk is a prospective cohort of 24,155 participants aged 40-79 years who attended a baseline health check and completed validated diet and activity questionnaires. We assessed the association between achievement of five diabetes healthy behaviour prevention goals (BMI <25 kg/m(2), fat intake <30% of energy intake, saturated fat intake <10% of energy intake, fibre intake > or =15 g/4,184 kJ, physical activity >4 h/week) and risk of developing diabetes at follow-up (mean 4.6 years). RESULTS: Only 20% of EPIC participants met three or more diabetes prevention goals. Diabetes incidence was inversely related to the number of goals achieved (p<0.001). None of the participants who met all five goals developed diabetes, whereas diabetes incidence was highest in those who did not meet any goals. If the entire population were able to meet one more goal, the total incidence of diabetes would be predicted to fall by 20%. CONCLUSIONS/INTERPRETATION: In this population-based study, the risk of diabetes was inversely associated with the number of behaviour goals for diabetes prevention that were met. Interventions that promote achievement of these goals in the general population could significantly reduce the growing burden of diabetes-related morbidity and mortality.
Keywords: Adult Aged *Behavior Therapy Body Mass Index Cohort Studies Diabetes Mellitus/*epidemiology/prevention & control/*psychology Dietary Fats Dietary Fiber Energy Intake Female Great Britain/epidemiology Health Behavior Humans Incidence Male Middle Aged Prospective Studies Social Class
PubMed Accession Number :: 16508778.

Harding, A. H.; Griffin, S. J.; Wareham, N. J. (2006) Population impact of strategies for identifying groups at high risk of type 2 diabetes Prev Med, 42 (5),364-8 [Journal Article] Online
Abstract: BACKGROUND: To assess the incidence of diabetes among sub-groups of the population defined by the presence of one or more simple risk factors, and to investigate population stratification as a means of identifying groups at high risk of diabetes. METHODS: Data from EPIC-Norfolk (1993-1998), a population-based cohort study of 24,714 men and women aged 40-78 years without self-reported diabetes at baseline, were analyzed. During 12 years of follow-up, 608 new cases of diabetes were recorded. RESULTS: Age (RR 1.03; 95% CI 1.02, 1.04), parental history of diabetes (RR 2.15; 95% CI 1.80, 2.57), BMI (RR 1.76; 95% CI 1.53, 2.02) and physical activity (RR 0.72-0.77 (reference sedentary)) were independently related to risk of diabetes. Sedentary, obese individuals aged over 55 years, with a parental history of diabetes were 18 times more likely to develop diabetes than those in the lowest risk group. CONCLUSION: Sedentary, obese men and women over 55 years with a parental history of diabetes form a readily identifiable group, which could be targeted for screening and primary prevention. Groups such as that defined by physical inactivity alone would be more suitable for population level approaches.
Keywords: Adult Aged Body Mass Index Cohort Studies Diabetes Mellitus, Type 2/diagnosis/*etiology England/epidemiology Exercise Female Humans Incidence Logistic Models Male Mass Screening Middle Aged Risk Factors Smoking/*adverse effects/epidemiology
PubMed Accession Number :: 16504278.

Forouhi, N. G.; Sattar, N. (2006) CVD risk factors and ethnicity-A homogeneous relationship? Atheroscler Suppl, 7 (1),11-9 [Journal Article] Online
Abstract: Current understanding of cardiovascular disease risk (CVD) is derived largely from studies of Caucasians of European origin. However, people of certain ethnic groups experience a disproportionately greater burden of CVD including coronary heart disease (CHD) and stroke. Adoption of a Westernised lifestyle has different effects on metabolic and vascular dysfunction across populations, e.g. South Asians have a higher prevalence of coronary heart disease (CHD) and cardiovascular mortality compared with Europeans. African-Americans demonstrate higher rates of CHD and stroke while African/Caribbeans in the UK have lower CHD rates and higher stroke rates than British Europeans. Other non-European groups such as the Chinese and Japanese exhibit consistently high rates of stroke but not CHD, while Mexican Americans have a higher prevalence of both stroke and CHD, and North American native Indians also have high rates of CHD. While conventional cardiovascular risk factors such as smoking, blood pressure and total cholesterol predict risk within these ethnic groups, they do not fully account for the differences in risk between ethnic groups, suggesting that alternative explanations might exist. Ethnic groups show differences in levels of visceral adiposity, insulin resistance, and novel risk markers such as C-reactive protein (CRP), adiponectin and plasma homocysteine. The marked differences across racial and ethnic groups in disease risk are likely due in part to each of genetic, host susceptibility and environmental factors, and can provide valuable aetiological clues to differences in patterns of disease presentation, therapeutic needs and response to treatment. Ongoing studies should increase understanding of ethnicity as a potential independent risk factor, thus enabling better identification of treatment targets and selection of therapy in specific populations.
PubMed Accession Number :: 16500156.

Ibanez, L.; Valls, C.; Ong, K.; Dunger, D. B.; de Zegher, F. (2006) Metformin Therapy during Puberty delays Menarche, Prolongs Pubertal Growth, and Augments Adult Height: a Randomized Study in Low-Birthweight Girls with Early-Normal Onset of Puberty J Clin Endocrinol Metab, 91 (6),2068-73 [Journal Article] Online
Abstract: Context and Objective: Low-birthweight (LBW) girls who enter puberty earlier (around 8-9 yr) tend to have earlier menarche, earlier growth arrest, and a shorter adult stature. At present, there is no therapy for most of these girls. In LBW girls with early puberty, hyperinsulinemic insulin resistance could underpin their rapid transit through puberty and their loss of adult stature. We explored the effects of insulin-sensitization with metformin during puberty. Setting, Design, and Patients: In an open-labeled, prospective study, 22 LBW girls (BW below -1.5 SD Score [SDS] for gestational age) with early-normal puberty (stage 2 breast development (B2) at age 8-9 yr) were randomized to remain untreated [n = 12] or to receive metformin [850 mg/d; n = 10] for 36 mo (mean age at start = 9.0 yr). All girls remained untreated between 36 and 42 mo. Main outcome measures: Pubertal growth, body composition by absorptiometry, uterine-ovarian size by ultrasound, fasting insulin, glucose, lipids, leptin, insulin-like growth factor-1 (IGF-1) and IGF-binding protein-1 (IGFBP-1). Results: Metformin treatment resulted in a longer duration from B2 to menarche (P < 0.01; median difference +1.0 yr), taller near-adult height (P < 0.01) and leaner body composition (P < 0.001). Metformin was also associated with lower insulin resistance, leptin and IGF-1 levels, higher SHBG and IGFBP-1 levels, and with a more favorable lipid profile. Bone mineral density and uterine-ovarian growth were unaffected. Conclusion: Metformin treatment for 36 mo in LBW girls with early-normal puberty normalized their pubertal progression to menarche and increased height gains up to adult stature. These data support the concept that insulin is a major co-determinant of the pubertal tempo and pubertal height gain in girls.
PubMed Accession Number :: 16492692.

Zhao, J. H. (2006) Pedigree-drawing with R and graphviz Bioinformatics, 22 (8),1013-4 [Journal Article] Online
Abstract: SUMMARY: Two functions for pedigree-drawing available in R (http://www.r-project.org): plot.pedigree in kinship and pedtodot in gap are described. The latter requires graphviz (http://www.graphviz.org). They can produce many pedigree diagrams quickly into a single file, serving as alternatives to programs that only offer interactive use. AVAILABILITY: Packages kinship and gap are available from http://cran.r-project.org. CONTACT: jinghua.zhao@mrc-epid.cam.ac.uk.
PubMed Accession Number :: 16488908.

Petry, C. J.; Ong, K. K.; Michelmore, K. F.; Artigas, S.; Wingate, D. L.; Balen, A. H.; de Zegher, F.; Ibanez, L.; Dunger, D. B. (2006) Associations between common variation in the aromatase gene promoter region and testosterone concentrations in two young female populations J Steroid Biochem Mol Biol, 98 (4-5),199-206 [Journal Article] Online
Abstract: We recently reported association between a coding-region single nucleotide polymorphism (SNP50) in the aromatase gene that encodes a key enzyme in testosterone metabolism, with risk for the development of precocious pubarche and circulating testosterone concentrations in two independent female populations. We have now explored further association with variation in the promoter-region of the aromatase gene. We genotyped six promoter-region haplotype-tag SNPs in young women from Oxford, UK (n=109), and in girls with precocious pubarche (n=186) and controls (n=71) from Barcelona, Spain. Aromatase distal promoter-region variation was associated with plasma testosterone concentrations in both Oxford (r(2)=18.3%, p=0.01) and Barcelona (r(2)=8.5%, p=0.03) females. These associations were independent of SNP50, but appeared to be dependent on different SNPs in Oxford (r(2)=13.7%, p=0.006 with SNPs 11 (p=0.009), 28 (p=0.02) and 39 (p=0.06)) and Barcelona (r(2)=5.9%, p=0.002 with SNP43 (p=0.002)) populations. Aromatase distal promoter-region variation was also associated with PCOS symptom score in Oxford women (r(2)=14.5%, p=0.048), but, unlike SNP50, was not associated with precocious pubarche risk in Barcelona girls. In conclusion, aromatase distal promoter-region variation appears to have functional consequences for plasma testosterone concentrations in females. The variable associations with androgen-related clinical features could possibly reflect the tissue-specific promoters of the aromatase gene.
PubMed Accession Number :: 16473000.

Ekelund, U.; Ong, K.; Linne, Y.; Neovius, M.; Brage, S.; Dunger, D. B.; Wareham, N. J.; Rossner, S. (2006) Upward weight percentile crossing in infancy and early childhood independently predicts fat mass in young adults: the Stockholm Weight Development Study (SWEDES) Am J Clin Nutr, 83 (2),324-30 [Journal Article] Online
Abstract: BACKGROUND: Rapid early postnatal weight gain predicts increased subsequent obesity and related disease risks. However, the exact timing of adverse rapid postnatal weight gain is unclear. OBJECTIVE: The objective was to examine the associations between rapid weight gain in infancy and in early childhood in relation to body composition at age 17 y. DESIGN: This prospective cohort study was conducted in 248 (103 males) singletons and their mothers. Height and weight were measured at birth, 6 mo, and 3 and 6 y. The rates of weight gain during infancy (0-6 mo) and early childhood (3-6 y) were calculated as changes in sex- and age-adjusted weight SD scores during these time periods. At 17 y, body composition was measured by air-displacement plethysmography. RESULTS: Increasing weight gain during infancy and early childhood were both independently associated with larger body mass index, fat mass, relative fat mass, fat-free mass, and waist circumference at 17 y (P < 0.005 for all; adjusted for sex, birth weight, gestational age, current height, maternal socioeconomic status, and maternal fat mass). Rapid weight gain in infancy, but not in early childhood, also predicted taller height at 17 y (P < 0.001). CONCLUSIONS: Rapid weight gain in both infancy and early childhood is a risk factor for adult adiposity and obesity. Rapid weight gain in infancy also predicted taller adult height. We hypothesize that rapid weight gains in infancy and early childhood are different processes and may allow separate opportunities for early intervention against obesity risk later in life.
Keywords: Adipose Tissue/*metabolism Adolescent Aging/*metabolism Body Composition/*physiology Body Constitution/physiology Body Height/physiology Body Mass Index Body Weight/*physiology Child Child, Preschool Cohort Studies Female Humans Infant Infant, Newborn Male Obesity/*epidemiology/etiology Plethysmography/methods Predictive Value of Tests Prospective Studies Risk Sweden/epidemiology Weight Gain/physiology
PubMed Accession Number :: 16469991.

Ioannidis, J. P.; Gwinn, M.; Little, J.; Higgins, J. P.; Bernstein, J. L.; Boffetta, P.; Bondy, M.; Bray, M. S.; Brenchley, P. E.; Buffler, P. A.; Casas, J. P.; Chokkalingam, A.; Danesh, J.; Smith, G. D.; Dolan, S.; Duncan, R.; Gruis, N. A.; Hartge, P.; Hashibe, M.; Hunter, D. J.; Jarvelin, M. R.; Malmer, B.; Maraganore, D. M.; Newton-Bishop, J. A.; O'Brien, T. R.; Petersen, G.; Riboli, E.; Salanti, G.; Seminara, D.; Smeeth, L.; Taioli, E.; Timpson, N.; Uitterlinden, A. G.; Vineis, P.; Wareham, N.; Winn, D. M.; Zimmern, R.; Khoury, M. J. (2006) A road map for efficient and reliable human genome epidemiology Nat Genet, 38 (1),3-5 [Journal Article] Online
Abstract: Networks of investigators have begun sharing best practices, tools and methods for analysis of associations between genetic variation and common diseases. A Network of Investigator Networks has been set up to drive the process, sponsored by the Human Genome Epidemiology Network. A workshop is planned to develop consensus guidelines for reporting results of genetic association studies. Published literature databases will be integrated, and unpublished data, including 'negative' studies, will be captured by online journals and through investigator networks. Systematic reviews will be expanded to include more meta-analyses of individual-level data and prospective meta-analyses. Field synopses will offer regularly updated overviews.
PubMed Accession Number :: 16468121.

Patel, B. D.; Welch, A. A.; Bingham, S. A.; Luben, R. N.; Day, N. E.; Khaw, K. T.; Lomas, D. A.; Wareham, N. J. (2006) Dietary anti-oxidants and symptomatic asthma in adults Thorax, 61 (5),388-93 [Journal Article] Online
Abstract: Objective: Several anti-oxidant nutrients have been reported to be inversely associated with asthma. The objective of this study was to assess the independent associations of these nutrients with asthma in adults. Design: A nested case control study in 515 adults with physician-diagnosed asthma and 515 matched controls with dietary data obtained from seven-day food diaries. Main outcome measures: Physician diagnosed asthma and current symptomatic asthma (diagnosed asthma and self-reported wheeze within the previous 12 months). Results: Cases were similar to controls in age, sex, social class and daily energy intake, but had a lower median intake of fruit (132.1 g/day Vs 149.1 g/day, p</=0.05). 51.5% of the population reported zero consumption of citrus fruit, relative to these individuals, people who consumed >46.3 g/day had a reduced risk of diagnosed and symptomatic asthma (OR adjusted for potential confounders 0.59, CI 0.43-0.82, and 0.51, 0.33-0.79, respectively). In nutrient analysis, dietary vitamin C and manganese were inversely and independently associated with symptomatic asthma (adjusted OR per quintile increase 0.88, 0.77-1.00, vitamin C and 0.85, 0.74-0.98, manganese) but only manganese was independently associated with diagnosed asthma (0.86, 0.77-0.95). Adjusted plasma vitamin C levels were significantly lower in symptomatic cases (54.3 micromol/L) than in controls (58.2micromol/L, p=0.003). Conclusions: Symptomatic asthma in adults is associated with a low dietary intake of fruit, the anti-oxidant nutrients vitamin C and manganese, and low plasma vitamin C levels. These findings suggest that diet may be a potentially modifiable risk factor for the development of asthma.
PubMed Accession Number :: 16467075.

Zhao, J. H.; Tan, Q. (2006) Integrated analysis of genetic data with R Hum Genomics, 2 (4),258-65 [Journal Article] Online
Abstract: Genetic data are now widely available. There is, however, an apparent lack of concerted effort to produce software systems for statistical analysis of genetic data compared with other fields of statistics. It is often a tremendous task for end-users to tailor them for particular data, especially when genetic data are analysed in conjunction with a large number of covariates. Here, R (http://www.r-project.org), a free, flexible and platform-independent environment for statistical modelling and graphics is explored as an integrated system for genetic data analysis. An overview of some packages currently available for analysis of genetic data is given. This is followed by examples of package development and practical applications. With clear advantages in data management, graphics, statistical analysis, programming, internet capability and use of available codes, it is a feasible, although challenging, task to develop it into an integrated platform for genetic analysis; this will require the joint efforts of many researchers.
PubMed Accession Number :: 16460651.

Lee, Y. S.; Challis, B. G.; Thompson, D. A.; Yeo, G. S.; Keogh, J. M.; Madonna, M. E.; Wraight, V.; Sims, M.; Vatin, V.; Meyre, D.; Shield, J.; Burren, C.; Ibrahim, Z.; Cheetham, T.; Swift, P.; Blackwood, A.; Hung, C. C.; Wareham, N. J.; Froguel, P.; Millhauser, G. L.; O'Rahilly, S.; Farooqi, I. S. (2006) A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance Cell Metab, 3 (2),135-40 [Journal Article] Online
Abstract: The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, alpha- and beta-MSH, the majority of attention has focused on alpha-MSH, partly reflecting the absence of beta-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding beta-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type beta-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for beta-MSH in the control of human energy homeostasis.
PubMed Accession Number :: 16459314.

Franks, P. W.; Looker, H. C.; Kobes, S.; Touger, L.; Tataranni, P. A.; Hanson, R. L.; Knowler, W. C. (2006) Gestational glucose tolerance and risk of type 2 diabetes in young Pima Indian offspring Diabetes, 55 (2),460-5 [Journal Article] Online
Abstract: The in utero environment is a powerful risk factor for type 2 diabetes in offspring, but little is known about the risk conveyed by nondiabetic gestational glucose levels. This issue was explored in 911 nondiabetic Pima Indian mothers and 1,436 of their children. Associations were assessed in multivariate models between maternal third trimester glucose tolerance and indexes of body composition and glycemic control in their children. At parturition, the mothers' ages ranged from 14 to 43 years. Offspring were studied at age 0-39 years. An SD (1.3 mmol/l) of maternal glucose was associated with 56 g higher birth weight (P = 0.0002). This effect persisted when only offspring of normal glucose tolerant mothers were examined (57 g, P < 0.0001). In Cox proportional hazards models, the adjusted hazard rate ratio for offspring risk of diabetes per SD maternal glucose was 1.6 (95% CI 1.3-2.0, P < 0.0001). When only offspring of normal glucose tolerant mothers were examined, the risk was reduced but remained significant (1.3 [1.04-1.71], P = 0.026). In conclusion, maternal glycemia during pregnancy is associated with increased birth weight and risk of diabetes in Pima Indian offspring, even when mothers are normal glucose tolerant during pregnancy. Thus, prevention of offspring type 2 diabetes may require strategies that focus on improving gestational glucose tolerance even within the normal range.
Keywords: Adolescent Adult Aging Birth Weight Blood Glucose/metabolism Child Diabetes Mellitus, Type 2/*ethnology/*etiology Female Glucose Intolerance/*ethnology/*etiology Humans *Indians, North American Pregnancy Pregnancy Trimester, Third Pregnancy in Diabetics Research Support, N.I.H., Intramural Risk Factors
PubMed Accession Number :: 16443781.

Canoy, D.; Wareham, N.; Luben, R.; Welch, A.; Bingham, S.; Day, N.; Khaw, K. T. (2006) Serum lipid concentration in relation to anthropometric indices of central and peripheral fat distribution in 20,021 British men and women: Results from the EPIC-Norfolk population-based cohort study Atherosclerosis, 189 (2),420-7 [Journal Article] Online
Abstract: AIMS: Central adiposity has been linked with adverse metabolic profile including dyslipidaemia but recent studies suggested that peripheral fat distribution play a role in regulating daily fluxes in circulating non-esterified fatty acids. We examine whether lipid levels vary between central and peripheral fat distribution in the general population. METHODS AND RESULTS: We examined the cross-sectional relation between fat distribution indices and lipid concentration in 20,021 apparently healthy men and women of the Norfolk cohort of the European Investigation into Cancer and Nutrition (EPIC-Norfolk). Waist-hip ratio was positively related to total and low density lipoprotein (LDL) cholesterol and negatively related to high density lipoprotein (HDL) cholesterol in both men and women, independently of body mass index (BMI). Although similar results were noted for waist circumference, individuals with bigger hip circumference had lower total and LDL-cholesterol and higher HDL-cholesterol when adjusting for BMI and/or waist circumference in both men and women. CONCLUSION: Regional fat distribution was related to lipid profile independently of BMI. The independent contribution of waist and hip circumference in opposite directions was intriguing. These findings may help explain the associations observed between different fat distribution phenotypes and coronary heart disease.
PubMed Accession Number :: 16442545.

Myint, P. K.; Luben, R. N.; Welch, A. A.; Bingham, S. A.; Wareham, N. J.; Khaw, K. T. (2006) Effect of Age on the Relationship of Occupational Social Class with Prevalence of Modifiable Cardiovascular Risk Factors and Cardiovascular Diseases. A Population-Based Cross-Sectional Study from European Prospective Investigation into Cancer - Norfolk (EPIC-Norfolk) Gerontology, 52 (1),51-8 [Journal Article] Online
Abstract: Background: Previous studies on cardiovascular risk profile in different socioeconomic status were focused on younger populations and many of them have not been able to take into account age and sex differences. Objectives: To investigate the relationship of occupational social class with the prevalence of cardiovascular disease risk factors and cardiovascular diseases in younger (<65 years) and older (>/=65 years) men and women. Methods: A population-based-cross sectional study was conducted in a general community in Norfolk, United Kingdom. Participants were 23,085 men and women aged 40-79 years, recruited from general practice age-sex registers as part of European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk). The prevalence of cardiovascular risk factors and cardiovascular diseases were examined. Results: The prevalence of smoking was significantly higher in those in manual social classes particularly in the younger (<65) age group. Younger women in manual social classes were more likely to be smokers compared to older women in the same social class. Being in manual social classes was associated with higher cholesterol levels in women but lower cholesterol levels in men. Manual social class was associated with higher physical activity in those younger than 65 years but this association was reversed in those 65 years or older. Conclusion: Occupational social class is differently related to cardiovascular risk factors in individuals depending on their age and sex. This may reflect differences in behavior at work and leisure, which vary by sex and pre- and postretirement. Interventions to promote health and reduce social inequalities need to take age and gender into account. Copyright (c) 2006 S. Karger AG, Basel.
PubMed Accession Number :: 16439825.

Bhattacharyya, S.; Luan, J.; Challis, B.; Keogh, J.; Montague, C.; Brennand, J.; Morten, J.; Lowenbeim, S.; Jenkins, S.; Farooqi, I. S.; Wareham, N. J.; O'Rahilly, S. (2006) Sequence variants in the melatonin-related receptor gene (GPR50) associate with circulating triglyceride and HDL levels J Lipid Res, 47 (4),761-6 [Journal Article] Online
Abstract: The gene encoding the melatonin-related receptor (GPR50) is highly expressed within hypothalamic nuclei concerned with the control of body weight and metabolism. We screened GPR50 for mutations in an obese cohort and identified an insertion of four amino acid residues (TTGH) at position 501, two common coding polymorphisms (T528A and V602I), and one noncoding polymorphism (C-16X2GPR50T). Single-nucleotide polymorphisms were then typed in 500 English Caucasian subjects, and associations were sought to intermediate obesity phenotypes. Although no association was seen with body mass index, carriers of two copies of the mutant allele at C-16X2GPR50T, Ins501Del, and A1582G had significantly higher fasting circulating triglyceride levels (P < 0.05). In a separate set of 585 subjects, the associations were replicated, with statistically significant effects of similar magnitude and direction. The association of C-16X2GPR50T with fasting triglycerides was highly significant (P < 0.001). In addition, a significant association between C-16X2GPR50T and circulating HDL levels was observed in the combined population, with C-16X2GPR50T carriers having significantly lower circulating HDL-cholesterol levels (1.39 mM) than wild-type subjects (1.47 mM) (P < 0.01). These findings suggest a previously unexpected role for this orphan receptor in the regulation of lipid metabolism that warrants further investigation.
PubMed Accession Number :: 16436372.

Barroso, I.; Luan, J.; Sandhu, M. S.; Franks, P. W.; Crowley, V.; Schafer, A. J.; O'Rahilly, S.; Wareham, N. J. (2006) Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes Diabetologia, 49 (3),501-505 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PPARGC1A) is a transcriptional co-activator with a central role in energy expenditure and glucose metabolism. Several studies have suggested that the common PPARGC1A polymorphism Gly482Ser may be associated with risk of type 2 diabetes, with conflicting results. To clarify the role of Gly482Ser in type 2 diabetes and related human metabolic phenotypes we genotyped this polymorphism in a case-control study and performed a meta-analysis of relevant published data. MATERIALS AND METHODS: Gly482Ser was genotyped in a type 2 diabetes case-control study (N=1,096) using MassArray technology. A literature search revealed publications that examined Gly482Ser for association with type 2 diabetes and related metabolic phenotypes. Meta-analysis of the current study and relevant published data was undertaken. RESULTS: In the pooled meta-analysis, including data from this study and seven published reports (3,718 cases, 4,818 controls), there was evidence of between-study heterogeneity (p<0.1). In the fixed-effects meta-analysis, the pooled odds ratio for risk of type 2 diabetes per Ser482 allele was 1.07 (95% CI 1.00-1.15, p=0.044). Elimination of one of the studies from the meta-analysis gave a summary odds ratio of 1.11 (95% CI 1.04-1.20, p=0.004), with no between-study heterogeneity (p=0.475). For quantitative metabolic traits in normoglycaemic subjects, we also found significant between-study heterogeneity. However, no significant association was observed between Gly482Ser and BMI, fasting glucose or fasting insulin. CONCLUSIONS/INTERPRETATION: This meta-analysis of data from the current and published studies supports a modest role for the Gly482Ser PPARGC1A variant in type 2 diabetes risk.
PubMed Accession Number :: 16435105.

Forouhi, N. G.; Merrick, D.; Goyder, E.; Ferguson, B. A.; Abbas, J.; Lachowycz, K.; Wild, S. H. (2006) Diabetes prevalence in England, 2001-estimates from an epidemiological model Diabet Med, 23 (2),189-97 [Journal Article] Online
Abstract: Aims To estimate the total prevalence of diabetes mellitus (diagnosed and undiagnosed) at national, regional and local level in England to support health-care planning and delivery. Methods An epidemiological model was constructed by applying age-sex-ethnic-specific reference prevalence rates from epidemiological studies to resident populations (2001 census) of England at national, regional, and local authority/Primary Care Trust levels. Results Estimated prevalence of total diabetes for all persons in England was 4.41% in 2001, equating to 2 168 000 persons. Type 2 diabetes was estimated to affect 2 002 000 persons (92.3%) and Type 1 diabetes 166 000 persons (7.7%). Diabetes prevalence was estimated to be higher in women (5.17%) than men (3.61%). People from ethnic minority groups had higher crude prevalence than White Europeans (4.29, 5.69, 6.63 and 2.13% among White Europeans, Black African/Caribbeans, South Asians and 'other' groups, respectively). Prevalence increased sharply with age (0.33, 3.37 and 13.92%, respectively, in those aged 0-29, 30-59 and 60+ years). The model allows use of user-defined population denominator estimates to derive numbers and prevalence of people with diabetes for a given local population group, such as at ward or general practice level. Conclusions Self-reported diabetes prevalence estimates from community surveys underestimate the true burden of diabetes. The model can be used to derive the expected total prevalence of diabetes in health areas that lack reliable data to facilitate the implementation of the National Service Framework for diabetes. It will also allow estimates of future diabetes prevalence to be derived, and can potentially be used for prevalence estimates in all of the UK. Diabet. Med. (2005).
PubMed Accession Number :: 16433718.

Ekelund, U.; Neovius, M.; Linne, Y.; Rossner, S. (2006) The criterion validity of a last 7-day physical activity questionnaire (SAPAQ) for use in adolescents with a wide variation in body fat: the Stockholm Weight Development Study Int J Obes (Lond), 30 ,1019-21 [Journal Article] Online
Abstract: Objective:The aim of the present study was to assess the criterion validity of a newly developed self-reported last 7-day physical activity questionnaire (SAPAQ) for use in Swedish adolescents with a wide variation in body fatness.Measurements:We compared the self-reported total number of MET-minutes with objectively assessed variables of physical activity obtained by accelerometry in 49 (18 male, 31 female subjects) 17-year-old adolescents.Results:Self-reported physical activity was significantly and inversely related to time spent sedentary (r=-0.45; P<0.001) and significantly and positively associated with time spent in physical activity (r=0.51; P<0.001) and the total amount of physical activity (r=0.49; P<0.001). Gender and body fat did not affect the associations between self-reported and objectively assessed physical activity.Conclusion:Our results indicate that the newly developed questionnaire is a valid method for ranking individuals in terms of the total amount of physical activity in Swedish adolescents.International Journal of Obesity advance online publication, 24 January 2006; doi:10.1038/sj.ijo.0803207.
PubMed Accession Number :: 16432550.

Mukhopadhyay, B.; Forouhi, N. G.; Fisher, B. M.; Kesson, C. M.; Sattar, N. (2006) A comparison of glycaemic and metabolic control over time among South Asian and European patients with Type 2 diabetes: results from follow-up in a routine diabetes clinic Diabet Med, 23 (1),94-8 [Journal Article] Online
Abstract: Aims Although South Asians have a higher prevalence of diabetes which develops at a younger age, data on change in metabolic parameters post-diagnosis are relatively sparse. We therefore wished to determine whether South Asians with diabetes had similar or greater year-on-year deterioration in metabolic parameters compared with Europeans. Methods We analysed longitudinal change in metabolic parameters [glycated haemoglobin (HbA(1c)), blood pressure, body mass index (BMI), lipids] among South Asian (n = 210) and European (n = 1557) patients consecutively attending the same diabetes clinic over a mean period of 5.3 years. Results South Asians were younger than Europeans at first recorded diagnosis of diabetes (mean age 45.9 vs. 57.3 years, P < 0.001) and had significantly lower ( approximately 1.2 units) BMI and blood pressure. Mean HbA(1c) was not different across ethnic groups at first visit, but with time glycaemic control was worse in South Asians than Europeans, with average deterioration 1.31% (= 0.23%/year) in Asians vs. 0.82% (0.16%/year) in Europeans, P = 0.003. This ethnic difference in mean change in HbA(1c) persisted after adjustment for age, sex, baseline HbA(1c), and weight change in linear regression analysis (beta = 0.46, 95% CI 0.24-0.69, P < 0.001), and with additional adjustment for time to referral and duration of diabetes (P = 0.01). Moreover, South Asians had significantly smaller improvements in blood pressure (P < 0.001) and cholesterol (P = 0.044) over the follow-up period in keeping with fewer prescriptions of anti-hypertensive agents and lipid-lowering agents. Conclusions These data suggest the need to be more aggressive in the management of diabetes and related risk factors in South Asians. Diabet. Med. (2005).
PubMed Accession Number :: 16409573.

Myint, P. K.; Welch, A. A.; Bingham, S. A.; Luben, R. N.; Wareham, N. J.; Day, N. E.; Khaw, K. T. (2006) Smoking predicts long-term mortality in stroke: The European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study Prev Med, 42 (2),128-31 [Journal Article] Online
Abstract: BACKGROUND.: While the relationship between risk factors and stroke is well established, there is less information about the risk factors and survival after stroke. We examined the independent association between cardiovascular and modifiable lifestyle risk factors and subsequent mortality in people with stroke. METHODS.: 308 free-living men and women with stroke at baseline survey in 1993-1997 participating in the European Prospective Investigation into Cancer (EPIC)-Norfolk were followed up for long-term mortality (average follow-up 7.5 years). Using Cox's proportional hazards model, we assessed the relationships between an individual's age, sex, cardiovascular risk profile including systolic blood pressure, body mass index, cholesterol, history of diabetes and lifestyle behaviors smoking and alcohol consumption and subsequent mortality up to July 2004. RESULTS.: There were a total of 100 deaths during follow-up (total person years = 2318). Advancing age (RR 1.72, 95%CI: 1.42, 2.09) and current smoking (RR 2.27, 95%CI: 1.12, 4.57) predicted higher risk while female sex was associated with reduced risk (RR 0.51, 95%CI; 0.31, 0.84) of subsequent mortality after stroke independently of other risk factors investigated. CONCLUSIONS.: Our findings may provide further empirical encouragement for smoking cessation after stroke.
PubMed Accession Number :: 16388841.

Rip, J.; Nierman, M. C.; Wareham, N. J.; Luben, R.; Bingham, S. A.; Day, N. E.; van Miert, J. N.; Hutten, B. A.; Kastelein, J. J.; Kuivenhoven, J. A.; Khaw, K. T.; Boekholdt, S. M. (2006) Serum lipoprotein lipase concentration and risk for future coronary artery disease: the EPIC-Norfolk prospective population study Arterioscler Thromb Vasc Biol, 26 (3),637-42 [Journal Article] Online
Abstract: BACKGROUND: Lipoprotein lipase (LPL) is associated with coronary artery disease (CAD) risk, but prospective population data are lacking. This is mainly because of the need for cumbersome heparin injections, which are necessary for LPL measurements. Recent retrospective studies, however, indicate that LPL concentration can be reliably measured in serum that enabled evaluation of the prospective association between LPL and future CAD. METHODS AND RESULTS: LPL concentration was determined in serum samples of men and women in the EPIC-Norfolk population cohort who developed fatal or nonfatal CAD during 7 years of follow-up. For each case (n=1006), 2 controls, matched for age, sex, and enrollment time, were identified. Serum LPL concentration was lower in cases compared with controls (median and interquartile range: 61 [43-85] versus 66 [46-92] ng/mL; P<0.0001). Those in the highest LPL concentration quartile had a 34% lower risk for future CAD compared with those in the lowest quartile (odds ratio [OR] 0.66; confidence interval [CI], 0.53 to 0.83; P<0.0001). This effect remained significant after adjustment for blood pressure, diabetes, smoking, body mass index, and low-density lipoprotein (LDL) cholesterol (OR, 0.77; CI, 0.60-0.99; P=0.02). As expected from LPL biology, additional adjustments for either high-density lipoprotein cholesterol (HDL-C) or triglyceride (TG) levels rendered loss of statistical significance. Of interest, serum LPL concentration was positively linear correlated with HDL and LDL size. CONCLUSIONS: Reduced levels of serum LPL are associated with an increased risk for future CAD. The data suggest that high LPL concentrations may be atheroprotective through decreasing TG levels and increasing HDL-C levels.
PubMed Accession Number :: 16373616.

Simmons, R. K.; Wareham, N. J. (2006) Commentary: Obesity is not a newly recognized public health problem--a commentary of Breslow's 1952 paper on 'public health aspects of weight control' Int J Epidemiol, 35 (1),14-6 [Journal Article] Online
PubMed Accession Number :: 16339602.

Al-Zahrani, A.; Sandhu, M. S.; Luben, R. N.; Thompson, D.; Baynes, C.; Pooley, K. A.; Luccarini, C.; Munday, H.; Perkins, B.; Smith, P.; Pharoah, P. D.; Wareham, N. J.; Easton, D. F.; Ponder, B. A.; Dunning, A. M. (2006) IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer Hum Mol Genet, 15 (1),1-10 [Journal Article] Online
Abstract: Experimental and observational studies in humans and animals suggest that insulin-like growth factor 1 (IGF1) and its principal binding protein, IGFBP3, may influence breast cancer susceptibility. We have examined the association of nine and four single nucleotide polymorphisms (SNPs) in the IGF1 gene and in the IGFBP3 genes, respectively, with circulating levels of their gene products in a population-based study of 600 middle-aged men and women, and in a breast cancer case-control study, comprised 4647 cases and 4564 controls. All study participants are from the East Anglian region of UK. SNPs were specifically chosen to tag all other known SNPs in each gene. Several SNPs in each gene are associated both with circulating levels of their respective proteins and with risk of breast cancer. In particular, the c allele of IGF1 SNPrs1520220 is associated with increased circulating IGF1 (r(2)=2.1%, P-trend=0.003) in females and an increased risk of breast cancer: odds ratio (OR) (cc/gg)=1.41; 95% confidence intervals (95% CI) 1.11-1.79, P-trend=0.03. The a allele of IGFBP3 SNP rs2854744 is associated with increased circulating IGFBP3 (r(2)=9.7%, P<10(-9)) and a decreased risk of breast cancer: OR (aa/cc)=0.87; 95% CI 0.77-0.99, P=0.03. Our data indicate that common variants in the IGF1 and IGFBP3 genes are associated with differences in circulating levels of IGF1 and IGFBP3 and with breast cancer risk. More specifically and consistent with experimental models, our data suggest that higher IGF1 levels may increase the risk of breast cancer but higher IGFBP3 levels may be protective.
PubMed Accession Number :: 16306136.

Boekholdt, S. M.; Hack, C. E.; Sandhu, M. S.; Luben, R.; Bingham, S. A.; Wareham, N. J.; Peters, R. J.; Jukema, J. W.; Day, N. E.; Kastelein, J. J.; Khaw, K. T. (2006) C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: The EPIC-Norfolk prospective population study 1993-2003 Atherosclerosis, 187 (2),415-22 [Journal Article] Online
Abstract: INTRODUCTION: Measurement of C-reactive protein (CRP) levels has been proposed as a useful marker to improve the prediction of future coronary artery disease (CAD) risk, but this notion has been challenged recently. METHODS AND RESULTS: We performed a prospective case-control study among apparently healthy men and women. The odds ratio (OR) for future CAD incidence was 2.49 (95% CI=2.02-3.08, p for linearity <0.0001) unadjusted, and 1.66 (95% CI=1.31-2.12, p for linearity <0.0001), after adjustment for classical cardiovascular risk factors, for top versus bottom quartile of the CRP distribution. Notably, the risk factor adjusted predictive value was substantially stronger for fatal CAD (OR=2.92, 95% CI=1.83-4.67, p for linearity <0.0001) than for non-fatal CAD (OR=1.25, 95% CI=0.93-1.66, p for linearity=0.06). CRP levels were among the strongest predictors of CAD incidence and mortality. CRP levels remained a statistically significant predictor of future CAD, even after adjustment for the Framingham risk score. CONCLUSIONS: In this British cohort with risk factor levels representative of a contemporary Western population, CRP concentration was among the strongest predictors of CAD incidence and mortality. We suggest that current guidelines on CRP measurement in clinical practice should be based on contemporary and representative populations.
PubMed Accession Number :: 16257408.

Myint, P. K.; Luben, R. N.; Surtees, P. G.; Wainwright, N. W.; Welch, A. A.; Bingham, S. A.; Day, N. E.; Wareham, N. J.; Khaw, K. T. (2006) Relation Between Self-Reported Physical Functional Health and Chronic Disease Mortality in Men And Women in the European Prospective Investigation Into Cancer (EPIC-Norfolk): A Prospective Population Study Ann Epidemiol, 16 ,492-500 [Journal Article] Online
Abstract: PURPOSE: To explore the relationship between self-reported physical functional health and mortality. METHODS: A cohort of 17,777 men and women aged 41-80 years who completed the anglicised 36-item short-form questionnaire (UK SF-36) in 1996-2000 were followed prospectively until 2004, average 6.5 years, for mortality from all causes, from cardiovascular disease, from cancer, and from all other causes. RESULTS: During 115,527 person-years of follow-up, 1065 deaths occurred. After adjusting for age, body mass index, systolic blood pressure, cholesterol, smoking, diabetes, and social class, the relative risks (RR) for all cause mortality were 2.15 (95% CI: 1.54, 2.99) and 2.42 (1.57, 3.74), cardiovascular mortality were RR=2.71 (1.47, 4.98) and 3.09 (1.30, 7.33), and death from other causes excluding cancer RR=2.88 (1.43, 5.79) and 5.22 (1.21, 22.53) in men and women respectively for those who were in the lowest compared to top quintile of SF-36 scores. These associations remained unchanged after exclusion of deaths during the first two years of follow-up and were also consistent in different age groups. CONCLUSIONS: Poor self-reported physical functional health in men and women without known instances of prevalent cardiovascular disease or cancer predicts total and cardiovascular disease mortality in the general population independently of known risk factors.
PubMed Accession Number :: 16005244.

Welch, A.A; Bingham, S.A.; Ive, J.; Friesen, M. D.; Wareham, N.J.; Riboli, E.; Khaw, K. T. (2006) Dietary fish intake and plasma phospholiplid n-3 polyunsaturated fatty acid concentrations in men and women in the European Prospective Investigation into Cancer-Norfolk United Kingdom cohort Am J Clin Nutr, 84 ,1330-9 [Journal Article]

Zhao, J. H.; Tan, Q. (2006) Genetic dissection of complex traits In Silico: approaches, problems and solutions Current Bioinformatics, 1 ,259-269 [Journal Article]

Canoy, D.; Wareham, N.; Welch, A.; Bingham, S.; Luben, R.; Day, N.; Khaw, K. T. (2005) Plasma ascorbic acid concentrations and fat distribution in 19 068 British men and women in the European Prospective Investigation into Cancer and Nutrition Norfolk cohort study Am J Clin Nutr, 82 (6),1203-1209 [Journal Article] Online
Abstract: BACKGROUND: Antioxidants, such as ascorbic acid, play a role in scavenging free radicals to protect against oxidative endothelial damage. Excess fat may promote fatty acid oxidation and increase free radical concentrations, which could result in increased antioxidant use. Whether plasma ascorbic acid concentrations are associated with fat distribution remains unclear. OBJECTIVE: Our aim was to examine the association between abdominal obesity, as measured by the waist-to-hip ratio, and plasma ascorbic acid concentrations in the general population. DESIGN: We examined the cross-sectional relation between anthropometric measurements of fat distribution and plasma ascorbic acid concentrations in 19 068 men and women aged 45-79 y without known chronic illness. Dietary ascorbic acid intake was estimated for a subgroup of 8178 men and women who kept 7-d food diaries coded for nutrient intake. RESULTS: The waist-to-hip ratio was inversely related to plasma ascorbic acid concentrations in both men and women. This association was independent of body mass index, age, vitamin supplement use, cigarette smoking, and socioeconomic group. Waist and hip circumferences showed separate and opposite associations with plasma ascorbic acid concentrations, independent of body mass index and other covariates. Dietary ascorbic acid intake only partly explained the observed associations. CONCLUSIONS: Plasma ascorbic acid was associated with fat distribution independent of body mass index. Differences in dietary intake and lifestyle habits, underlying systemic oxidative stress, or both may explain the inverse relation between fat distribution and plasma ascorbic acid concentrations. Additional studies are needed to determine the underlying explanation of these observations.
PubMed Accession Number :: 16332652.

Mericq, V.; Ong, K. K.; Bazaes, R.; Pena, V.; Avila, A.; Salazar, T.; Soto, N.; Iniguez, G.; Dunger, D. B. (2005) Longitudinal changes in insulin sensitivity and secretion from birth to age three years in small- and appropriate-for-gestational-age children Diabetologia, 48 (12),2609-14 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: Insulin resistance and type 2 diabetes risk in human subjects who were small-for-gestational-age (SGA) at birth may be a consequence of rapid early postnatal weight gain. MATERIALS AND METHODS: We prospectively studied early changes in fasting insulin sensitivity and insulin secretion, assessed by a short intravenous glucose tolerance test that was conducted several times from birth to 3 years of age in 55 SGA (birthweight below fifth percentile) newborns and in 13 newborns with a birthweight appropriate for gestational age (AGA). RESULTS: Most SGA infants showed postnatal upward weight centile crossing and by 3 years were similar in size to AGA infants. SGA infants had lower pre-feed insulin levels at postnatal age 48 h than AGA infants (median 34.4 vs 59.7 pmol/l, p<0.05), but by the age of 3 years they had higher fasting insulin levels (median 38.9 vs 23.8 pmol/l, p<0.005), which were related to rate of weight gain between 0 and 3 years (r=0.47, p=0.0003). First-phase insulin secretion did not differ between SGA and AGA infants, but SGA infants had a lower glucose disposition index (beta cell compensation) (median 235 vs 501 min mmol(-1) l(-1), p=0.02), which persisted after allowing for postnatal weight gain (p=0.009). CONCLUSIONS/INTERPRETATION: SGA infants showed a marked transition from lower pre-feed insulin and increased insulin sensitivity at birth to insulin resistance over the first 3 years of life. This transition was related to rapid postnatal weight gain, which could indicate a propensity to central fat deposition. The additional observation of reduced compensatory beta cell secretion underlines the need for long-term surveillance of glucose homeostasis in all SGA subjects, whether or not they show postnatal catch-up growth.
PubMed Accession Number :: 16283238.

Ong, K.; Beardsall, K.; de Zegher, F. (2005) Growth hormone therapy in short children born small for gestational age Early Hum Dev, 81 (12),973-80 [Journal Article] Online
Abstract: Being born small for gestational age (SGA) is one of the most common causes of childhood short stature, and recombinant GH therapy has been recently licensed to promote growth in short SGA children from the age of 4 years old. Studies are now reporting very encouraging effects on adult height gains, especially in those children who started GH therapy early, at least 2 years prior to the onset of puberty. Compared to the age at starting treatment, the GH dose has a less significant impact on final height, and more attention needs to be paid now to identify earlier those SGA children who fail to catch-up spontaneously. The benefits are not just in terms of height, but also in body composition and possibly blood pressure and lipid levels. However the risk of side effects and long-term complications, particularly related to the expected metabolic effects of GH in inducing insulin resistance and hyperinsulinaemia, need to be carefully monitored especially in SGA children with a family history of type 2 diabetes. Recently, GH therapy was found to amplify the adrenarche of short SGA children and to induce a pro-inflammatory shift, as judged by a rise of neutrophil count and circulating interleukin-6 (IL-6), and a fall in adiponectin levels. Further progress is anticipated to assess the addition of insulin-sensitizing therapy to attenuate the GH-induced hyperinsulinemia, in order to alter the pro-inflammatory course, to avoid excessive release of adrenal androgens, and to slow down the potential rapid tempo of pubertal progression in SGA children. In the meantime, post-SGA short stature is rapidly becoming one of the prime indications for GH therapy in childhood.
PubMed Accession Number :: 16271835.

Low, Y. L.; Taylor, J. I.; Grace, P. B.; Dowsett, M.; Folkerd, E.; Doody, D.; Dunning, A. M.; Scollen, S.; Mulligan, A. A.; Welch, A. A.; Luben, R. N.; Khaw, K. T.; Day, N. E.; Wareham, N. J.; Bingham, S. A. (2005) Polymorphisms in the CYP19 Gene May Affect the Positive Correlations between Serum and Urine Phytoestrogen Metabolites and Plasma Androgen Concentrations in Men J Nutr, 135 (11),2680-6 [Journal Article] Online
Abstract: Phytoestrogens have been hypothesized to protect against prostate cancer via modulation of circulating androgen concentrations. We conducted a cross-sectional study of 267 men in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with 2 aims: first, to investigate the association between phytoestrogen exposure (measured from diet, urine, and serum) and plasma concentrations of sex hormone-binding globulin (SHBG), androstanediol glucuronide, testosterone and Free Androgen Index (FAI); and second, whether the association may be modified by polymorphisms in CYP19 and SHBG genes. Dietary daidzein and genistein intakes were obtained from food diaries and computed using an in-house food composition database. Urinary and serum concentrations of 3 isoflavones (daidzein, genistein, glycitein), 2 daidzein metabolites O-desmethylangolensin (O-DMA) and 2 lignan metabolites (enterodiol and enterolactone) were measured using mass spectrometry. There was no association between dietary, urinary, and serum phytoestrogens and plasma SHBG concentrations. Enterolactone was positively associated with plasma androstanediol glucuronide concentrations (urinary enterolactone: r = 0.127, P = 0.043; serum enterolactone: r = 0.172, P = 0.006) and FAI (urinary enterolactone: r = 0.115, P = 0.067; serum enterolactone: r = 0.158, P = 0.011). Both urinary and serum equol were associated with plasma testosterone (urinary equol: r = 0.332, P = 0.013; serum equol: r = 0.318, P = 0.018) and FAI (urinary equol: r = 0.297, P = 0.027; serum equol: r = 0.380, P = 0.004) among men with the TT genotype but not the CC or CT genotypes (r = -0.029 to -0.134, P = 0.091-0.717) for the CYP19 3'untranslated region (UTR) T-C polymorphism. Urinary and serum enterolactone showed similar genotype-dependent associations with testosterone but not with FAI. In this first study on phytoestrogen-gene associations in men, we conclude that enterolactone and equol are positively associated with plasma androgen concentrations, and interactions with CYP19 gene may be involved.
PubMed Accession Number :: 16251630.

Qiao, Q.; Tuomilehto, J.; Balkau, B.; Borch-Johnsen, K.; Heine, R.; Wareham, N. J. (2005) Are insulin resistance, impaired fasting glucose and impaired glucose tolerance all equally strongly related to age? Diabet Med, 22 (11),1476-81 [Journal Article] Online
Abstract: BACKGROUND: Insulin resistance (IR) has been considered an underlying cause of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Whether IR increases with age has been debated. We investigated the age-associated deterioration in the homeostasis model assessment (HOMA) of IR and in glucose metabolism. METHODS: Ten (nine including women) European studies contributed data on 6314 men and 6393 women aged 30-88 years. The cohort- and sex-specific top 25% of HOMA of IR in non-diabetic subjects was used to define HOMA-IR. RESULTS: Compared with subjects aged 50-59 years, the cohort- and body mass index-adjusted odds ratio (95% confidence interval) for HOMA-IR was 0.83 (0.64, 1.08), 0.87 (0.74, 1.03), 1.20 (1.02, 1.42) and 1.45 (1.10, 1.92) in men and 0.84 (0.62, 1.14), 0.91 (0.77, 1.09), 1.38 (1.19, 1.62) and 1.71 (1.35, 2.17) in women, respectively, aged 30-39, 40-49, 60-69 and > or = 70 years (P < 0.0001 for trend test). The same increasing trend was also observed for IFG. In contrast, the corresponding odds ratios for IGT increased linearly and more strongly with age, being 0.37 (0.22, 0.63), 0.67 (0.52, 0.87), 1.55 (1.24, 1.92) and 2.96 (2.13, 4.13) in men and 0.51 (0.31, 0.85), 0.66 (0.52, 0.86), 1.92 (1.57, 2.35) and 3.85 (2.89, 5.12) in women, respectively. CONCLUSIONS: Age is more strongly associated with IGT than with HOMA-IR or IFG in non-diabetic European populations.
Keywords: Adult Age Factors Aged Aged, 80 and over Blood Glucose/*metabolism Cohort Studies Diabetes Mellitus, Type 2/*metabolism Fasting/metabolism Female Glucose Tolerance Test Homeostasis/physiology Humans Insulin Resistance/*physiology Male Middle Aged Research Support, Non-U.S. Gov't
PubMed Accession Number :: 16241909.

Tillin, T.; Forouhi, N.; McKeigue, P.; Chaturvedi, N. (2005) Microalbuminuria and Coronary Heart Disease Risk in an Ethnically Diverse UK Population: A Prospective Cohort Study J Am Soc Nephrol, 16 (12),3702-3710 [Journal Article] Online
Abstract: Microalbuminuria (MA) is a strong risk factor for subsequent chronic disease, both renal and coronary heart disease (CHD), in European origin populations, but CHD risks differ by ethnicity, and it was hypothesized that prevalence of MA and relations with CHD may also differ. Combined analyses of two population-based cohorts started in 1988 and consisted of 1460 Europeans (70% male), 946 South Asians (78% male), and 559 African Caribbeans (51% male) who resided in London and were aged 40 to 69. Baseline fasting blood, overnight urine collection, and clinical measurements were performed. Prevalent CHD was defined by clinical history or major electrocardiogram changes. Age-adjusted albumin excretion rates (AER; geometric means, mug/min) were significantly higher in African Caribbeans (men: 6.1, 95% confidence interval [CI] 5.5 to 6.7; women: 5.7, 95% CI 5.2 to 6.2) than in South Asians (men: 4.3, 95% CI 4.0 to 4.5; women 3.4, 95% CI 3.0 to 3.8) and Europeans (men: 4.5, 95% CI 4.3 to 4.8; women: 3.3, 95% CI 3.1 to 3.6). MA was associated with both prevalent CHD and CHD mortality in South Asian men (hazard ratio 2.5; 95% CI 1.3 to 4.8) and in European women (hazard ratio 13.0; 95% CI 2.6 to 64.2) but not in any other group. Greater AER in African Caribbeans and the absence of association with CHD contrast with lower AER in South Asian men and European women, both strongly associated with CHD prevalence and mortality. These differences suggest that the pathogenesis of kidney disease and its link with CHD differ by ethnicity and gender.
PubMed Accession Number :: 16207830.

Jurca, R.; Jackson, A. S.; Lamonte, M. J.; Morrow, J. R., Jr.; Blair, S. N.; Wareham, N. J.; Haskell, W. L.; van Mechelen, W.; Church, T. S.; Jakicic, J. M.; Laukkanen, R. (2005) Assessing cardiorespiratory fitness without performing exercise testing Am J Prev Med, 29 (3),185-93 [Journal Article] Online
Abstract: BACKGROUND: Low cardiorespiratory fitness (CRF) is associated with increased risk of chronic diseases and mortality; however, CRF assessment is usually not performed in many healthcare settings. The purpose of this study is to extend previous work on a non-exercise test model to predict CRF from health indicators that are easily obtained. METHODS: Participants were men and women aged 20 to 70 years whose CRF level was quantified with a maximal or submaximal exercise test as part of the National Aeronautics and Space Administration/Johnson Space Center (NASA, n=1863), Aerobics Center Longitudinal Study (ACLS, n=46,190), or Allied Dunbar National Fitness Survey (ADNFS, n=1706). Other variables included gender, age, body mass index, resting heart rate, and self-reported physical activity levels. RESULTS: All variables used in the multiple linear regression models were independently related to the CRF in each of the study cohorts. The multiple correlation coefficients obtained within NASA, ACLS, and ADNFS participants, respectively, were 0.81, 0.77, and 0.76. The standard error of estimate (SEE) was 1.45, 1.50, and 1.97 metabolic equivalents (METs) (1 MET=3.5 ml O(2) uptake.kilograms of body mass(-1).minutes(-1)), respectively, for the NASA, ACLS, and ADNFS regression models. All regression models demonstrated a high level of cross-validity (0.72<R<0.80). The highest cross-validation coefficients were seen when the NASA regression model was applied to the ACLS and ADNFS cohorts (R=0.76 and R=0.75, respectively). CONCLUSIONS: This study suggests that CRF may be accurately estimated in adults from a non-exercise test model including gender, age, body mass index, resting heart rate, and self-reported physical activity.
PubMed Accession Number :: 16168867.

Kanagalingam, M. G.; Forouhi, N. G.; Greer, I. A.; Sattar, N. (2005) Changes in booking body mass index over a decade: retrospective analysis from a Glasgow Maternity Hospital Bjog, 112 (10),1431-3 [Journal Article] Online
Abstract: Whether booking body mass index (BMI) in the UK is increasing is unknown but is of clinical interest since overweight or obese pregnant women face far greater risks of pregnancy complications including pre-eclampsia and gestational diabetes. We examined booking BMI in 1990 and 2002/2004, of women with singleton pregnancies. Our analyses indicate an increase of 1 U in mean BMI over this period despite lower parity in recent years. When the model was adjusted for maternal age, parity, smoking status and deprivation category the mean BMI was 1.37 U higher in 2002/2004 than in 1990. More striking was the significant increase in the proportion of women who were obese (BMI >/= 30 kg/m(2)) at booking-more than twofold higher in unadjusted analysis (18.9%vs 9.4%) rising to greater than threefold higher in multivariate analysis. These findings suggest that obesity-related pregnancy complications are likely to increase with implications for both mother and child.
PubMed Accession Number :: 16167951.

Myint, P. K.; Luben, R. N.; Surtees, P. G.; Wainwright, N. W.; Welch, A. A.; Bingham, S. A.; Wareham, N. J.; Day, N. E.; Khaw, K. T. (2005) Respiratory function and self-reported functional health: EPIC-Norfolk population study Eur Respir J, 26 (3),494-502 [Journal Article] Online
Abstract: Respiratory function is known to be associated with mortality. However, its association with health related quality of life (HRQoL) has not yet been examined. A population-based cross sectional study was conducted in 16,738 subjects aged 40-79 yrs and resident in Norfolk, to examine the association between forced expiratory volume in one second (FEV(1)) and HRQoL measured by the 36-item short form questionnaire. Individuals who were in the highest quintiles of FEV(1) were more likely to report good physical functional health (odds ratio (OR) 1.60; 95% confidence interval (CI) 1.28-2.01 and OR 1.71; 95% CI 1.40-2.10 for males and females, respectively) controlling for age, height, weight or body mass index, smoking, physical activity, prevalent illness and social class. Being in the highest quintile for FEV(1) was associated with significantly lower likelihood of poor self-reported mental functional health status in males (OR 0.78; 95% CI 0.61-0.99), but not in females (OR 1.00; 95% CI 0.82-1.22). In conclusion, forced expiratory volume in one second independently predicts self perceived physical well being in a general population across the whole normal distribution of respiratory function.
PubMed Accession Number :: 16135734.

Canoy, D.; Wareham, N.; Luben, R.; Welch, A.; Bingham, S.; Day, N.; Khaw, K. T. (2005) Cigarette Smoking and Fat Distribution in 21,828 British Men and Women: A Population-based Study Obes Res, 13 (8),1466-1475 [Journal Article] Online
Abstract: OBJECTIVE: To examine the relationship between cigarette smoking habits and fat distribution in a population-based cohort of men and women. RESEARCH METHODS AND PROCEDURES: We analyzed cross-sectional data from 21,828 men and women who were 45 to 79 years of age, residents in Norfolk, United Kingdom, and were recruited between 1993 and 1997. Cigarette smoking habits and other lifestyle factors were assessed using self-reported questionnaires. Anthropometric measures were obtained during a health examination. RESULTS: Waist-hip ratio was highest among current smokers and least among never smokers after adjusting for age, BMI, alcohol intake, total energy intake, physical activity, and education. Higher waist-hip ratio was directly associated with higher smoking pack-years in current and former smokers and inversely with duration since quitting smoking in former smokers. Adjusting for age, BMI, and other covariates, current smokers had higher waist circumference but lower hip circumference compared with former or never smokers. DISCUSSION: Cigarette smoking habits seem to influence fat distribution patterns. Although smokers have lower mean BMI compared with nonsmokers, they have a more metabolically adverse fat distribution profile, with higher central adiposity. The explanation for this association may help elucidate the mechanisms underlying the adverse health consequences of cigarette smoking and abdominal obesity.
PubMed Accession Number :: 16129730.

Ramachandran, A.; Snehalatha, C.; Vijay, V.; Wareham, N. J.; Colagiuri, S. (2005) Derivation and validation of diabetes risk score for urban Asian Indians Diabetes Res Clin Pract, 70 (1),63-70 [Journal Article] Online
Abstract: OBJECTIVE:: Simple risk scores for identifying people with undiagnosed diabetes have been developed, mostly in Caucasian groups. This may not be suitable for Asian Indians, therefore this study was undertaken to develop and validate a simple diabetes risk score in an urban Asian Indian population with a high prevalence of diabetes. We also tested whether this score was applicable to South Asian migrants living in a different cultural context. RESEARCH DESIGN AND METHODS:: A population based Cohort of 10,003 participants aged >/=20 years was divided into two equal halves (Cohorts 1 and 2), after excluding people with known diabetes. Cohort 1 (n=4993) was used to derive the risk score. Validation of the score was performed in the other half of the survey population (Cohort 2) (n=5010). The validation was also done in a separate survey population in Chennai, India (Cohort 3) (n=2002) (diagnosis of diabetes was based on OGTT) and in the South Asian Cohort of the 1999 Health Survey for England (n=676) (fasting glucose value>/=7mmol/l and HbA1c>/=6.5% were used for diagnosis). A logistic regression model was used to compute the beta coefficients for risk factors. The risk score value was derived from a receiver operating characteristic curve. RESULTS:: The significant risk factors included in the risk score were age, BMI, waist circumference, family history of diabetes and sedentary physical activity. A risk score value of >21 gave a sensitivity, specificity, positive predictive value and negative predictive value of 76.6%, 59.9%, 9.4% and 97.9% in Cohort 1, 72.4%, 59%, 8.3% and 97.6% in Cohort 2 and 73.7%, 61.0%, 12.2% and 96.9% in Cohort 3, respectively. The higher distribution of risk factors in the UK Cohort means that at the same cut point the score was much more sensitive but also less specific. (sensitivity 92.2%, specificity 25.7%, positive predictive value of 21.6% and negative predictive value of 93.7%). CONCLUSIONS:: A diabetes risk score involving simple non-biochemical measurements was developed and validated in a native Asian Indian population. This easily applicable simple score could play an important role as the first step in the process of identifying individuals with an increased likelihood of having prevalent but undiagnosed diabetes. The different distribution of risk factors with the migrant Asian Indians living in England and the different relationship between sensitivity and specificity for the same score demonstrate that risk scores and cut-points developed and tested even within one ethnic group cannot be generalized to individuals of the same ethnic group living in a different cultural setting where the distribution of risk factors for diabetes is different.
PubMed Accession Number :: 16126124.

Sandhu, M. S.; Heude, B.; Young, E. H.; Luben, R.; Luan, J.; Khaw, K. T.; Todd, J.; Wareham, N. J. (2005) INS VNTR Class Genotype and Indexes of Body Size and Obesity: Population-Based Studies of 7,999 Middle-Aged Men and Women Diabetes, 54 (9),2812-2815 [Journal Article] Online
Abstract: The relevance of the insulin gene (INS) variable number tandem repeat (VNTR) polymorphism to indexes of body size and adult obesity is inconclusive. Given the equivocal reports on the association between the VNTR class genotype at the insulin gene locus and indexes of body size and obesity, we assessed these associations in a series of cohort studies based on 7,999 middle-aged men and women. We found no convincing evidence that INS VNTR class genotype was associated with indexes of body size and adult obesity. These data suggest that INS VNTR class is not an important determinant of size and body weight regulation in middle-aged men and women.
PubMed Accession Number :: 16123374.

Jenab, M.; Bingham, S.; Ferrari, P.; Friesen, M. D.; Al-Delaimy, W. K.; Luben, R.; Wareham, N.; Khaw, K. T.; Riboli, E. (2005) Long-term Cryoconservation and Stability of Vitamin C in Serum Samples of the European Prospective Investigation into Cancer and Nutrition Cancer Epidemiol Biomarkers Prev, 14 (7),1837-40 [Journal Article] Online
Abstract: Plasma vitamin C level may be associated with risk of some chronic diseases. The rapid degradability of vitamin C in biological samples necessitates its stabilization with metaphosphoric acid or similar agents. However, in most cohort studies, prospectively collected biological samples are not treated with stabilizing agents before long-term frozen storage and it is not known whether vitamin C can be properly measured in such samples. The objective of this study was to determine the degree of vitamin C degradation in plasma samples stored without stabilization for 7 to 11 years at -196 degrees C. Spearman's correlation coefficients indicate a moderate correlation between baseline and final plasma vitamin C levels in both men (r = 0.57, P < 0.0001) and women (r = 0.52, P < 0.0001). Samples were also categorized based on low or high baseline levels of plasma vitamin C, with the latter category showing the highest rate of loss per year of frozen storage in men (1.96 mumol/L, P value for difference <0.0001; percent loss 24.6%) and women (2.35 mumol/L, P value for difference <0.0001; percent loss 24.2%), as determined by multiple regression analysis adjusted for smoking status, age, and body mass index. In men, both baseline and final plasma vitamin C values were lower in smokers than never smokers, but for both men and women the rate of vitamin C loss during storage was not significantly different between smokers and never smokers. The results of this study show that vitamin C can be measured with reasonable reliability in plasma samples frozen for long periods of time without addition of any stabilizing agents.
PubMed Accession Number :: 16030126.

Wareham, N. J.; Forouhi, N. G. (2005) Is there really an epidemic of diabetes? Diabetologia, 48 (8 August),1454-1455 [Journal Article] Online
PubMed Accession Number :: 16001234.

Lesueur, F.; Pharoah, P. D.; Laing, S.; Ahmed, S.; Jordan, C.; Smith, P. L.; Luben, R.; Wareham, N. J.; Easton, D. F.; Dunning, A. M.; Ponder, B. A. (2005) Allelic association of the human homologue of the mouse modifier Ptprj with breast cancer Hum Mol Genet, 14 (16),2349-56 [Journal Article] Online
Abstract: Human homologues of mouse cancer modifier genes may play a role in cancer risk and prognosis. A proportion of the familial risk of common cancers may be attributable to variants in such genes, each contributing to a small effect. The protein tyrosine phosphatase receptor type J (PTPRJ) has been recently identified as being the protein encoded by the Scc1 mouse gene (susceptibility to colon cancer-1). In addition, the PTPRJ gene has been shown to be somatically altered in several human cancer types such as colon, lung and breast cancers and to have the characteristics of a tumour-suppressor gene. The purpose of this study was to determine whether common variants in the PTPRJ gene represent low penetrance breast cancer susceptibility alleles. To test this hypothesis, we assessed single nucleotide polymorphisms (SNPs) tagging the common SNPs and haplotypes of the gene in 4512 cases and 4554 controls from the East Anglian population. We observed a difference in the haplotype frequency distributions between cases and controls (P=0.0023, OR=0.81 [0.72-0.92]). Thus, carrying a specific PTPRJ haplotype confers a protective effect on the risk of breast cancer. This result establishes the principle that mouse cancer modifier genes are candidates for low penetrance human breast cancer susceptibility genes.
PubMed Accession Number :: 16000320.

Sattar, N.; Forouhi, N. G. (2005) Metabolic syndrome criteria: ready for clinical prime time or work in progress? Eur Heart J, 26 (13),1249-51 [Journal Article] Online
Keywords: Coronary Disease/*prevention & control Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use Metabolic Syndrome X/*complications Pravastatin/*therapeutic use Randomized Controlled Trials
PubMed Accession Number :: 15829487.

Yuyun, M. F.; Adler, A. I.; Wareham, N. J. (2005) What is the evidence that microalbuminuria is a predictor of cardiovascular disease events? Curr Opin Nephrol Hypertens, 14 (3),271-6 [Journal Article] Online
Abstract: PURPOSE OF REVIEW: This review describes recently published studies evaluating the association between microalbuminuria and the development of cardiovascular disease events either in the presence of diabetes or hypertension, or in the population as a whole. RECENT FINDINGS: Prospective studies confirm that microalbuminuria is predictive, independently of classical risk factors, of cardiovascular disease events and all-cause mortality within groups of patients with diabetes or hypertension and in the general population. However, these studies suggest that levels of albuminuria below the conventional cutoff point definition of microalbuminuria are significantly associated with cardiovascular morbidity and mortality. The pathophysiological mechanism underyling this association is still uncertain. Data from recent intervention studies suggest that treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, as well as intensive multi-factorial intervention including behaviour modification and targeted pharmacotherapy in patients with microalbuminuria, offers significant reduction in cardiovascular and renal morbidity in people with albuminuria. SUMMARY: Future absolute risk prediction scores for primary cardiovascular events could include microalbuminuria as a modifiable risk factor. The association between levels of albuminuria and cardiovascular outcomes in individuals within the normoalbuminuric range questions the current categorical definition of microalbuminuria. Intensive multifactorial interventions, including the use of agents that affect the renin-angiotensin pathway, are effective in reducing cardiovascular risk in patients with microalbuminuria and diabetes or hypertension.
PubMed Accession Number :: 15821422.

Sinha, S.; Luben, R. N.; Welch, A.; Bingham, S.; Wareham, N. J.; Day, N. E.; Khaw, K. T. (2005) Fibrinogen and cigarette smoking in men and women in the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population Eur J Cardio Prev Rehab, 12 (2),144-50 [Journal Article] Online
Abstract: BACKGROUND: Plasma fibrinogen may be an independent risk factor for cardiovascular disease. Cigarette smoking is a well-recognized determinant of plasma fibrinogen however it remains unclear how fibrinogen levels relate to the degree and duration of smoking, or to time since smoking cessation. METHODS: In a population-based study of 11 059 men and women aged 45-74 years, we examined the cross-sectional relationship between plasma fibrinogen and cigarette smoking habit. RESULTS: Mean fibrinogen concentrations were higher in current smokers compared to non-current smokers (men: 3.13+/-0.77 versus 2.80+/-0.71 g/l, P<0.0001; women: 3.03+/-0.72 versus 2.95+/-0.71 g/l, P=0.01), independent of age, body mass index and hormone replacement therapy in women In men, fibrinogen concentrations declined with years since stopping smoking but remained higher than in life-long non-smokers for 15 years. No relationship between fibrinogen and duration of smoking cessation was observed in women. On multivariate analysis, age, body mass index, use of hormone-replacement therapy, smoking status and pack-years of smoking were independent predictors of plasma fibrinogen. CONCLUSIONS: Plasma fibrinogen is strongly associated with cigarette smoking with a dose-response relationship with total pack-years of smoking. In men who stop smoking plasma fibrinogen may remain elevated for several years after cessation.
PubMed Accession Number :: 15785300.

Hardeman, W.; Sutton, S.; Griffin, S.; Johnston, M.; White, A.; Wareham, N. J.; Kinmonth, A. L. (2005) A causal modelling approach to the development of theory-based behaviour change programmes for trial evaluation Health Educ Res, 20 (6),676-87 [Journal Article] Online
Abstract: Theory-based intervention programmes to support health-related behaviour change aim to increase health impact and improve understanding of mechanisms of behaviour change. However, the science of intervention development remains at an early stage. We present a causal modelling approach to developing complex interventions for evaluation in randomized trials. In this approach a generic model links behavioural determinants, causally through behaviour, to physiological and biochemical variables, and health outcomes. It is tailored to context, target population, behaviours and health outcomes. The development of a specific causal model based on theory and evidence is illustrated by the ProActive programme, supporting increased physical activity among individuals at risk of Type 2 diabetes. The model provides a rational guide to appropriate measures, intervention points and intervention techniques, and can be tested quantitatively. Causal modelling is critically compared to other approaches to intervention development and evaluation, and research directions are indicated.
PubMed Accession Number :: 15781446.

Tillin, T.; Forouhi, N.; Johnston, D. G.; McKeigue, P. M.; Chaturvedi, N.; Godsland, I. F. (2005) Metabolic syndrome and coronary heart disease in South Asians, African-Caribbeans and white Europeans: a UK population-based cross-sectional study Diabetologia, 48 (4),649-56 [Journal Article] Online
Abstract: AIMS/HYPOTHESIS: The aim of this study was to study differences in the prevalence of the metabolic syndrome and its associations with prevalent CHD according to ethnicity and sex. METHODS: We performed a combined analysis of two population-based cross-sectional studies conducted between 1988 and 1991 that followed identical protocols. Participants (aged 40-69 years) comprised 2,346 Europeans (76% male), 1,711 South Asians (83% male) and 803 African-Caribbeans (57% male) resident in west London. Fasting blood, overnight urine collection, clinical and anthropometric measurements were performed. Clinical history or major ECG changes defined prevalent CHD. The metabolic syndrome was defined according to the criteria recommended by the World Health Organization (WHO) and the National Cholesterol Education Programme (NCEP). RESULTS: The prevalence of the metabolic syndrome was highest in South Asians (WHO, men 46%, women 31%; NCEP, men 29%, women 32%) and lowest in European women (WHO, 9%; NCEP, 14%). The prevalence of CHD was 10% in South Asian men, 9% in European men, 5-6% in African-Caribbeans and European women, and 2% in South Asian women. The metabolic syndrome was associated with prevalent CHD in European men [NCEP, odds ratio (OR)=1.6, 95% CI 1.2-2.4; WHO, OR=1.7, 95% CI 1.2-2.5] and South Asian men (NCEP, OR=2.1, 95% CI 1.5-3.1; WHO, OR=1.6, 95% CI 1.1-2.3). Associations with CHD were weaker in African-Caribbeans and were inconsistent among European women. CONCLUSIONS/INTERPRETATION: The current definitions of the metabolic syndrome give an inconsistent picture of cardiovascular disease risk when applied to different ethnic groups within the UK. Prospective studies are needed to validate workable ethnic-specific definitions.
Keywords: Adult *African Continental Ancestry Group Age Factors Aged *Asian Continental Ancestry Group Caribbean Region/ethnology Coronary Disease/complications/*ethnology Cross-Sectional Studies Electrocardiography *European Continental Ancestry Group Female Great Britain/epidemiology Humans Hyperlipidemia/complications Insulin Resistance Male Metabolic Syndrome X/complications/*ethnology Middle Aged Prevalence Research Support, Non-U.S. Gov't Sex Factors Smoking
PubMed Accession Number :: 15759110.

Boekholdt, S. M.; Keller, T. T.; Wareham, N. J.; Luben, R.; Bingham, S. A.; Day, N. E.; Sandhu, M. S.; Jukema, J. W.; Kastelein, J. J.; Hack, C. E.; Khaw, K. T. (2005) Serum Levels of Type II Secretory Phospholipase A2 and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women. The EPIC-Norfolk Prospective Population Study Arterioscler Thromb Vasc Biol, 25 (4),839-46 [Journal Article] Online
Abstract: OBJECTIVE: To study the prospective relationship between serum levels of type II secretory phospholipase A2 (sPLA2) and the risk of future coronary artery disease (CAD) in apparently healthy men and women. METHODS AND RESULTS: We conducted a prospective nested case-control study among apparently healthy men and women aged 45 to 79 years. Cases (n=1105) were people in whom fatal or nonfatal CAD developed during follow-up. Controls (n=2209) were matched by age, sex, and enrollment time. sPLA2 levels were significantly higher in cases than controls (9.5 ng/mL; interquartile range [IQR], 6.4 to 14.8 versus 8.3 ng/mL; IQR, 5.8 to 12.6; P<0.0001). sPLA2 plasma levels significantly correlated with age, body mass index, systolic blood pressure, high-density lipoprotein (HDL) cholesterol levels, and C-reactive protein (CRP) levels. Taking into account matching for sex and age and adjusting for body mass index, smoking, diabetes, systolic blood pressure, low-density lipoprotein cholesterol, HDL cholesterol, and CRP levels, the risk of future CAD was 1.34 (1.02 to 1.71; P=0.02) for people in the highest sPLA2 quartile, compared with those in the lowest (P for linearity=0.03). CONCLUSIONS: Elevated levels of sPLA2 were associated with an increased risk of future CAD in apparently healthy individuals. The magnitude of the association was similar to that observed between CRP and CAD risk, and both associations were independent.
PubMed Accession Number :: 15692105.

Low, Y. L.; Taylor, J. I.; Grace, P. B.; Dowsett, M.; Scollen, S.; Dunning, A. M.; Mulligan, A. A.; Welch, A. A.; Luben, R. N.; Khaw, K. T.; Day, N. E.; Wareham, N. J.; Bingham, S. A. (2005) Phytoestrogen exposure correlation with plasma estradiol in postmenopausal women in European Prospective Investigation of Cancer and Nutrition-Norfolk may involve diet-gene interactions Cancer Epidemiol Biomarkers Prev, 14 (1),213-20 [Journal Article] Online
Abstract: Cross-sectional studies investigating the relationship between phytoestrogens in diet, urine, or blood with plasma estradiol and sex hormone binding globulin (SHBG) have been inconclusive. We investigated the relationship among phytoestrogen exposure, polymorphisms in the ESR1, COMT, CYP19, and SHBG genes, and plasma estradiol and SHBG levels in 125 free-living postmenopausal women taking part in a cohort study (European Prospective Investigation of Cancer and Nutrition-Norfolk) using three different markers: dietary, urinary, and serum phytoestrogens. Phytoestrogen levels (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) in spot urine and serum were analyzed by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, respectively. Plasma estradiol and SHBG were measured by immunoassays. Adjusting for age and body mass index, urinary daidzein, genistein, glycitein, and serum daidzein and glycitein were negatively correlated with plasma estradiol (R = -0.199 to -0.277, P <0.03), with particularly strong associations found in the 18 women with CC genotype for ESR1 PvuII polymorphism (R = -0.597 to -0.834, P < 0.03). The negative correlations observed between isoflavones and estradiol in women as a whole became no longer significant when we excluded women with ESR1 PvuII CC genotype, indicating that the correlations observed were due mainly to this group of women. There was no relationship between dietary isoflavones and plasma estradiol and no association was found between any of the dietary, urinary, and serum phytoestrogen and plasma SHBG or between these factors and polymorphisms in CYP19, SHBG, and COMT. We conclude that higher isoflavone exposure is associated with lower plasma estradiol in postmenopausal women and that this preliminary study is suggestive of the involvement of diet-gene interactions.
PubMed Accession Number :: 15668497.

O'Rahilly, S.; Barroso, I.; Wareham, N. J. (2005) Genetic factors in type 2 diabetes: the end of the beginning? Science, 307 (5708),370-3 [Journal Article] Online
Abstract: The intensive search for genetic variants that predispose to type 2 diabetes was launched with optimism, but progress has been slower than was hoped. Even so, major advances have been made in the understanding of monogenic forms of the disease which together represent a substantial health burden, and a few common gene variants that influence susceptibility have now been unequivocally identified. Armed with a better understanding of the tools needed to detect such genes, it seems inevitable that the rate of progress will increase and the relevance of genetic information to the diagnosis, treatment, and prevention of diabetes will become increasingly tangible.
PubMed Accession Number :: 15662000.

French, D.P.; Sutton, S.; Hennings, S.; Mitchell, J.; Wareham, N. J.; Griffin, S.; Hardeman, W.; Kinmonth, A. L. (2005) The importance of affective beliefs and attitudes in the theory of planned behavior: predicting intention to increase physical activity Journal of Applied Social Psychology, 35 (9),1824-1848 [Journal Article]

Hall, P; Badman, S; Jakes, R. W.; Moore, V; Pencheon, D; Rigarlsford, A; Walford, H (2005) Physical activity in the East of England , ,46 [Report] Online

The DECODE Study, Group (2005) Comparison of three different definitions for the metabolic syndrome in non-diabetic Europeans Br J Diabetes Vasc Dis, 5 ,161-8 [Journal Article]

Khaw, K. T.; Bingham, S.; Welch, A.; Luben, R.; O'Brien, E.; Wareham, N.; Day, N. (2004) Blood pressure and urinary sodium in men and women: the Norfolk Cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) Am J Clin Nutr, 80 (5),1397-403 [Journal Article] Online
Abstract: BACKGROUND: Abundant evidence indicates that a high sodium intake is causally related to high blood pressure, but debate over recommendations to reduce dietary sodium in the general population continues. A key issue is whether differences in usual sodium intake within the range feasible in free-living populations have clinical or public health relevance. OBJECTIVE: We examined the relation between blood pressure and urinary sodium as a marker of dietary intake. DESIGN: This was a study of 23104 community-living adults aged 45-79 y. RESULTS: Mean systolic and diastolic blood pressure increased as the ratio of urinary sodium to creatinine increased (as estimated from a casual urine sample), with differences of 7.2 mm Hg for systolic blood pressure and 3.0 mm Hg for diastolic blood pressure (P < 0.0001) between the top and bottom quintiles. This trend was independent of age, body mass index, urinary potassium:creatinine, and smoking and was consistent by sex and history of hypertension. The prevalence of those with systolic blood pressure >/= 160 mm Hg halved from 12% in the top quintile to 6% in the bottom quintile; the odds ratio for having systolic blood pressure >/= 160 mm Hg was 2.48 (95% CI: 1.90, 3.22) for men and 2.67 (95% CI: 2.08, 3.43) for women in the top compared with the bottom quintile of urinary sodium. Estimated mean sodium intakes in the lowest and highest quintiles were approximately 80 and 220 mmol/d, respectively. CONCLUSIONS: Within the usual range found in a free-living population, differences in urinary sodium, an indicator of dietary sodium intake, are associated with blood pressure differences of clinical and public health relevance. Our findings reinforce recommendations to lower average sodium intakes in the general population.
PubMed Accession Number :: 15531692.

Bhattacharyya, S.; Luan, J.; Farooqi, I. S.; Keogh, J.; Montague, C.; Brennand, J.; Jorde, L.; Wareham, N. J.; O'Rahilly, S. (2004) Studies of the neuromedin U-2 receptor gene in human obesity: evidence for the existence of two ancestral forms of the receptor J Endocrinol, 183 (1),115-20 [Journal Article] Online
Abstract: Central administration of neuromedin U (NMU) suppresses food intake acting through the NMU-2 receptor (NMU2R), which is expressed in the hypothalamus. We screened the NMU2R gene in 96 patients with severe early-onset obesity. A common variant haplotype was found (f-0.21). This common variant haplotype was unusual in nature, consisting of four non-contiguous missense changes in complete linkage disequilibrium, and across two separate exons. The variant haplotype resulted in four amino acid substitutions (S295T/F312L/P380L/ M385 V) and was present in several other Europid populations and in subjects of South Asian, East Asian and African American origin, but not in eleven African Pygmies. This variant haplotype was not associated with obesity or related traits in 500 subjects from a prospective population-based cohort. In summary, we have identified two markedly different isoforms of the NMU-2 receptor, presumably arising through an ancient and complex mutational event; no genetic associations between this haplotype and obesity-related traits were, however, discerned. Further investigation of the pharmacogenomic consequences of NMU2R variation in humans is warranted.
PubMed Accession Number :: 15525579.

Kaushal, K.; Heald, A. H.; Siddals, K. W.; Sandhu, M. S.; Dunger, D. B.; Gibson, J. M.; Wareham, N. J. (2004) The Impact of Abnormalities in IGF and Inflammatory Systems on the Metabolic Syndrome Diabetes Care, 27 (11),2682-2688 [Journal Article] Online
Abstract: OBJECTIVE: Low plasma levels of IGF-I, particularly when coupled with low levels of the potentially inhibitory IGF binding protein (IGFBP)-1 and higher levels of C-reactive protein (CRP), have been implicated in the pathogenesis of metabolic syndrome X and cardiovascular disease. We report the relative contributions of IGFBP-1 and CRP to the occurrence of the metabolic syndrome in a healthy population cohort to establish the extent to which these factors may contribute to subsequent risk of cardiovascular disease. RESEARCH DESIGN AND METHODS: The volunteers in the study were all participants in the Ely study, a continuing population-based cohort in Ely, Cambridgeshire, U.K. Of 839 individuals studied, 154 (18.4%) fulfilled criteria for the metabolic syndrome. RESULTS: Subjects with the metabolic syndrome had lower IGFBP-1 (14.4 μg/l [95% CI 12.9-16.0] vs. 25.4 [24.1-26.7], P < 0.001) and higher CRP (1.9 mg/l [1.6-2.2] vs. 1.0 [0.9-1.1], P < 0.001). Logistic regression, adjusted for age, sex, fasting insulin, and IGF-I, demonstrated a striking 14-fold increased risk for the metabolic syndrome (odds ratio 14.1 [4.1-48.4], P < 0.001) in individuals with a CRP value in the highest tertile and IGFBP-1 levels below the median. CONCLUSIONS: The combination of a high CRP concentration coupled with a low IGFBP-1 results in a dramatic increase in an individual's risk of having the metabolic syndrome. Further elucidation of the biological processes linking the IGF and inflammatory systems may allow the identification of novel therapeutic targets for cardiovascular risk reduction.
PubMed Accession Number :: 15505005.

Canoy, D.; Luben, R.; Welch, A.; Bingham, S.; Wareham, N.; Day, N.; Khaw, K. T. (2004) Fat distribution, body mass index and blood pressure in 22 090 men and women in the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study J Hypertens, 22 (11),2067-74 [Journal Article] Online
Abstract: OBJECTIVE: To determine the relation between fat distribution and blood pressure, independent of body mass index. DESIGN: Cross-sectional, population-based study. PARTICIPANTS AND METHODS: Participants, 9936 men and 12 154 women aged 45-79 years, were recruited from general practices in Norfolk, United Kingdom for the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study. Participants filled in a health and lifestyle questionnaire and their blood pressure and anthropometry were measured at a clinic. We mainly used waist-hip ratio (WHR) to assess body fat distribution. RESULTS: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) increased linearly across the whole range of waist-hip ratio in both men and women. The relation was independent of age, body mass index (BMI) and other covariates. Separately, waist and hip circumferences were positively related to SBP and DBP. When adjusted for BMI, waist circumference was positively related to SBP (in women) and DBP (in both men and women), whereas hip circumference was inversely related to SBP (but not DBP) in both men and women. Stratifying by tertiles of waist and hip circumference, age- and BMI-adjusted SBP and DBP were highest among those with high waist and small hip circumference measures. CONCLUSION: Waist-hip ratio was independently related to blood pressure. Waist-hip ratio could reflect the separate and opposite relations of waist and hip circumferences on blood pressure. Characterizing patterns of fat distribution may have implications in the assessment and control of obesity-related blood pressure elevation.
PubMed Accession Number :: 15480089.

Khaw, K. T.; Wareham, N.; Bingham, S.; Luben, R.; Welch, A.; Day, N. (2004) Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk Ann Intern Med, 141 (6),413-20 [Journal Article] Online
Abstract: BACKGROUND: Increasing evidence suggests a continuous relationship between blood glucose concentrations and cardiovascular risk, even below diagnostic threshold levels for diabetes. OBJECTIVE: To examine the relationship between hemoglobin A1c, cardiovascular disease, and total mortality. DESIGN: Prospective population study. SETTING: Norfolk, United Kingdom. PARTICIPANTS: 4662 men and 5570 women who were 45 to 79 years of age and were residents of Norfolk. MEASUREMENTS: Hemoglobin A1c and cardiovascular disease risk factors were assessed from 1995 to 1997, and cardiovascular disease events and mortality were assessed during the follow-up period to 2003. RESULTS: In men and women, the relationship between hemoglobin A1c and cardiovascular disease (806 events) and between hemoglobin A1c and all-cause mortality (521 deaths) was continuous and significant throughout the whole distribution. The relationship was apparent in persons without known diabetes. Persons with hemoglobin A1c concentrations less than 5% had the lowest rates of cardiovascular disease and mortality. An increase in hemoglobin A1c of 1 percentage point was associated with a relative risk for death from any cause of 1.24 (95% CI, 1.14 to 1.34; P < 0.001) in men and with a relative risk of 1.28 (CI, 1.06 to 1.32; P < 0.001) in women. These relative risks were independent of age, body mass index, waist-to-hip ratio, systolic blood pressure, serum cholesterol concentration, cigarette smoking, and history of cardiovascular disease. When persons with known diabetes, hemoglobin A(1c) concentrations of 7% or greater, or a history of cardiovascular disease were excluded, the result was similar (adjusted relative risk, 1.26 [CI, 1.04 to 1.52]; P = 0.02). Fifteen percent (68 of 521) of the deaths in the sample occurred in persons with diabetes (4% of the sample), but 72% (375 of 521) occurred in persons with HbA1c concentrations between 5% and 6.9%. LIMITATIONS: Whether HbA1c concentrations and cardiovascular disease are causally related cannot be concluded from an observational study; intervention studies are needed to determine whether decreasing HbA1c concentrations would reduce cardiovascular disease. CONCLUSIONS: The risk for cardiovascular disease and total mortality associated with hemoglobin A1c concentrations increased continuously through the sample distribution. Most of the events in the sample occurred in persons with moderately elevated HbA1c concentrations. These findings support the need for randomized trials of interventions to reduce hemoglobin A1c concentrations in persons without diabetes.
Keywords: Aged Cardiovascular Diseases/*blood/*epidemiology/mortality Cause of Death Coronary Disease/blood/epidemiology/mortality Diabetes Mellitus/blood/complications Diabetic Angiopathies/blood/epidemiology/mortality Female Follow-Up Studies Hemoglobin A, Glycosylated/*metabolism Human Male Middle Aged Prospective Studies Risk Factors Support, Non-U.S. Gov't
PubMed Accession Number :: 15381514.

Boekholdt, S. M.; Peters, R. J.; Day, N. E.; Luben, R.; Bingham, S. A.; Wareham, N. J.; Hack, C. E.; Reitsma, P. H.; Khaw, K. T. (2004) Macrophage migration inhibitory factor and the risk of myocardial infarction or death due to coronary artery disease in adults without prior myocardial infarction or stroke: the EPIC-Norfolk Prospective Population study Am J Med, 117 (6),390-7 [Journal Article] Online
Abstract: PURPOSE: To determine whether plasma levels of macrophage migration inhibitory factor, a proinflammatory cytokine involved in atherogenesis, are predictive of myocardial infarction or death from coronary artery disease. METHODS: We performed a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. We selected men and women who did not report a history of myocardial infarction or stroke at baseline. Baseline concentrations of macrophage migration inhibitory factor were measured among 777 patients who had a myocardial infarction or died of coronary artery disease during follow-up, and 1554 matched controls who remained free of coronary artery disease. RESULTS: Baseline macrophage migration inhibitory factor concentrations were higher in cases than controls (median, 107.4 microg/L vs. 90.7 microg/L, P = 0.001). The risk of myocardial infarction or death from coronary artery disease increased with increasing quartiles of macrophage migration inhibitory factor (P for linearity <0.0001). Patients in the highest quartile had the greatest likelihood of myocardial infarction or death due to coronary artery disease (unadjusted odds ratio [OR] = 1.6; 95% confidence interval [CI]: 1.2 to 2.0). After adjustment for traditional risk factors and C-reactive protein level, the odds ratio decreased slightly (OR = 1.3; 95% CI: 1.0 to 1.7). Upon additional adjustment for white cell count, this association was no longer statistically significant. CONCLUSION: Prospective data suggest that the relation between macrophage migration inhibitory factor and the risk of myocardial infarction or death due to coronary artery disease in adults without a history of myocardial infarction or stroke is not very strong. However, the data support a regulatory role for macrophage migration inhibitory factor in the process of atherosclerosis.
Keywords: Adult Aged Biological Markers/blood Blood Pressure/physiology C-Reactive Protein/metabolism Case-Control Studies Cerebrovascular Accident/*epidemiology/*metabolism Comparative Study Coronary Arteriosclerosis/complications/*epidemiology/*metabolism Female Follow-Up Studies Great Britain/epidemiology Human Lipoproteins, HDL Cholesterol/blood Macrophage Migration-Inhibitory Factors/*metabolism Male Middle Aged Myocardial Infarction/*epidemiology/etiology/*metabolism Prospective Studies Risk Factors Sex Factors Support, Non-U.S. Gov't Survival Analysis
PubMed Accession Number :: 15380495.

Boekholdt, S. M.; Kuivenhoven, J. A.; Wareham, N. J.; Peters, R. J.; Jukema, J. W.; Luben, R.; Bingham, S. A.; Day, N. E.; Kastelein, J. J.; Khaw, K. T. (2004) Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk population study Circulation, 110 (11),1418-23 [Journal Article] Online
Abstract: BACKGROUND: Low plasma levels of cholesteryl ester transfer protein (CETP) are associated with elevated levels of HDL cholesterol (HDL-C), but it remains unclear whether this translates into a concomitant reduction in the risk of coronary artery disease (CAD). Evidence exists that the effect of CETP depends on metabolic context, in particular on triglyceride levels. METHODS AND RESULTS: A nested case-control study was performed in the prospective EPIC-Norfolk cohort study. Cases were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during follow-up. Control subjects were matched by age, sex, and enrollment time. CETP levels were not significantly different between cases and controls (4.0+/-2.2 versus 3.8+/-2.1 mg/L, P=0.07). CETP levels were significantly related to plasma levels of total cholesterol, LDL cholesterol, and HDL-C. The risk of CAD increased with increasing CETP quintiles (P for linearity=0.02), such that subjects in the highest quintile had an adjusted OR of 1.43 (95% CI 1.03 to 1.99, P=0.03) versus those in the lowest. Among individuals with triglyceride levels below the median (1.7 mmol/L), no relationship between CETP levels and CAD risk was observed (P for linearity=0.5), but this relationship was strong among those with high triglyceride levels (P for linearity=0.02), such that those in the highest CETP quintile had an OR of 1.87 (95% CI 1.06 to 3.30, P=0.02). CONCLUSIONS: Elevated CETP levels are associated with an increasing risk of future CAD in apparently healthy individuals, but only in those with high triglyceride levels.
PubMed Accession Number :: 15337694.

Khaw, K. T.; Day, N.; Bingham, S.; Wareham, N. (2004) Observational versus randomised trial evidence Lancet, 364 (9436),753-4; author reply 754-5 [Journal Article] Online
Keywords: Anthropometry Antioxidants/*administration & dosage/metabolism Ascorbic Acid/*administration & dosage/blood Cardiovascular Diseases/*prevention & control Confounding Factors (Epidemiology) Diet Female Human Male *Observation *Randomized Controlled Trials Socioeconomic Factors
PubMed Accession Number :: 15337392.

Jakes, R. W.; Day, N. E.; Luben, R.; Welch, A.; Bingham, S.; Mitchell, J.; Hennings, S.; Rennie, K.; Wareham, N. J. (2004) Adjusting for energy intake--what measure to use in nutritional epidemiological studies? Int J Epidemiol, 33 (6),1382-6 [Journal Article] Online
Abstract: BACKGROUND: The measurement of energy intake in epidemiological studies is difficult. However, it is important that energy intake is assessed if epidemiological analyses are to correspond to isocaloric experiments. The aim of this study was to compare self-reported energy intake, physical activity, and body weight with energy expenditure measured by 4 days of heart rate monitoring with individual calibration of the relationship between heart rate and oxygen consumption. METHODS: Volunteer sub-study of 97 men and women (mean ages 54 and 51 years respectively) within the European Investigation into Cancer (EPIC) study in Norfolk (UK). Dietary assessment of energy intake and physical activity was by self-report and weight was measured using standard techniques. Energy expenditure was assessed objectively by recording heart rate for 4 days following a calibration of the relationship between heart rate and oxygen consumption. RESULTS: Self-reported energy intake by 7-day diary (mean 8.5 MJ/day) and food frequency questionnaire (FFQ) (mean 8.8 MJ/day) were significantly lower than objectively measured total energy expenditure (mean 11.2 MJ/day). The deattenuated partial correlations between total energy expenditure were 0.33 (7-day diary), 0.34 (FFQ), 0.50 (physical activity), and 0.56 (weight). Weight accounted for 31% (deattenuated) of the sum of squares about the mean of true energy intake after adjusting for age and sex. With the addition of self-reported physical activity, the model was significantly improved (R(2) = 0.57). Adding energy either assessed by the diary or FFQ did not improve the model. CONCLUSIONS: The results presented here indicate that to adjust for energy intake, for the purpose of replicating an isocaloric experiment in an observational epidemiological study, one would do considerably better adjusting for weight and physical activity, than adjusting for energy intake estimated from an FFQ.
PubMed Accession Number :: 15333618.

Day, N. E.; Wong, M. Y.; Bingham, S.; Khaw, K. T.; Luben, R.; Michels, K. B.; Welch, A.; Wareham, N. J. (2004) Correlated measurement error--implications for nutritional epidemiology Int J Epidemiol, , [Journal Article] Online
Abstract: BACKGROUND: In nutritional epidemiology, it is common to fit models in which several dietary variables are included. However, with standard instruments for dietary assessment, not only are the intakes of many nutrients often highly correlated, but the errors in the estimation of the intake of different nutrients are also correlated. The effect of this error correlation on the results of observational studies has been little investigated. This paper describes the effect on multivariate regression coefficients of different levels of correlation, both between the variables themselves and between the errors of estimation of these variables. METHODS: Using a simple model for the multivariate error structure, we examine the effect on the estimates of bivariate linear regression coefficients of (1) differential precision of measurement of the two independent variables, (2) differing levels of correlation between the true values of the two variables, and (3) differing levels of correlation between the errors of measurement of the two variables. As an example, the prediction of plasma vitamin C levels by dietary intake variables is considered, using data from the European Prospective Investigation of Cancer (EPIC) Norfolk study in which dietary intake was estimated using both a food frequency questionaire (FFQ) and a 7-day diary (7DD). The dietary variables considered are vitamin C, fat, and energy, with different approaches taken to energy adjustment. RESULTS: When the error correlation is zero, the estimates of the bivariate regression coefficients reflect the precision of measurement of the two variables and mutual confounding. The sum of the observed regression coefficients is biased towards the null as in univariate regression. When the error correlation is non-zero but below about 0.7, the effect is minor. However, as the error correlation increases beyond 0.8 the effect becomes large and highly dependent on the relative precision with which the two variables are measured. At the extreme, the bivariate estimates can become indefinitely large. In the example, the error correlation between fat and energy using the FFQ appears to be over 0.9, the corresponding value for the 7DD being approximately 0.85. The error correlation between vitamin C and fat, and vitamin C and energy, appears to be below 0.5 and smaller for the 7DD than for the FFQ. The impact of these error correlations on bivariate regression coefficients is large. The effect of energy adjustment differs widely between vitamin C and fat. CONCLUSION: High levels of error correlation can have a large effect on bivariate regression estimates, varying widely depending on which two variables are considered. In particular, the effect of energy adjustment will vary widely. For vitamin C, the effect of energy adjustment appears negligible, whereas for fat the effect is large indicating that error correlation close to one can partially remove regression dilution due to measurement error. If, for fat intake, energy adjustment is performed by using energy density, the partial removal of regression dilution is achieved at the expense of substantial reduction in the true variance.
PubMed Accession Number :: 15333617.

Connie Hung, C. C.; Pirie, F.; Luan, J.; Lank, E.; Motala, A.; Yeo, G. S.; Keogh, J. M.; Wareham, N. J.; O'Rahilly, S.; Farooqi, I. S. (2004) Studies of the Peptide YY and Neuropeptide Y2 Receptor Genes in Relation to Human Obesity and Obesity-Related Traits Diabetes, 53 (9),2461-6 [Journal Article] Online
Abstract: Peptide-YY (PYY) is secreted from endocrine L-cells of the gastrointestinal tract in response to caloric ingestion and may mediate postprandial satiety through the hypothalamic neuropeptide Y2 receptor (Y2R). We examined whether variants in the genes encoding PYY and Y2R might be associated with obesity-related phenotypes in humans. Among 101 subjects with severe early-onset obesity and a history of hyperphagia, we found two rare sequence variants-L73P and IVS2 + 32delG-in PYY and three rare missense mutations-L40F, F87I, and A172T-in Y2R. Although none of these were found in 100 normal-weight white control subjects, L73P in PYY and F87I and A172T in Y2R did not segregate with obesity in family studies, and family data were unavailable for IVS2 + 32delG in PYY and L40F in Y2R. Two common single nucleotide polymorphisms (SNPs), R72T and IVS3 + 68C>T, in PYY were in tight linkage disequilibrium but showed no association with BMI in a large white population. In the Y2R, two SNPs, 585T>C and 936T>C, were found and were in tight linkage disequilibrium. Men, homozygous for the rarer variant, had significantly lower BMI (P = 0.017), waist-to-hip ratio (P = 0.013), and, surprisingly, higher nonesterified fatty acid levels (P = 0.01). In conclusion, mutations in PYY and Y2R are not commonly found in humans with severe early-onset obesity. The relationship between common variants in Y2R and obesity-related traits deserves further exploration in other populations.
PubMed Accession Number :: 15331560.

Shohaimi, S.; Welch, A.; Bingham, S.; Luben, R.; Day, N.; Wareham, N.; Khaw, K. T. (2004) Area deprivation predicts lung function independently of education and social class Eur Respir J, 24 (1),157-61 [Journal Article] Online
Abstract: The cross-sectional association between socioeconomic status (at both the individual and area-based level) and lung function, as measured by forced expiratory volume in one second, in a large population-based cohort was investigated. The study population consisted of 22,675 males and females aged 39-79 yrs. They were recruited from the general community in Norfolk, UK using general practice age/sex registers, as part of the European Prospective Investigation into Cancer (EPIC-Norfolk). It was found that being in a manual occupational social class, having no educational qualifications and living in a deprived area all independently predicted significantly lower lung function, even after controlling for smoking habit. The influence of area-deprivation on lung function, independent of individual socioeconomic status and of individual smoking habit, suggests that apart from targeting individuals who are at high-risk, such as smokers, environmental determinants also need to be examined when considering measures to improve respiratory health.
PubMed Accession Number :: 15293619.

Patel, B. D.; Luben, R. N.; Welch, A. A.; Bingham, S. A.; Khaw, K. T.; Day, N. E.; Lomas, D. A.; Wareham, N. J. (2004) Childhood smoking is an independent risk factor for obstructive airways disease in women Thorax, 59 (8),682-6 [Journal Article] Online
Abstract: OBJECTIVE: To assess whether starting to smoke in childhood increases the risk of obstructive airways disease (OAD) in adult life. METHODS: A retrospective cohort analysis was undertaken of 12 504 current and ex-smokers in the EPIC-Norfolk cohort. The main exposure was starting to smoke during childhood (age <16 years). Three definitions of OAD were used: doctor diagnosed asthma, doctor diagnosed bronchitis/emphysema, and "any OAD" (doctor diagnosed asthma or bronchitis/emphysema, or taking medication used in the treatment of OAD). RESULTS: Childhood smokers had significantly more pack years of exposure and poorer lung function than subjects who started to smoke in adulthood (>/=16 years). Compared with starting in adulthood, starting to smoke in childhood was associated with a greater risk of bronchitis/emphysema in female smokers (OR 1.79, 95% CI 1.25 to 2.56) and ex-smokers of both sexes (OR 1.29, 95% CI 1.07 to 1.55 in men and OR 1.40, 95% CI 1.05 to 1.85 in women), and of "any OAD" in female smokers (OR 1.72, 95% CI 1.24 to 2.38) and male and female ex-smokers (OR 1.20, 95% CI 1.03 to 1.40 in men and 1.34, 95% CI 1.07 to 1.57 in women). After adjustment for pack years, childhood smoking was associated with poorer lung function (FEV(1) 92.3% predicted in adult smokers and 89.5% in childhood smokers, p = 0.03) and a greater risk of bronchitis/emphysema (adjusted OR 1.55, 95% CI 1.08 to 2.24) and for "any OAD" (OR 1.54, 95% CI 1.10 to 2.13) in female smokers but not in male and female ex-smokers. CONCLUSION: Starting to smoke in childhood is associated with an increased risk of airways disease because of the extra pack years smoked. In women, childhood smoking is itself an independent risk factor for the development of airways disease.
PubMed Accession Number :: 15282389.

Shohaimi, S.; Welch, A.; Bingham, S.; Luben, R.; Day, N.; Wareham, N.; Khaw, K. T. (2004) Residential area deprivation predicts fruit and vegetable consumption independently of individual educational level and occupational social class: a cross sectional population study in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) J Epidemiol Community Health, 58 (8),686-91 [Journal Article] Online
Abstract: STUDY OBJECTIVE: To investigate the independent association between individual and area based socioeconomic measures and fruit and vegetable consumption. DESIGN: Cross sectional population based study. SETTING AND PARTICIPANTS: 22,562 men and women aged 39-79 years living in the general community in Norfolk, United Kingdom, recruited using general practice age-sex registers. OUTCOME MEASURES: Fruit and vegetable intake assessed using a food frequency questionnaire. MAIN RESULTS: Being in a manual occupational social class, having no educational qualifications, and living in a deprived area all independently predicted significantly lower consumption of fruit and vegetables. The effect of residential area deprivation was predominantly in those in manual occupational social class and no educational qualifications. CONCLUSIONS: Understanding some of the community level barriers to changing health related behaviours may lead to more effective interventions to improving health in the whole community, particularly those who are most vulnerable.
PubMed Accession Number :: 15252072.

Yuen, K.; Wareham, N.; Frystyk, J.; Hennings, S.; Mitchell, J.; Fryklund, L.; Dunger, D. (2004) Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and the metabolic syndrome: effects on beta-cell function and post-load glucose tolerance Eur J Endocrinol, 151 (1),39-45 [Journal Article] Online
Abstract: OBJECTIVE: Modest elevations in circulating IGF-I levels have been suggested to protect against the development of glucose intolerance in insulin-resistant subjects. To further understand the interactions of GH and IGF-I on beta-cell function and post-load glucose tolerance in glucose-intolerant subjects predisposed to diabetes, we performed a pilot study in 12 subjects with impaired glucose tolerance and the metabolic syndrome using a low GH dose (1.7 microg/kg per day) known to increase endogenous IGF-I production. DESIGN: Fourteen daily GH or placebo injections in a double-blind cross-over study. METHODS: Baseline and post-treatment oral glucose tolerance tests were performed. The homeostasis model assessment and the insulinogenic index was used to estimate fasting insulin sensitivity (S(I)) and beta-cell function respectively, whereas changes in the incremental area under the curve were used to estimate post-load glucose tolerance (DeltaAUC(glu)) and post-load insulin levels (DeltaAUC(ins)). RESULTS: GH increased total IGF-I (P<0.02), free IGF-I (P<0.04) and fasting insulin (P<0.04) levels, but did not modify plasma IGF-binding proteins (IGFBPs)-1 and -3, fasting glucose, non-esterified fatty acid and C-peptide levels, and fasting S(I). After oral glucose intake, glucose tolerance improved (P<0.03), but post-load insulin levels and beta-cell function remained unchanged. CONCLUSION: Short-term low-dose GH administration induced fasting hyperinsulinaemia possibly by reducing insulin clearance but improved post-load glucose tolerance, suggesting that increased bioavailable IGF-I enhanced post-load S(I) without altering beta-cell function. Longer-term studies are required to ascertain whether these positive effects on post-load glucose tolerance and the preservation of beta-cell function can be sustained by this GH dose in these high-risk subjects.
PubMed Accession Number :: 15248820.

Canoy, D.; Luben, R.; Welch, A.; Bingham, S.; Wareham, N.; Day, N.; Khaw, K. T. (2004) Abdominal obesity and respiratory function in men and women in the EPIC-Norfolk Study, United Kingdom Am J Epidemiol, 159 (12),1140-9 [Journal Article] Online
Abstract: Poor respiratory function and obesity are associated with all-cause and cardiovascular disease mortality. Obese persons may also have impaired lung function, but the mechanism is unclear. The authors investigated the relation between abdominal pattern of obesity and respiratory function in the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk) cohort in Norfolk, United Kingdom. This analysis included 9,674 men and 11,876 women aged 45-79 years with no known preexisting serious illness who had complete anthropometric and respiratory function measures obtained at a health visit between 1993 and 1997. Waist:hip ratio was used to assess abdominal obesity, and forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), obtained by spirometry, were used to assess respiratory function. Both FEV1 and FVC were linearly and inversely related across the entire range of waist:hip ratio in both men and women. This relation persisted after adjustment for age, body mass index, cigarette smoking, social class, physical activity index, prevalent bronchitis/emphysema, and prevalent asthma. The association remained significant among nonobese nonsmokers without preexisting respiratory disease. In the general adult population, abdominal fat deposition may play a role in the impairment of respiratory function among the abdominally obese.
Keywords: Abdomen Aged Anthropometry Cohort Studies England Female Human Male Middle Aged Obesity/*complications Respiratory Function Tests Respiratory Tract Diseases/*etiology Support, Non-U.S. Gov't
PubMed Accession Number :: 15191931.

Duffy, S. W.; Jakes, R. W.; Ng, F. C.; Gao, F. (2004) Interaction of dense breast patterns with other breast cancer risk factors in a case-control study Br J Cancer, 91 (2),233-6 [Journal Article] Online
Abstract: The question of interactions between breast density and other breast cancer risk factors is of interest, since it bears upon the use of density as a marker for changes in breast cancer risk. We studied breast parenchymal patterns and 13 other potential risk factors for breast cancer in 172 breast cancer cases and 338 age-matched controls in Singapore. Dense breast patterns were defined as having Tabar parenchymal pattern IV or V. We found significant interactions between dense patterns and ethnic group (P=0.046), and between dense patterns and number of deliveries (P=0.04). Among women with nondense breast patterns, the non-Chinese had lower risk than the Chinese with an odds ratio (OR) of 0.47 (95% CI 0.24, 0.88), whereas in those with dense patterns, the non-Chinese had considerably higher risks (OR=5.34, 95% CI 0.54, 52.51). Alternatively expressed, the increased risk with dense patterns was only observed in the non-Chinese (OR=13.99, 95% CI 1.33, 146.99). Among parous women, the protective effect of three or more deliveries was only observed in those with dense breast patterns (OR=0.21, 95% CI 0.06, 0.70). Suggestive but nonsignificant interactions with dense patterns were observed for ever having delivered, age at first delivery, breast feeding and body mass index. The results are consistent with dense breast patterns as a marker for hormonal modification of breast cancer risk.
Keywords: Adolescent Adult Body Mass Index Breast/*pathology Breast Feeding Breast Neoplasms/*pathology/prevention & control Case-Control Studies Comparative Study Delivery, Obstetric Female Human *Mammography Mass Screening Middle Aged Odds Ratio Risk Factors
PubMed Accession Number :: 15188001.

Khaw, K. T.; Wareham, N.; Bingham, S.; Luben, R.; Welch, A.; Day, N. (2004) Preliminary communication: glycated hemoglobin, diabetes, and incident colorectal cancer in men and women: a prospective analysis from the European prospective investigation into cancer-norfolk study Cancer Epidemiol Biomarkers Prev, 13 (6),915-9 [Journal Article] Online
Abstract: BACKGROUND: Increasing evidence suggests that abnormal glucose metabolism may be associated with increased risk of colorectal cancer. METHODS: We examined the relationship between known diabetes and glycated hemoglobin (HbA1c) concentrations measured in 1995 to 1997 and subsequent incident colorectal cancer after 6 years follow-up in 9,605 men and women ages 45 to 79 years in the European Prospective Investigation into Cancer-Norfolk Study. RESULTS: Among individuals not known to have cancer at the baseline survey, there were 67 incident colorectal cancers. HbA1c concentration appeared continuously related to incident colorectal cancer risk, with lowest rates observed in those with HbA1c below 5%. Known diabetes was also associated with incident colorectal cancer, with relative risk (RR) 3.18 and 95% confidence interval (CI) 1.36-7.40 (P < 0.01) adjusting for age and sex and RR 2.78 and 95% CI 1.10-7.00 (P = 0.03) adjusting for age, sex, body mass index, and smoking compared with those without known diabetes. The RR (95% CI) of incident colorectal cancer per 1% absolute increase in HbA1c was 1.34 (1.12-1.59; P < 0.001). HbA1c concentrations appeared to explain the increased colorectal cancer risk associated with diabetes in multivariate models. CONCLUSIONS: Known diabetes was associated with approximately 3-fold risk of colorectal cancer in this analysis; this increased risk was largely explained by HbA1c concentrations, which appears continuously related to colorectal cancer risk across the population distribution.
PubMed Accession Number :: 15184246.

Yuyun, M. F.; Khaw, K. T.; Luben, R.; Welch, A.; Bingham, S.; Day, N. E.; Wareham, N. J. (2004) Microalbuminuria, cardiovascular risk factors and cardiovascular morbidity in a British population: the EPIC-Norfolk population-based study Eur J Cardiovasc Prev Rehabil, 11 (3),207-13 [Journal Article] Online
Abstract: BACKGROUND: Microalbuminuria is independently associated with increased cardiovascular risk and renal function deterioration in diabetes and hypertension, but the clinical relevance of raised albuminuria in the general population is less certain. We examined the prevalence of microalbuminuria and its relationship to cardiovascular risk factors and cardiovascular morbidity in the UK general population. METHODS: Cross-sectional population-based study of 23,964 individuals, aged 40-79 years recruited in 1993-1997 for the EPIC-Norfolk Study. Smoking status, prevalent physician diagnosed diabetes, hypertension, cardiovascular disease and cancer were derived from a health and lifestyle questionnaire. Albumin-to-creatinine ratios were estimated from random spot urine specimens collected at the survey visit, and using these ratios participants were categorized into normoalbuminuria, microalbuminuria (2.5-25 mg/mmol), and macroalbuminuria. RESULTS: The prevalence of microalbuminuria and macroalbuminuria was 11.8% and 0.9% respectively in the total population and significantly higher in women (14.4%) compared with men (8.9%) (P<0.001). Independent determinants of microalbuminuria were age, sex, systolic blood pressure and current smoking. Microalbuminuria was independently associated with cardiovascular morbidity, after adjusting for known cardiovascular risk factors, with odds ratio (95% confidence interval) for prevalent cardiovascular disease of 1.30 (1.12-1.51) in all men and women. CONCLUSION: Microalbuminuria was present in approximately 12% of this population. It was independently associated with cardiovascular risk factors and prevalent cardiovascular disease. Microalbuminuria may be a useful indicator of high absolute cardiovascular risk in the community but prospective data are needed to establish its independent predictive value for future events.
PubMed Accession Number :: 15179101.

Boekholdt, S. M.; Peters, R. J.; Hack, C. E.; Day, N. E.; Luben, R.; Bingham, S. A.; Wareham, N. J.; Reitsma, P. H.; Khaw, K. T. (2004) IL-8 plasma concentrations and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study Arterioscler Thromb Vasc Biol, 24 (8),1503-8 [Journal Article] Online
Abstract: OBJECTIVE: To study the role of IL-8 in predicting future coronary artery disease (CAD) in apparently healthy men and women. METHODS AND RESULTS: A nested case-control study was performed in the prospective EPIC-Norfolk population study. We measured baseline IL-8 concentrations among 785 apparently healthy individuals in whom fatal or nonfatal CAD developed during follow-up and 1570 matched controls. Baseline IL-8 concentrations were higher in cases than in matched controls (3.5 pg/mL versus 3.1 pg/mL, P=0.001). The risk of future CAD increased with increasing quartiles of IL-8 (P linearity <0.0001). Among individuals in the highest IL-8 quartile, the unadjusted odds ratio for future CAD was 1.72 (95% CI, 1.34 to 2.21; P<0.0001). The odds ratio for future CAD was still significant after adjustment for traditional risk factors (OR, 1.58; 95%CI, 1.19 to 2.09; P=0.002) and after additional adjustment for C-reactive protein and white cell count (OR, 1.77; 95% CI, 1.21 to 2.60; P=0.001). CONCLUSIONS: We conclude that among apparently healthy men and women, elevated levels of IL-8 are associated with an increased risk of future CAD. These prospective data support a role for IL-8 in the development of CAD events.
PubMed Accession Number :: 15178568.

George, S.; Rochford, J. J.; Wolfrum, C.; Gray, S. L.; Schinner, S.; Wilson, J. C.; Soos, M. A.; Murgatroyd, P. R.; Williams, R. M.; Acerini, C. L.; Dunger, D. B.; Barford, D.; Umpleby, A. M.; Wareham, N. J.; Davies, H. A.; Schafer, A. J.; Stoffel, M.; O'Rahilly, S.; Barroso, I. (2004) A family with severe insulin resistance and diabetes due to a mutation in AKT2 Science, 304 (5675),1325-8 [Journal Article] Online
Abstract: Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.
Keywords: Active Transport, Cell Nucleus Adipocytes/cytology/metabolism Adult Aged Amino Acid Motifs Amino Acid Sequence Amino Acid Substitution Catalytic Domain Cell Differentiation Cell Line Cell Nucleus/metabolism Cytosol/metabolism DNA-Binding Proteins/metabolism Diabetes Mellitus/*genetics/metabolism Female Genes, Dominant Human Hyperinsulinism/genetics/metabolism Insulin/metabolism Insulin Resistance/*genetics Lipids/metabolism Male Middle Aged Molecular Sequence Data *Mutation, Missense Nuclear Proteins/metabolism Pedigree Phosphorylation Protein-Serine-Threonine Kinases/chemistry/*genetics/metabolism Proto-Oncogene Proteins/chemistry/*genetics/metabolism Signal Transduction Support, Non-U.S. Gov't
PubMed Accession Number :: 15166380.

Gibson, W. T.; Pissios, P.; Trombly, D. J.; Luan, J.; Keogh, J.; Wareham, N. J.; Maratos-Flier, E.; O'Rahilly, S.; Farooqi, I. S. (2004) Melanin-concentrating hormone receptor mutations and human obesity: functional analysis Obes Res, 12 (5),743-9 [Journal Article] Online
Abstract: Melanin-concentrating hormone (MCH), a neuropeptide highly expressed in the lateral hypothalamus, has an important role in the regulation of energy balance and body weight in rodents. We examined whether mutations in the two known MCH receptors might be associated with obesity-related phenotypes in humans. Among 106 subjects with severe early onset obesity and a history of hyperphagia, we found two missense variants in MCHR1: Y181H and R248Q. Neither of these was found in 192 normal weight controls. R248Q cosegregated with obesity across two generations; family data were unavailable for Y181H. When expressed in HEK293 cells, R248Q showed no evidence of constitutive activation or ligand hypersensitivity for extracellular signal-regulated kinase phosphorylation. In addition, R248Q showed no enhanced suppression of cAMP generation. Two common single-nucleotide polymorphisms were found to be in linkage disequilibrium: g.-114A>G and c.39C>T. No association between either of these single-nucleotide polymorphisms and obesity-related phenotypes was found among a population cohort of 541 whites. Only two rare noncoding variants were found in MCHR2. In conclusion, mutations in the MCH receptors are not commonly found in humans with severe early onset obesity. Clarification of the relationship of these variants to obesity must await study in other populations and/or in genetically modified mice.
PubMed Accession Number :: 15166293.

Grace, P. B.; Taylor, J. I.; Low, Y. L.; Luben, R. N.; Mulligan, A. A.; Botting, N. P.; Dowsett, M.; Welch, A. A.; Khaw, K. T.; Wareham, N. J.; Day, N. E.; Bingham, S. A. (2004) Phytoestrogen concentrations in serum and spot urine as biomarkers for dietary phytoestrogen intake and their relation to breast cancer risk in European prospective investigation of cancer and nutrition-norfolk Cancer Epidemiol Biomarkers Prev, 13 (5),698-708 [Journal Article] Online
Abstract: Subjects of this study consisted of 333 women (aged 45-75 years) drawn from a large United Kingdom prospective study of diet and cancer, the European Prospective Investigation of Cancer and Nutrition-Norfolk study. Using newly developed gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry methods incorporating triply (13)C-labeled standards, seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in 114 spot urines and 97 available serum samples from women who later developed breast cancer. Results were compared with those from 219 urines and 187 serum samples from healthy controls matched by age and date of recruitment. Dietary levels were low, but even so, mean serum levels of phytoestrogens were up to 600 times greater than postmenopausal estradiol levels. Phytoestrogen concentrations in spot urine (adjusted for urinary creatinine) correlated strongly with that in serum, with Pearson correlation coefficients > 0.8. There were significant relationships (P < 0.02) between both urinary and serum concentrations of isoflavones across increasing tertiles of dietary intakes. Urinary enterodiol and enterolactone and serum enterolactone were significantly correlated with dietary fiber intake (r = 0.13-0.29). Exposure to all isoflavones was associated with increased breast cancer risk, significantly so for equol and daidzein. For a doubling of levels, odds ratios increased by 20-45% [log(2) odds ratio = 1.34 (1.06-1.70; P = 0.013) for urine equol, 1.46 (1.05-2.02; P = 0.024) for serum equol, and 1.22 (1.01-1.48; P = 0.044) for serum daidzein]. These estimates of risk are similar to those established for estrogens and androgens in postmenopausal breast cancer but need confirmation in larger studies.
PubMed Accession Number :: 15159299.

Hu, G.; Qiao, Q.; Tuomilehto, J.; Balkau, B.; Borch-Johnsen, K.; Pyorala, K. (2004) Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women Arch Intern Med, 164 (10),1066-76 [Journal Article] Online
Abstract: BACKGROUND: Few studies have evaluated the associations between the metabolic syndrome (by any definition) and mortality. This study examined the age- and sex-specific prevalence of the metabolic syndrome and its association with all-cause and cardiovascular mortality in nondiabetic European men and women. METHODS: The study was based on 11 prospective European cohort studies comprising 6156 men and 5356 women without diabetes and aged from 30 to 89 years, and had a median follow-up of 8.8 years. A modification of the World Health Organization definition of the metabolic syndrome was used. The subjects were considered to have the metabolic syndrome if they had hyperinsulinemia and 2 or more of the following: obesity, hypertension, dyslipidemia, or impaired glucose regulation; however, other definitions were also studied. Hazard ratios for all-cause and cardiovascular mortality were estimated with Cox models in each cohort. Meta-analyses were performed to assess the overall association of the metabolic syndrome with mortality risk. RESULTS: The age-standardized prevalence of the metabolic syndrome was slightly higher in men (15.7%) than in women (14.2%). Of the 1119 deaths recorded during follow-up, 432 were caused by cardiovascular disease. The overall hazard ratios for all-cause and cardiovascular mortality in persons with the metabolic syndrome compared with persons without it were 1.44 (95% confidence interval [CI], 1.17-1.84) and 2.26 (95% CI, 1.61-3.17) in men and 1.38 (95% CI, 1.02-1.87) and 2.78 (95% CI, 1.57-4.94) in women after adjustment for age, blood cholesterol levels, and smoking. CONCLUSIONS: The overall prevalence of the metabolic syndrome in nondiabetic adult Europeans is 15%. Nondiabetic persons with the metabolic syndrome have an increased risk of death from all causes as well as cardiovascular disease.
Keywords: Adult Age Distribution Aged Aged, 80 and over Cardiovascular Diseases/diagnosis/*epidemiology *Cause of Death Cohort Studies Comorbidity Comparative Study Europe/epidemiology Female Human Male Metabolic Syndrome X/diagnosis/*epidemiology Middle Aged Multicenter Studies Prevalence Proportional Hazards Models Risk Assessment Sex Distribution Support, Non-U.S. Gov't Survival Analysis
PubMed Accession Number :: 15159263.

Young, E. H.; Wareham, N. J. (2004) Screening for coeliac disease: what evidence is required before population programmes could be considered? Arch Dis Child, 89 (6),499-500 [Journal Article] Online
Keywords: Celiac Disease/*diagnosis Human Mass Screening/*organization & administration Predictive Value of Tests Support, Non-U.S. Gov't
PubMed Accession Number :: 15155386.

Yuyun, M. F.; Khaw, K. T.; Luben, R.; Welch, A.; Bingham, S.; Day, N. E.; Wareham, N. J. (2004) Microalbuminuria independently predicts all-cause and cardiovascular mortality in a British population: The European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study Int J Epidemiol, 33 (1),189-98 [Journal Article] Online
Abstract: BACKGROUND: In patients with diabetes or hypertension, raised albuminuria is independently associated with an increased risk of all mortality, cardiovascular morbidity and mortality, and renal insufficiency. The role of albuminuria in the general population is still controversial. We therefore undertook this study to examine the relationship between albuminuria and all-cause, cardiovascular disease (CVD) and non-CVD mortality in the general population. METHODS: Prospective population-based cohort study of 20 911 individuals aged 40-79 years recruited in 1993-1997 for the EPIC-Norfolk Study (UK) and followed-up for an average of 6.3 years. Random spot urine specimens were collected at baseline and the albumin-to-creatinine ratio measured. Participants were categorized into normoalbuminuria, microalbuminuria, and macroalbuminuria ordered groups. At follow-up, vital status and cause of death were obtained from the UK Office for National Statistics. RESULTS: During follow-up, 934 deaths were registered. Age-adjusted all-cause mortality rate increased significantly across categories of baseline albuminuria (5.3, 5.2, and 6.3/1000 person years (pyrs) across tertiles of normoalbuminuria, 8.7/1000 pyrs for microalbuminuria, and 18.4/1000 pyrs for macroalbuminuria, P < 0.001 for trend); CVD, 1.6, 1.7, 2.1, 4.3, 12.6/1000 pyrs (P < 0.001); and non-CVD, 3.7, 3.5, 4.2, 4.4, 5.8/1000 pyrs (P = 0.052) respectively. The multivariate hazard ratio for all-cause mortality associated with microalbuminuria was 1.48 (95% CI: 1.20, 1.79), and CVD 2.03 (95% CI: 1.55, 2.67). The association with non-CVD mortality was only significant in men. CONCLUSIONS: The significant increased risk of all-cause mortality especially from CVD associated with microalbuminuria, suggest that this may be a useful indicator in identifying those in the population at greatest absolute risk of fatal CVD events alongside conventional CVD risk factors.
Keywords: Adult Age Distribution Aged Albuminuria/complications/*epidemiology Cardiovascular Diseases/complications/*mortality *Cause of Death Female Great Britain/epidemiology Human Male Middle Aged Neoplasms/complications/mortality Prevalence Prospective Studies Risk Factors Sex Distribution Support, Non-U.S. Gov't
PubMed Accession Number :: 15075168.

Shohaimi, S.; Bingham, S.; Welch, A.; Luben, R.; Day, N.; Wareham, N.; Khaw, K. T. (2004) Occupational social class, educational level and area deprivation independently predict plasma ascorbic acid concentration: a cross-sectional population based study in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) Eur J Clin Nutr, 58 (10),1432-5 [Journal Article] Online
Abstract: OBJECTIVE: To investigate the independent association between three different measures of socioeconomic status and plasma ascorbic acid level. DESIGN: Cross-sectional population based study. SETTING AND PARTICIPANTS: 20 292 men and women aged 39-79 y who participated in the EPIC-Norfolk study. RESULTS: Individuals in manual social classes, who had no educational qualifications or those who lived in the most deprived areas had significantly lower levels of plasma ascorbic acid compared to those in nonmanual social classes, with at least O-level qualifications or who lived in less deprived areas. The magnitude of effect for each measure of socioeconomic status was greater in current smokers compared to current nonsmokers. CONCLUSION: Education and social class were stronger predictors of differences in ascorbic acid levels, an indicator of dietary health behaviour, than a deprivation index based on the Townsend score. This suggests that education could be particularly important in influencing large socioeconomic differentials in health related behaviours and potentially, health outcomes in the UK.
Keywords: Adult Aged Ascorbic Acid/*blood Cohort Studies Cross-Sectional Studies *Educational Status England Female Health Surveys Humans Male Middle Aged Occupations Poverty *Poverty Areas Prospective Studies Research Support, Non-U.S. Gov't Risk Factors Smoking/adverse effects/*blood *Social Class Socioeconomic Factors
PubMed Accession Number :: 15054419.

Wong, M. Y.; Day, N. E.; Luan, J. A.; Wareham, N. J. (2004) Estimation of magnitude in gene-environment interactions in the presence of measurement error Stat Med, 23 (6),987-98 [Journal Article] Online
Abstract: The design of studies aimed at identifying the interaction between genetic and environmental determinants in disease risk is attracting increased attention. In this paper, we study the effect of errors on measuring exposures and the effect of assessing genotype at one locus on the association of a continuous outcome measure with continuous exposures and genotype. The estimation of misclassification errors in assessing genotypes from a separate study is proposed. If the exposure measurement error is substantial, then even relatively small errors in genotyping within limits that are often quoted can have an appreciable effect on interaction estimates. We, thus, consider a method for correcting the measurement errors when the interaction between the exposures and the genetic factor is significant. Finally, we present an epidemiological example to demonstrate the importance of correcting measurement errors.
Keywords: Alleles Bias (Epidemiology) Blood Pressure/genetics *Data Interpretation, Statistical Energy Metabolism/genetics *Environmental Exposure Female *Genotype Human Male Polymorphism (Genetics) Support, Non-U.S. Gov't
PubMed Accession Number :: 15027084.

Laudes, M.; Barroso, I.; Luan, J.; Soos, M. A.; Yeo, G.; Meirhaeghe, A.; Logie, L.; Vidal-Puig, A.; Schafer, A. J.; Wareham, N. J.; O'Rahilly, S. (2004) Genetic variants in human sterol regulatory element binding protein-1c in syndromes of severe insulin resistance and type 2 diabetes Diabetes, 53 (3),842-6 [Journal Article] Online
Abstract: The transcription factor sterol regulatory element binding protein (SREBP)-1c is intimately involved in the regulation of lipid and glucose metabolism. To investigate whether mutations in this gene might contribute to insulin resistance, we screened the exons encoding the aminoterminal transcriptional activation domain in a cohort of 85 unrelated human subjects with severe insulin resistance. Two missense mutations (P87L and P416A) were found in single affected patients but not in 47 control subjects. However, these variants were indistinguishable from the wild-type in their ability to bind DNA or to transactivate an SREBP-1 responsive promoter construct. We also identified a common intronic single nucleotide polymorphism (C/T) located between exon 18c and 19c. In a case-control study of 517 U.K. Caucasian case subjects and 517 age- and sex-matched control subjects, the T-allele at this locus was significantly associated with type 2 diabetes in men (odds ratio = 1.42 [1.11-1.82], P = 0.005) but not women. In a separate population-based study of 1,100 Caucasians, carriers of the T-allele showed significantly higher levels of total and LDL cholesterol (P < 0.05) compared with wild-type individuals. In summary, we have conducted the first study of the SREBP-1c gene as a candidate for human insulin resistance. Although the rare mutations identified were functionally silent in the assays used, we obtained some evidence, which requires conformation in other populations, that a common variant in the SREBP-1c gene might influence diabetes risk and plasma cholesterol level.
Keywords: Base Sequence CCAAT-Enhancer-Binding Proteins/*genetics Case-Control Studies Cholesterol/blood Comparative Study DNA Primers DNA-Binding Proteins/*genetics Diabetes Mellitus, Type II/*genetics European Continental Ancestry Group/genetics Female Human Insulin Resistance/*genetics Introns Male Polymorphism, Single Nucleotide Reference Values Reverse Transcriptase Polymerase Chain Reaction Support, Non-U.S. Gov't *Variation (Genetics)
PubMed Accession Number :: 14988272.

Harding, A. H.; Day, N. E.; Khaw, K. T.; Bingham, S. A.; Luben, R. N.; Welsh, A.; Wareham, N. J. (2004) Habitual fish consumption and glycated haemoglobin: the EPIC-Norfolk study Eur J Clin Nutr, 58 (2),277-84 [Journal Article] Online
Abstract: OBJECTIVE: To investigate the association between habitual fish consumption and a continuous measure of glycaemia. DESIGN: Cross-sectional study. SETTING: EPIC-Norfolk, a population-based cohort study of diet and chronic disease. SUBJECTS AND METHODS: In all, 4500 men and 5509 women, aged 40-78 y, without self-reported diabetes. Diet was assessed by a semiquantitative food frequency questionnaire, and glycaemia was measured by glycated haemoglobin. RESULTS: In women only, in analyses adjusted for age, the HbA(1c) level was positively associated with eating fried fish and inversely associated with eating oily fish (b=0.036, 95% confidence interval (CI): 0.0033, 0.069; and b=-0.046, 95% CI:-0.086, -0.0064 respectively). These associations were attenuated by adjustment for family history of diabetes, smoking status and physical activity level, but the association with fried fish remained statistically significant (b=0.033, 95% CI: 0.00056, 0.066). Adjusting for total energy, alcohol, fruit and vegetable intakes resulted in further attenuation and both associations were no longer statistically significant. In men, there was no evidence that HbA(1c) level was associated with fish consumption. CONCLUSIONS: The study found no evidence of an association between fish consumption and HbA(1c) after taking other lifestyle factors into account.
Keywords: Adult Aged Animals Cohort Studies Comparative Study Diet Surveys Energy Intake Fatty Acids, Omega-3/administration & dosage Female Fish Oils/*administration & dosage Fishes/*classification Food Preferences/*physiology *Glycemic Index Great Britain/epidemiology Hemoglobin A, Glycosylated/*analysis/metabolism Human Life Style Linear Models Male Middle Aged Seafood/*classification Sex Factors Support, Non-U.S. Gov't
PubMed Accession Number :: 14749748.

Yuyun, M. F.; Khaw, K. T.; Luben, R.; Welch, A.; Bingham, S.; Day, N. E.; Wareham, N. J. (2004) Microalbuminuria and stroke in a British population: the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study J Intern Med, 255 (2),247-56 [Journal Article] Online
Abstract: OBJECTIVES: To examine the relationship between microalbuminuria and incident stroke in the general population. DESIGN: Population-based prospective cohort study. SETTING: Participants were recruited in a primary care setting from 35 participating general practice units in Norfolk, UK. SUBJECTS AND MAIN OUTCOME MEASURES: The study population consisted of 23,630 individuals aged 40-79 years recruited between 1993 and 1997 for the EPIC-Norfolk Study and followed up for an average of 7.2 years. Random spot urine specimens were collected at baseline and albumin-to-creatinine ratio measured. Participants were categorized into normoalbuminuria, microalbuminuria and macroalbuminuria groups. During follow-up, the main end point was stroke incidence (fatal and nonfatal), ascertained from the UK Office for National Statistics and from the National Health Service Health District database of all hospital admissions. RESULTS: A total of 246 stroke events occurred during follow-up [crude incidence rate of stroke, 1.5 per 1000 person years (pyrs)]. The age-adjusted incidence of stroke increased significantly across categories of baseline albuminuria (0.9, 1.1 and 1.4/1000 pyrs for tertiles of normoalbuminuria, 2.6/1000 pyrs for microalbuminuria, and 6/1000 pyrs for macroalbuminuria in the total population, P < 0.001 for trend). In all women and men, the multivariate hazard ratio [95% confidence interval (CI)] for stroke associated with microalbuminuria was 1.49 (1.13-2.14) and macroalbuminuria 2.43 (1.11-6.26). After stratifying by stroke subtype, microalbuminuria was only independently predictive of ischaemic stroke, with hazard ratio (95% CI) of 2.01 (1.29-3.31). CONCLUSION: Microalbuminuria is independently associated with approximately 50% increased risk of stroke in the general population. Microalbuminuria may be useful in identifying those at increased risk of stroke in the general population.
Keywords: Adult Aged Albuminuria/*complications Cerebrovascular Accident/epidemiology/*etiology Disease-Free Survival England/epidemiology Female Follow-Up Studies Human Incidence Male Middle Aged Proportional Hazards Models Prospective Studies Risk Assessment Support, Non-U.S. Gov't
PubMed Accession Number :: 14746562.

Sandhu, M. S.; Gibson, J. M.; Heald, A. H.; Dunger, D. B.; Wareham, N. J. (2004) Association between insulin-like growth factor-I: insulin-like growth factor-binding protein-1 ratio and metabolic and anthropometric factors in men and women Cancer Epidemiol Biomarkers Prev, 13 (1),166-70 [Journal Article] Online
Abstract: Several prospective observational studies have suggested that elevated circulating IGF-I levels are associated with an increased risk of cancer. These observations may provide a potential mechanism through which previously identified metabolic and anthropometric factors, such as obesity and elevated insulin and glucose levels, may operate. We therefore examined metabolic and anthropometric influences on circulating levels of insulin-like growth factor-I (IGF-I), insulin-like growth factor-binding protein-1 (IGFBP-1), and the IGF-I:IGFBP-1 ratio in a middle-aged population of 349 men and 492 women. IGF-I showed only modest inverse associations with indices of adiposity. However, we found that low IGFBP-I levels and an increased IGF-I:IGFBP-1 ratio were strongly associated with increased levels of insulin and glucose in men and women. Body mass index was also positively related to the IGF-I:IGFBP-1 ratio in men (P < 0.001) and women (P < 0.001), independent of metabolic correlates of IGFBP-1 and IGF-I. Similarly, waist:hip ratio and waist circumference were also associated with an increased IGF-I:IGFBP-1 ratio and low circulating IGFBP-1 levels. These findings suggest that individuals with greater fat mass and upper body obesity may have elevated levels of bioavailable or free IGF-I, which could, in part, mediate the reported associations among metabolic and anthropometric factors and cancer risk.
Keywords: Adipose Tissue/*metabolism *Anthropometry Blood Glucose Body Constitution Body Mass Index Female Human Insulin/blood Insulin-Like Growth Factor I/*metabolism Insulin-Like Growth-Factor Binding Protein 1/*metabolism Linear Models Male Middle Aged Support, Non-U.S. Gov't
PubMed Accession Number :: 14744751.

Yuyun, M. F.; Khaw, K. T.; Luben, R.; Welch, A.; Bingham, S.; Day, N. E.; Wareham, N. J. (2004) A prospective study of microalbuminuria and incident coronary heart disease and its prognostic significance in a British population: the EPIC-Norfolk study Am J Epidemiol, 159 (3),284-93 [Journal Article] Online
Abstract: Microalbuminuria is associated with an increased risk of cardiovascular and renal disease in patients with diabetes and hypertension. The role of microalbuminuria as a predictor of coronary heart disease (CHD) has not been examined in large general-population cohorts, and its prognostic significance in persons with established CHD is uncertain. The authors examined the relation between microalbuminuria and incident CHD (1993-2002) in a population-based British cohort of 22,368 men and women aged 40-79 years without prevalent baseline CHD and evaluated its prognostic significance in 1,596 participants with baseline CHD. Participants were members of the Norfolk, United Kingdom, component of the European Prospective Investigation into Cancer and Nutrition (the EPIC-Norfolk Study). At baseline, participants were categorized into normoalbuminuria, microalbuminuria, and macroalbuminuria groups. During an average of 6.4 years of follow-up, 800 primary CHD events were registered. The age-adjusted incidence of CHD increased significantly across ordered categories of albuminuria (4.3, 4.4, and 5.6/1,000 person-years across tertiles of normoalbuminuria, 7.1/1,000 person-years for microalbuminuria, and 12.2/1,000 person-years for macroalbuminuria; p for trend < 0.001). The multivariate hazard ratio for incident primary CHD was 1.36 (95% confidence interval (CI): 1.12, 1.64) for microalbuminuria and 1.59 (95% CI: 1.10, 2.37) for macroalbuminuria. Among participants with established baseline CHD, the independent risk of all-cause mortality associated with microalbuminuria was 1.61 (95% CI: 1.19, 2.07). Microalbuminuria may be useful in identifying persons at increased risk of CHD and subsequent death in the general population.
Keywords: Adult Age Distribution Aged Albuminuria/*diagnosis/epidemiology Coronary Disease/*epidemiology/etiology/urine Female Great Britain/epidemiology Human Incidence Male Middle Aged Predictive Value of Tests Prevalence Prognosis Prospective Studies Risk Factors Support, Non-U.S. Gov't
PubMed Accession Number :: 14742289.

Khaw, K. T.; Reeve, J.; Luben, R.; Bingham, S.; Welch, A.; Wareham, N.; Oakes, S.; Day, N. (2004) Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus: EPIC-Norfolk prospective population study Lancet, 363 (9404),197-202 [Journal Article] Online
Abstract: BACKGROUND: A quarter of fractures needing admission happen in men, but few data are available that show the value of bone measures for prediction of fracture risk in men. We aimed to assess quantitative ultrasound of the calcaneum and fracture incidence in a prospective observational population study. METHODS: Calcaneum broadband ultrasound attenuation (BUA) was measured in men and women in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) between 1997 and 2000. Incident fractures were ascertained by hospital record linkage. FINDINGS: In 14824 men and women aged 42-82 years, during mean follow-up of 1.9 years (SD 0.7), there were 121 incident fractures that needed admission, including 31 hip fractures. Men and women in the lowest 10% of the calcaneum BUA distribution had a relative risk of fracture of 4.44 (95% CI 2.24-8.89, p<0.0001) compared with those in the upper 30% of the distribution. A fall of about 1 SD in BUA (20 db/MHz) was associated with a relative risk of fracture of 1.95 (95% CI 1.50-2.52, p<0.0001), independent of age, sex, weight, height, cigarette smoking habit, and past history of fracture. BUA predicted fractures with consistent magnitude in subgroups stratified by sex, age 65 years or older and younger than 65 years, smoking habit, past history of fracture, and hip and non-hip fractures separately. The sex difference in fracture risk was largely accounted for by differences in BUA. INTERPRETATION: Quantitative calcaneum ultrasound predicts total and hip fracture risk in men and women in a continuous relation. The challenge now is to identify interventions to improve bone health in the whole population.
Keywords: Adult Aged Bone Density/*physiology Calcaneus/*ultrasonography Cohort Studies Comparative Study Female Follow-Up Studies Fractures/*epidemiology/prevention & control Great Britain/epidemiology Hip Fractures/*epidemiology/prevention & control Human Incidence Male Middle Aged Osteoporosis/ultrasonography Predictive Value of Tests Risk Support, Non-U.S. Gov't
PubMed Accession Number :: 14738792.

Challis, B. G.; Luan, J.; Keogh, J.; Wareham, N. J.; Farooqi, I. S.; O'Rahilly, S. (2004) Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians Int J Obes Relat Metab Disord, 28 (3),442-6 [Journal Article] Online
Abstract: OBJECTIVE: To investigate whether genetic variation at the loci encoding the corticotropin-releasing factor receptors-1 and -2 (CRF-R1 and CRF-R2) contributes to human obesity. DESIGN: The coding region of the CRF-R1 and CRF-R2 genes was screened in 51 severely obese children (body mass index (BMI)>4 kg/m(2) standard deviations above the age-related mean) using denaturing high-performance liquid chromatography and direct nucleotide sequencing. Common polymorphisms that were identified were typed from a UK Caucasian population-based cohort by a PCR-based forced restriction digestion. A repeated measures analysis was used to determine associations between the C861T and G1047A genotypes and anthropometric and biochemical indices relevant to obesity. RESULTS: In subjects with extreme early-onset obesity, four missense mutations were found, each in a single individual: CRF-R1 (Val161Met) and CRF-R2 (Glu220Asp, Val240Ile and Val411Met). However, none of these missense mutations clearly cosegregated with obesity in family studies. Two common single-nucleotide polymorphisms, C861T (Cys287Cys) in CRF-R1 and G1047A (Ser349Ser) in CRF-R2, were also detected. G1047A did not associate with any obesity-related phenotype. In contrast, carriers of the CRF-R1 polymorphism, C861T, had a significantly higher body mass index (BMI). CONCLUSION: Mutations in the coding sequence of the CRF-R1 and CRF-R2 genes are unlikely to be a common monogenic cause of early-onset obesity. In an adult UK Caucasian population, the CRF-R1 C861T polymorphism is associated with increased BMI.
Keywords: Age of Onset Body Mass Index Child Child, Preschool Female Heterozygote Human Male Mutation, Missense Obesity/*genetics Pedigree *Polymorphism, Single Nucleotide Receptors, Corticotropin-Releasing Hormone/*genetics Support, Non-U.S. Gov't *Variation (Genetics)
PubMed Accession Number :: 14724656.

Neal, D. A.; Tom, B. D.; Luan, J.; Wareham, N. J.; Gimson, A. E.; Delriviere, L. D.; Byrne, C. D.; Alexander, G. J. (2004) Is there disparity between risk and incidence of cardiovascular disease after liver transplant? Transplantation, 77 (1),93-9 [Journal Article] Online
Abstract: BACKGROUND: Hypertension and hypercholesterolemia are recognized complications of liver transplantation, but whether they contribute to the development of cardiovascular disease is uncertain. We aimed first to determine the prevalence of risk factors for coronary heart disease (CHD) after liver transplantation and second to study the effect of liver transplantation on the predicted 10-year risk of developing CHD and the incidence of cardiovascular events in comparison with a matched local population. METHODS: Data on blood pressure, serum lipids, weight, diabetes mellitus, smoking, and incidence of myocardial infarction (MI) and stroke were obtained retrospectively from the case notes of 181 consecutive adult liver transplant recipients (median follow-up 54 months). The Framingham coronary risk equations were used to calculate the 10-year probability of developing CHD. RESULTS: The prevalences of hypertension and hypercholesterolemia after transplantation were 77% and 62%, respectively. The predicted 10-year risk of CHD increased from 6.9% before transplantation to 11.5% at 1 year after transplantation, whereas that of a matched local population was 7%. Compared with a matched nontransplant population, the incidence ratios for MI and stroke were 0.55 (95% confidence interval, 0.01-3.06 ) and 1.45 (95% confidence interval, 0.18-5.22), respectively. No patients died from MI or stroke. CONCLUSIONS: Liver transplant recipients have a high prevalence of risk factors for cardiovascular disease, exceeding that of the general population, and have a higher predicted risk of developing CHD. Despite this, there were no deaths from CHD or stroke during the study period.
Keywords: Adolescent Adult Aged Body Mass Index Cardiovascular Diseases/*epidemiology/*etiology Cholesterol/blood Coronary Disease/etiology Diabetes Mellitus/complications Female Human Hypertension/epidemiology Incidence Liver Transplantation/*adverse effects/mortality Male Middle Aged Postoperative Period Retrospective Studies Risk Assessment Risk Factors Smoking/epidemiology Triglycerides/blood
PubMed Accession Number :: 14724441.

Spijkerman, A. M.; Yuyun, M. F.; Griffin, S. J.; Dekker, J. M.; Nijpels, G.; Wareham, N. J. (2004) The performance of a risk score as a screening test for undiagnosed hyperglycemia in ethnic minority groups: data from the 1999 health survey for England Diabetes Care, 27 (1),116-22 [Journal Article] Online
Abstract: OBJECTIVE: To assess the performance of the Cambridge Risk Score (CRS) to predict undiagnosed hyperglycemia in Caribbean and South Asian people living in the U.K. RESEARCH DESIGN AND METHODS: The CRS uses routinely available data from primary care records to identify people at high risk for undiagnosed type 2 diabetes. The sensitivity, specificity, and area under the receiver operator characteristic (ROC) curve for the CRS cut point of 0.199 were 77, 72, and 80% (95% CI 68-91), respectively. The risk score was calculated for 248 Caribbean and 555 South Asian participants aged 40-75 years in the 1999 Health Survey for England. Undiagnosed hyperglycemia was considered present if fasting plasma glucose was >/=7.0 mmol/l or HbA(1c) was >/=6.5%. Sensitivity, specificity, and predictive values were calculated for various cut points of the risk score, and ROC curves were constructed. RESULTS: The area under the ROC curve was 67% (59-76) and 72% (67-78) for Caribbeans and South Asians, respectively. The optimal cut point in Caribbean participants was 0.236, sensitivity was 63% (46-77), and specificity was 63% (56-69). In the South Asian population, the optimal cut point was and 0.127, sensitivity was 69% (60-78), and specificity was 64% (60-69). CONCLUSIONS: The CRS, using routinely available data, can be used in a strategy to detect undiagnosed hyperglycemia in Caribbean and South Asian populations. The existence of ethnic group-specific cut points must be further established in future studies.
Keywords: Adult Aged Area Under Curve Blood Glucose/analysis England/epidemiology *Ethnic Groups Female Health Surveys Human Hyperglycemia/blood/diagnosis/*epidemiology Male Mass Screening Middle Aged *Minority Groups ROC Curve Risk Assessment Sensitivity and Specificity Support, Non-U.S. Gov't
PubMed Accession Number :: 14693976.

Harding, A. H.; Day, N. E.; Khaw, K. T.; Bingham, S.; Luben, R.; Welsh, A.; Wareham, N. J. (2004) Dietary fat and the risk of clinical type 2 diabetes: the European prospective investigation of Cancer-Norfolk study Am J Epidemiol, 159 (1),73-82 [Journal Article] Online
Abstract: The role of dietary fat in the etiology of type 2 diabetes remains uncertain. The authors investigated the association between dietary fat composition and risk of clinical type 2 diabetes in the European Prospective Investigation of Cancer-Norfolk study and identified food consumption patterns associated with dietary fat composition. Diet was assessed at baseline (1993-1997) using a semiquantitative food frequency questionnaire. From multiple sources of information, 414 incident cases of diabetes were identified among 23,631 men and women aged 40-78 years during 3-7 years of follow-up. The capture-recapture ascertainment level was 99%. The energy-adjusted dietary polyunsaturated:saturated fat ratio was inversely associated with the risk of diabetes (odds ratio (OR) = 0.84 per standard deviation change, 95% confidence interval (CI): 0.75, 0.94). Adjustment for age, sex, family history of diabetes, smoking, physical activity, total fat, protein, and alcohol attenuated the association (OR = 0.88, 95% CI: 0.78, 0.99), and it was no longer statistically significant after including body mass index and the waist:hip ratio (OR = 0.91, 95% CI: 0.81, 1.03). This prospective study showed that an increased dietary polyunsaturated:saturated fat ratio was associated with a reduced risk of diabetes, independent of age, sex, family history of diabetes, and other lifestyle factors.
Keywords: Adult Aged Diabetes Mellitus, Type II/blood/*epidemiology/*etiology Diet Diet Records *Dietary Fats Dietary Fats, Unsaturated Europe/epidemiology Female Hemoglobin A, Glycosylated Human Male Middle Aged Odds Ratio Prospective Studies Questionnaires Risk Factors Support, Non-U.S. Gov't
PubMed Accession Number :: 14693662.

Franks, P. W.; Luan, J.; Browne, P. O.; Harding, A. H.; O'Rahilly, S.; Chatterjee, V. K.; Wareham, N. J. (2004) Does peroxisome proliferator-activated receptor gamma genotype (Pro12ala) modify the association of physical activity and dietary fat with fasting insulin level? Metabolism, 53 (1),11-6 [Journal Article] Online
Abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) has a role in controlling adipogenesis and insulin sensitivity. Previous studies have suggested that a common polymorphism (Pro12Ala) in the PPARgamma-2 isoform of this gene may be associated with markers of insulin resistance. We have previously shown that in combination, the relationships with fasting insulin of dietary polyunsaturated to saturated fatty acid ratio (P:S ratio) and physical activity are additive. We have also demonstrated that the association between P:S ratio and fasting insulin level is modified by the Pro12Ala genotype. The purpose of the present study was to investigate whether the Pro12Ala genotype modified the combined relationships of P:S ratio and physical activity level (PAL) on fasting insulin concentration. A population-based cohort of 506 Caucasian men and women aged 31 to 71 years was genotyped for the Pro12Ala polymorphism. P:S ratio was assessed by food-frequency questionnaire (FFQ) and PAL was estimated from 4 days of free-living heart rate monitoring following individual calibration of heart rate against energy expenditure during an exercise stress test. The combined associations of PAL and P:S ratio on fasting insulin level were examined stratified by Pro12Ala genotypes in a dominant model for the Ala allele. Among Pro allele homozygotes, there was no interaction between PAL and P:S ratio on fasting insulin (P =.929). However, in carriers of the Ala allele the association of P:S ratio with fasting insulin was modified by activity level (interaction P = 0.038). In those who were inactive and carried the Ala allele, the age-, sex-, and body mass-adjusted relationship between P:S ratio and log insulin was not significant (beta = -0.03, P =.93). In contrast, in physically active Ala carriers, the association of P:S ratio with log fasting insulin was highly significant (beta = -0.93, P =.004). In conclusion, this study examined the modification by PPARgamma genotype of the association between energy expenditure, P:S ratio, and fasting insulin level, a measure of insulin resistance. These data show that in Pro allele homozygotes the combined associations of P:S ratio and PAL are additive. In contrast, in Ala allele carriers, PAL modifies the association between P:S ratio and fasting insulin level in a multiplicative manner.
Keywords: Adult Aged Alanine Alleles Body Mass Index Cohort Studies Diet Records Dietary Fats/*administration & dosage Energy Metabolism Exercise/*physiology Fasting Fatty Acids/administration & dosage Fatty Acids, Unsaturated/administration & dosage Female Genotype Heart Rate Human Insulin/*blood Male Middle Aged *Polymorphism (Genetics) Proline Prospective Studies Protein Isoforms/genetics Questionnaires Receptors, Cytoplasmic and Nuclear/*genetics/*physiology Support, Non-U.S. Gov't Transcription Factors/*genetics/*physiology
PubMed Accession Number :: 14681835.

Barroso, I.; Luan, J.; Middelberg, R. P.; Harding, A. H.; Franks, P. W.; Jakes, R. W.; Clayton, D.; Schafer, A. J.; O'Rahilly, S.; Wareham, N. J. (2003) Candidate Gene Association Study in Type 2 Diabetes Indicates a Role for Genes Involved in beta-Cell Function as Well as Insulin Action PLoS Biol, 1 (1),E20 [Journal Article] Online
Abstract: Type 2 diabetes is an increasingly common, serious metabolic disorder with a substantial inherited component. It is characterised by defects in both insulin secretion and action. Progress in identification of specific genetic variants predisposing to the disease has been limited. To complement ongoing positional cloning efforts, we have undertaken a large-scale candidate gene association study. We examined 152 SNPs in 71 candidate genes for association with diabetes status and related phenotypes in 2,134 Caucasians in a case-control study and an independent quantitative trait (QT) cohort in the United Kingdom. Polymorphisms in five of 15 genes (33%) encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor), KCNJ11 (KIR6.2), SLC2A2 (GLUT2), HNF4A (HNF4alpha), and INS (insulin)-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. We examined 35 genes predicted to have their major influence on insulin action, and three (9%)-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. These results confirm the genetic complexity of Type 2 diabetes and provide evidence that common variants in genes influencing pancreatic beta-cell function may make a significant contribution to the inherited component of this disease. This study additionally demonstrates that the systematic examination of panels of biological candidate genes in large, well-characterised populations can be an effective complement to positional cloning approaches. The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases.
PubMed Accession Number :: 14551916.

Kaptoge, S.; Dalzell, N.; Jakes, R. W.; Wareham, N.; Day, N. E.; Khaw, K. T.; Beck, T. J.; Loveridge, N.; Reeve, J. (2003) Hip section modulus, a measure of bending resistance, is more strongly related to reported physical activity than BMD Osteoporos Int, 14 (11),941-9 [Journal Article] Online
Abstract: We hypothesized that measures of physical activity would have a closer relationship with section modulus (SM), an indicator of bending resistance, than with bone mineral density (BMD) because physical activity might expand the bony envelope, which tends to reduce BMD for a constant bone mineral content. Four hundred twenty-three men and 436 women (mean age 72 years, SD =3) were recruited from a prospective population-based cohort study to a study of hip bone loss. Hip BMD was measured on two occasions 2-5 years apart (mean 2.7, DXA-Hologic 1,000 W). Hip structural analysis (HSA) software was used to calculate SM and BMD from the DXA scans on three narrow regions: the narrow neck (NN), intertrochanter (IT) and shaft (S). A physical activity and lifestyle questionnaire was administered at baseline. Multivariate repeated measures analysis of variance was used to model the associations between personal attributes (weight, height, age), physical activity and lifestyle variables with SM, cross-sectional area (CSA), sub-periosteal diameter (PD) and BMD. Men and women were analysed together after tests for interactions with gender, which were found not to be significant. In all regions female gender was associated with having lower values of all outcomes, and body weight was positively associated with all outcomes, i.e., SM, CSA, PD and BMD ( P<0.0001). Sub-periosteal diameter was positively associated with reported lifetime physical activity (IT and S, P<0.0001). There was a significant decline of BMD with age at the NN and S regions ( P<0.026), and the PD increased with age (NN and S, P<0.019). Previous fracture history was associated with having lower values of BMD, SM and CSA (except for S; P<0.022). Both section modulus and CSA were positively associated with heavy physical activity after age 50 years in all regions ( P<0.019), whereas NN BMD was the only BMD associate of heavy physical activity after 50 ( P=0.036). Time spent per week on recreational activities classified as no impact activity was positively associated with BMD, CSA and SM (multivariate P<0.016). In conclusion, proximal femur diameter is associated positively with reported life-long physical activity. If this is mediated through a loading related effect on sub-periosteal expansion, BMD would be an unsatisfactory outcome measure in physical activity studies since it is inversely related to projected bone area. SM in contrast was associated with several measures of recent physical activity and relates more directly to the bending experienced by the proximal femur in response to a given load. These data are consistent with an effect of mechanical loading to regulate bone strength through an anabolic effect maximal in the subperiosteal cortex, where the highest loading-related strains are experienced.
Keywords: Aged Aging/physiology Bone Density/*physiology Densitometry, X-Ray Elasticity Female Femur/*physiology Femur Neck/physiology Follow-Up Studies Human Male Motor Activity/*physiology Prospective Studies Stress, Mechanical Support, Non-U.S. Gov't Weight-Bearing/physiology
PubMed Accession Number :: 12955315.

Jakes, R. W.; Day, N. E.; Khaw, K. T.; Luben, R.; Oakes, S.; Welch, A.; Bingham, S.; Wareham, N. J. (2003) Television viewing and low participation in vigorous recreation are independently associated with obesity and markers of cardiovascular disease risk: EPIC-Norfolk population-based study Eur J Clin Nutr, 57 (9),1089-96 [Journal Article] Online
Abstract: OBJECTIVE: This study describes the associations between sedentary behaviour (television viewing) and participation in vigorous recreational activity with obesity and with biomarkers of cardiovascular disease (CVD) risk profile. DESIGN: Cross-sectional analysis of the EPIC-Norfolk cohort study. SETTING: The study is a population-based study of participants living in Norfolk, UK. SUBJECTS: A total of 15 515 men and women aged between 45 and 74 y, recruited through General Practice lists, who completed the detailed physical activity questionnaire. RESULTS: Following exclusion of those with self-reported myocardial infarction, stroke and diabetes, 14 189 participants remained for the analysis. Self-reported television viewing was positively and participation in vigorous activity negatively associated with markers of obesity, blood pressure and plasma lipids. In multiple regression analysis, adjusting for age, alcohol, smoking, treatment for hypertension, vigorous and total physical activity, these associations remained significant. For women who participated in more than 1 h/week of vigorous activity and who watched fewer than 2 h of television each day, the adjusted mean body mass index was 1.92 kg/m(2) less than for women who reported participating in no vigorous activity and who watched more than 4 h of television each day (P<0.001). The equivalent figure for men was 1.44 kg/m(2) (P<0.001). In a similar analysis, with blood pressure as the outcome, mean diastolic blood pressure difference between the extreme groups of vigorous activity and television viewing was 3.6 mmHg in men (P<0.001) and 2.7 mmHg (P=0.001) in women. CONCLUSIONS: These data suggest that time spent participating in vigorous recreational physical activity and television viewing, an indicator of a sedentary lifestyle, are associated with obesity and markers of CVD disease risk independent of total reported physical activity. Whether these observations represent the true underlying aetiological relations or are a manifestation of the different precision with which the subdimensions of activity are measured remains uncertain.
Keywords: Aged Anthropometry Biological Markers/analysis Blood Pressure/physiology Cardiovascular Diseases/*epidemiology Causality Cohort Studies Comorbidity Cross-Sectional Studies Exercise/*physiology Female Great Britain/epidemiology Human Lipids/blood Male Middle Aged Obesity/*epidemiology Questionnaires Recreation/*physiology Regression Analysis Risk Factors Support, Non-U.S. Gov't *Television
PubMed Accession Number :: 12947427.

Smith, M. R.; Kinmonth, A. L.; Luben, R. N.; Bingham, S.; Day, N. E.; Wareham, N. J.; Welch, A.; Khaw, K. T. (2003) Smoking status and differential white cell count in men and women in the EPIC-Norfolk population Atherosclerosis, 169 (2),331-7 [Journal Article] Online
Abstract: The total white blood cell (WBC) count is reported to be an independent predictor of mortality in several prospective studies. We investigated the association between total and differential WBC counts and cigarette smoking habit in a cross-sectional population-based study of 6902 men and 8405 women 39-79 years of age participating between July 1994 and 1997 in the European Prospective Investigation of Cancer (EPIC-Norfolk) study. Main outcome measures included WBC, granulocyte, lymphocyte and monocyte counts measured at a baseline health check and self-reported cigarette smoking habit. The age- and body mass index-adjusted mean total WBC counts were 7.8, 6.4, and 6.2x10(3) per ul (P<0.0001) among male current, former and never smokers, respectively, and 7.4, 6.3 and 6.2x10(3) per ul (P<0.0001), respectively, in women. The greatest absolute and percentage differences between smoking groups were observed for the granulocyte count. Current smoking habit had a stronger effect on mean total WBC counts than cumulative exposure as measured by pack years. Among former smokers mean age- and body mass index-adjusted WBC, granulocyte and lymphocyte counts were inversely related to duration of smoking cessation (P< or =0.02). Smokers who had given up less than 12 months previously had WBC counts substantially lower (6.7 and 6.9x10(3) per ul, respectively, in men and women) than current smokers. In conclusion, the total WBC count and its components (particularly the granulocyte count) are strongly associated with cigarette smoking habit. Smoking cessation may have an almost immediate impact at least on pathophysiologic processes such as inflammation that may be indicated by the WBC count. The apparent almost immediate reversibility of effects of smoking on inflammation, as indicated by the WBC count, may help motivate efforts to stop smoking.
Keywords: Adult Aged Cross-Sectional Studies Female Granulocytes Human *Leukocyte Count Lymphocyte Count Male Middle Aged Prospective Studies *Smoking Smoking Cessation Support, Non-U.S. Gov't
PubMed Accession Number :: 12921986.

Bingham, S. A.; Luben, R.; Welch, A.; Wareham, N.; Khaw, K. T.; Day, N. (2003) Are imprecise methods obscuring a relation between fat and breast cancer? Lancet, 362 (9379),212-4 [Journal Article] Online
Abstract: Pooled analyses of cohort studies show no relation between fat intake and breast-cancer risk. However, food-frequency questionnaire (FFQ) methods used in these studies are prone to measurement error. We assessed diet with an FFQ and a detailed 7-day food diary in 13070 women between 1993 and 1997. We compared 168 breast-cancer cases incident by 2000 with four matched controls. Risk of breast cancer was associated with saturated-fat intake measured with the food diary (hazard ratio 1.22 [95% CI 1.06-1.40], p=0.005, per quintile increase in energy-adjusted fat intake), but not with saturated fat measured with the FFQ (1.10 [0.94-1.29], p=0.23). Dietary measurement error might explain the absence of a significant association between dietary fat and breast-cancer risk in cohort studies.
Keywords: Aged Breast Neoplasms/*epidemiology/etiology Cohort Studies Comparative Study *Diet Records Dietary Fats/administration & dosage/*adverse effects Eating Female Health Status Human Incidence Male Middle Aged Questionnaires Research Design/*standards Risk Factors Support, Non-U.S. Gov't
PubMed Accession Number :: 12885485.

Franks, P. W.; Farooqi, I. S.; Luan, J.; Wong, M. Y.; Halsall, I.; O'Rahilly, S.; Wareham, N. J. (2003) Does physical activity energy expenditure explain the between-individual variation in plasma leptin concentrations after adjusting for differences in body composition? J Clin Endocrinol Metab, 88 (7),3258-63 [Journal Article] Online
Abstract: Leptin is secreted by adipose tissue and acts upon receptors located in the hypothalamus to modify energy balance. Investigations of the relationship between leptin and physical activity energy expenditure (PAEE) at population level are scarce. The majority of studies addressing this topic are limited by their measurement of PAEE (i.e. questionnaires or ecological comparisons between rural and urban ethnic groups). To our knowledge, no studies have directly examined the relationship of objectively assessed PAEE and leptin in a large free-living population-based cohort. Therefore, we measured fasting plasma leptin and insulin concentrations, cardiorespiratory fitness (O(2max.pred)), PAEE, and body composition in 758 Caucasian people (aged 40-65 yr). In sex-combined multiple regression analyses, leptin was significantly associated with PAEE (beta = -0.19, P = 0.0027), but not with O(2max.pred) (beta = -0.0002, p = NS). The association between PAEE and leptin was significant in men when adjusted for percentage of body fat (beta = -0.28, P = 0.004) but not women (beta = -0.12, P = 0.18) but was significant in both men and women when adjusted for body mass index (men: beta = -0.28, P = 0.005; women: beta = -0.23, P = 0.01; combined: beta = -0.26, P = 0.00008). These data suggest the existence in this population of an independent inverse association between PAEE and fasting plasma leptin level.
Keywords: Adult Aged Body Composition/*physiology Cohort Studies Diabetes Mellitus, Type I/blood/etiology/physiopathology Energy Metabolism/*physiology Fasting/physiology Female Great Britain Human Insulin/blood Leptin/*blood Male Middle Aged Motor Activity/*physiology Support, Non-U.S. Gov't
PubMed Accession Number :: 12843173.

Wareham, N. J.; Jakes, R. W.; Rennie, K. L.; Schuit, J.; Mitchell, J.; Hennings, S.; Day, N. E. (2003) Validity and repeatability of a simple index derived from the short physical activity questionnaire used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study Public Health Nutr, 6 (4),407-13 [Journal Article] Online
Abstract: OBJECTIVE: To assess the validity and repeatability of a simple index designed to rank participants according to their energy expenditure estimated by self-report, by comparison with objectively measured energy expenditure assessed by heart-rate monitoring with individual calibration. DESIGN: Energy expenditure was assessed over one year by four separate episodes of 4-day heart-rate monitoring, a method previously validated against whole-body calorimetry and doubly labelled water. Cardio-respiratory fitness was assessed by four repeated measures of sub-maximum oxygen uptake. At the end of the 12-month period, participants completed a physical activity questionnaire that assessed past-year activity. A simple four-level physical activity index was derived by combining occupational physical activity together with time participating in cycling and other physical exercise (such as keep fit, aerobics, swimming and jogging). SUBJECTS: One hundred and seventy-three randomly selected men and women aged 40 to 65 years. RESULTS: The repeatability of the physical activity index was high (weighted kappa=0.6, ). There were positive associations between the physical activity index from the questionnaire and the objective measures of the ratio of daytime energy expenditure to resting metabolic rate and cardio-respiratory fitness As an indirect test of validity, there was a positive association between the physical activity index and the ratio of energy intake, assessed by 7-day food diaries, to predicted basal metabolic rate. CONCLUSIONS: The summary index of physical activity derived from the questions used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study suggest it is useful for ranking participants in terms of their physical activity in large epidemiological studies. The index is simple and easy to comprehend, which may make it suitable for situations that require a concise, global index of activity.
Keywords: Adult Aged Basal Metabolism Cohort Studies *Energy Metabolism Exercise/*physiology Female Heart Rate/*physiology Human Leisure Activities Male Middle Aged Oxygen Consumption *Physical Fitness Prospective Studies Reproducibility of Results Sensitivity and Specificity Support, Non-U.S. Gov't
PubMed Accession Number :: 12795830.

Halsall, D. J.; McFarlane, I.; Luan, J.; Cox, T. M.; Wareham, N. J. (2003) Typical type 2 diabetes mellitus and HFE gene mutations: a population-based case - control study Hum Mol Genet, 12 (12),1361-5 [Journal Article] Online
Abstract: Diabetes mellitus is a recognized consequence of hereditary haemochromatosis. Whether the common HFE mutations, that associate with this condition and pre-dispose to increases in serum iron indices, are over-represented in diabetic populations remains controversial. We present data from the largest case-control study of the C282Y and H63D HFE allele frequencies in typical type 2 diabetes mellitus, as defined by an age of onset greater than 30 years and no requirement for insulin in the first year post-diagnosis. We also present a meta-analysis of all similar studies to date. We see no evidence for over-representation of iron loading HFE alleles in type 2 diabetes mellitus, suggesting that screening for HFE mutations in this population is of no value.
Keywords: Age of Onset Aged Case-Control Studies Cohort Studies Diabetes Mellitus, Type II/*genetics Female Gene Frequency Genotype Great Britain Hemochromatosis/genetics Heterozygote Histocompatibility Antigens Class I/*genetics Human Male Membrane Proteins/*genetics Middle Aged *Point Mutation Support, Non-U.S. Gov't
PubMed Accession Number :: 12783844.

Sandhu, M. S.; Gibson, J. M.; Heald, A. H.; Dunger, D. B.; Wareham, N. J. (2003) Low circulating IGF-II concentrations predict weight gain and obesity in humans Diabetes, 52 (6),1403-8 [Journal Article] Online
Abstract: Results from experimental and gene-association studies suggest that IGF-II may influence body weight regulation and that individuals with low IGF-II levels may be more susceptible to weight gain and obesity. We therefore assessed the association between circulating concentrations of IGF-II and subsequent weight gain and progression to obesity. Participants in this study were 463 nonobese men and women aged between 45 and 60 years with normal glucose tolerance and with metabolic and anthropometric assessments at baseline and follow-up clinic visits. We examined the association between baseline concentrations of fasting serum IGF-II and risk of gaining > or =2.5 kg body wt or developing obesity using unconditional logistic regression. A total of 217 participants gained > or =2.5 kg body wt, and 29 developed obesity after >4 years of follow-up. In multivariate analysis, baseline IGF-II levels were significantly lower in participants who subsequently gained weight compared with individuals who remained stable or lost weight (P = 0.010). Similarly, individuals who developed obesity had lower baseline IGF-II levels (P = 0.006). Relatively higher IGF-II levels were also associated with a reduced risk of gaining weight (P for trend across quintiles of IGF-II = 0.006). Our data suggest that circulating IGF-II levels may play a role in body weight regulation and development of obesity in men and women with normal glucose tolerance.
Keywords: Biological Markers Body Mass Index Body Weight/*physiology Cohort Studies Follow-Up Studies Great Britain Human Insulin-Like Growth Factor II/*metabolism Middle Aged Obesity/blood/*physiopathology Odds Ratio Predictive Value of Tests Smoking Support, Non-U.S. Gov't Time Factors Weight Gain/*physiology
PubMed Accession Number :: 12765950.

Rahman, M.; Griffin, S. J.; Rathmann, W.; Wareham, N. J. (2003) How should peripheral neuropathy be assessed in people with diabetes in primary care? A population-based comparison of four measures Diabet Med, 20 (5),368-74 [Journal Article] Online
Abstract: AIMS: To test the accuracy of four measures of peripheral diabetic neuropathy in a primary care population. METHODS: Type 2 diabetic (n = 544) and 544 non-diabetic participants aged 45-76 years were randomly selected from general practice registers. Neuropathy was assessed using vibration threshold (VT) and scores for light touch, thermal sense and modified Michigan Neuropathy Screening Instrument questionnaire. These measures were assessed for variation with diabetes status, age, diabetes duration, HbA1c, and presence of retinopathy and nephropathy. Light touch, thermal sense and questionnaire scores were assessed against VT using ROC curve analysis. RESULTS: Only VT and light touch were different between diabetic and non-diabetic groups (P = 0.02 and < 0.0001, respectively). All measures were significantly associated with diabetes duration and retinopathy, and all except questionnaire score (P = 0.14) with age. None was associated with nephropathy and only questionnaire score was associated with HbA1c (P = 0.033). VT varied as expected across scores of light touch (chi2 = 41.65, P = 0.0001), thermal sense (chi2 = 15.86, P = 0.015) and questionnaire (chi2 = 21.22, P = 0.047). Area under the curve values for light touch, thermal and questionnaire scores were 0.72 (95% confidence interval (CI) 0.63, 0.82), 0.63 (95% CI 0.52, 0.73) and 0.64 (95% CI 0.53, 0.74), respectively. CONCLUSIONS: All measures had associations with risk factors for neuropathy, but light touch score (monofilament) had the strongest association with vibration threshold (the chosen gold standard) and thus appeared the most appropriate tool for use in primary care, because of its validity and simplicity of use.
Keywords: Adult Aged Anthropometry/methods Cross-Sectional Studies Diabetes Mellitus, Type II/complications/*etiology Diabetic Neuropathies/complications/*diagnosis Female Hemoglobin A, Glycosylated/metabolism Human Male Middle Aged Neurologic Examination/methods Primary Health Care/standards Questionnaires Risk Factors Sensory Thresholds Vibration/therapeutic use
PubMed Accession Number :: 12752485.

Hu, G. (2003) Gender difference in all-cause and cardiovascular mortality related to hyperglycaemia and newly-diagnosed diabetes Diabetologia, 46 (5),608-17 [Journal Article] Online
Abstract: AIM/HYPOTHESIS: Diabetic women generally have a greater relative risk of cardiovascular diseases than diabetic men in comparison with non-diabetic women and men. Reasons for this excess risk in diabetic women is still unclear. The aim of this study is to evaluate whether the association between different degrees of hyperglycaemia and the risk of all-cause and cardiovascular mortality is different in women and men. METHODS: We analysed baseline glucose concentrations from 14 prospective European cohorts including 8172 men and 9407 women aged 30 to 89 years without history of diabetes, with a median follow-up of 8.3 years. Hazards ratios for all-cause and cardiovascular mortality were estimated adjusting for other risk factors. RESULTS: The mortality rates for all-cause and cardiovascular diseases were higher in men than in women in normoglycaemia, impaired glucose regulation and newly-diagnosed diabetes; the largest sex differential for cardiovascular mortality was in normoglycaemic people. The hazards ratios for all-cause and cardiovascular mortality were higher in newly-diagnosed diabetic women than men compared with normoglycaemic women and men, respectively; however, this sex difference was only significant for cardiovascular mortality. For smokers and for subjects with hypertension, hypercholesterolaemia or who where overweight, the hazards ratios for cardiovascular mortality in diabetic patients compared with normoglycaemic people were also higher in women than in men. CONCLUSIONS/INTERPRETATION: Newly diagnosed diabetic women showed higher relative risks for death from cardiovascular disease than diabetic men. Thus a more aggressive control of hyperglycaemia as well as of other cardiovascular risk factors might be appropriate in women with asymptomatic hyperglycaemia.
Keywords: Adult Aged Aged, 80 and over Cardiovascular Diseases/*epidemiology/mortality Comparative Study Diabetic Angiopathies/*complications/*epidemiology/mortality Europe/epidemiology Female Follow-Up Studies Human Hyperglycemia/*complications Male Middle Aged Proportional Hazards Models Risk Factors Sex Characteristics Support, Non-U.S. Gov't Time Factors
PubMed Accession Number :: 12750769.

Bhattacharyya, S.; Luan, J.; Challis, B.; Schmitz, C.; Clarkson, P.; Franks, P. W.; Middelberg, R.; Keogh, J.; Farooqi, I. S.; Montague, C.; Brennand, J.; Wareham, N. J.; O'Rahilly, S. (2003) Association of polymorphisms in GPR10, the gene encoding the prolactin-releasing peptide receptor with blood pressure, but not obesity, in a U.K. Caucasian population Diabetes, 52 (5),1296-9 [Journal Article] Online
Abstract: Prolactin-releasing peptide (PrRP) and its G-protein-coupled receptor, GPR10, have been implicated in the central control of appetite and blood pressure. To determine whether mutations in these genes might contribute to morbid obesity, we screened both genes in 94 subjects with severe early-onset obesity. Four rare silent variants in PrRP and eight polymorphisms in GPR10 were found, two of which (V283I and P305L) altered amino acid sequence but were also found in U.K. Caucasian control subjects. Cells expressing the P305L variant receptor generated less intracellular calcium in response to PrRP than cells expressing the wild-type receptor. To examine whether genetic variation of the GPR10 locus might be associated with phenotypes relevant to obesity and/or blood pressure, the most common noncoding (G-62A) and coding (C914T [P305L]) polymorphisms were typed in 1,084 U.K. Caucasians. While no association was found with BMI, carriers of the P305L allelic variant had significantly lower systolic (123.95 vs. 128.55 mmHg, P < 0.05) and diastolic (74.90 vs. 78.20 mmHg, P < 0.01) blood pressure than wild-type subjects. In conclusion, we have conducted the first genetic study of GPR10 and its ligand PrRP in relation to metabolic phenotypes and have identified an association between GPR10 polymorphisms and diastolic and systolic blood pressure. The alteration in signaling properties of the receptor produced by P305L may provide a functional basis for this association.
Keywords: Blood Pressure/*genetics European Continental Ancestry Group/*genetics Great Britain Human Obesity/*genetics Phenotype *Polymorphism (Genetics) Receptors, Cell Surface/*genetics *Receptors, G-Protein-Coupled Support, Non-U.S. Gov't
PubMed Accession Number :: 12716769.

Hung, C. C.; Farooqi, I. S.; Ong, K.; Luan, J.; Keogh, J. M.; Pembrey, M.; Yeo, G. S.; Dunger, D.; Wareham, N. J.; S, O' Rahilly (2003) Contribution of variants in the small heterodimer partner gene to birthweight, adiposity, and insulin levels: mutational analysis and association studies in multiple populations Diabetes, 52 (5),1288-91 [Journal Article] Online
Abstract: Loss of function mutations in the small heterodimer partner (SHP) gene have been reported to cause obesity and increased birth weight. We examined the relation between genetic variation in SHP and birth weight, adiposity, and insulin levels in three independent populations. The coding regions and 562 bases of the SHP promoter were screened for mutations in 329 subjects with severe early-onset obesity. Two novel missense mutations, R34G and R36C, were identified; these were not found in control subjects and did not cosegregate with obesity in family studies. Two common polymorphisms, G171A and -195CTGAdel, were found in 12 and 16% of subjects, respectively. Within the obese cohort, G171A and -195CTGAdel carriers had higher and lower birth weights, respectively, than wild-type subjects, the rare homozygotes for G171A being particularly large at birth. In a U.K. population-based cohort of 1,079 children, the 171A allele was associated with higher BMI (P < 0.05) and waist circumference (P = 0.001). Children carrying the G171A variant had higher 30-min insulin responses to a glucose load (P = 0.03). In conclusion, although mutations in SHP are not a common cause of severe human obesity, genetic variation in the SHP locus may influence birth weight and have effects on BMI, possibly through effects on insulin secretion.
Keywords: Adipose Tissue/*anatomy & histology *Birth Weight Body Constitution Child DNA Mutational Analysis Fasting Female Heterozygote Detection Human Insulin/*blood Male Obesity/genetics *Polymorphism (Genetics) Receptors, Cytoplasmic and Nuclear/*genetics Support, Non-U.S. Gov't *Variation (Genetics)
PubMed Accession Number :: 12716767.

Waterworth, D. M.; Talmud, P. J.; Luan, J.; Flavell, D. M.; Byrne, C. D.; Humphries, S. E.; Wareham, N. J. (2003) Variants in the APOC3 promoter insulin responsive element modulate insulin secretion and lipids in middle-aged men Biochim Biophys Acta, 1637 (3),200-6 [Journal Article] Online
Abstract: Variation in the insulin responsive element (IRE) of the APOC3 promoter has been shown to be associated with insulin and glucose concentrations after an oral glucose tolerance test (OGTT) in young healthy men. We evaluated two variants in the IRE (-455T>C and -482C>T) in the Ely study, a prospective cohort study of middle-aged men (n=223) and women (n=279), to determine if the effect of these variants on glucose homeostasis could be explained by altered nonesterified fatty acid (NEFA) levels and if these effects are modulated by age and gender. Both variants had significant effects on the 30-min insulin incremental response in men alone (-482C>T, P=0.007; -455T>C, P=0.0155), with rare allele homozygotes having a 33.3% and 23.3% lower insulin increment as compared to common allele homozygotes, respectively. Thirty-minute NEFA concentrations were also significantly associated with genotype in men and levels were approximately 10% higher in carriers homozygous for the rare alleles as compared to subjects homozygous for the common alleles (-482C>T, P=0.04; -455T>C, P=0.006). In addition, there was a strong interaction between both variants and cigarette smoking affecting fasting triglyceride levels in both men (interaction: -455T>C, P=0.02; -482C>T, P=0.008) and women (interaction: -455T>C, P=0.007; -482C>T, P=0.013). Taken together, the data shows that men who carry the rare alleles of the IRE variants have disturbed glucose homeostasis and an unfavourable lipid phenotype. The finding of an elevated 30-min NEFA may be an important mechanistic link between triglyceride-rich lipoprotein (TRL) metabolism and glucose homeostasis.
Keywords: Apolipoproteins C/*genetics Blood Glucose/*analysis Diabetes Mellitus, Type II/blood/etiology/genetics Fasting Female Human Insulin/*blood Male Middle Aged Multivariate Analysis Mutation *Promoter Regions (Genetics) Response Elements Sex Factors Smoking Support, Non-U.S. Gov't Time Factors Triglycerides/blood
PubMed Accession Number :: 12697301.

Wong, M. Y.; Day, N. E.; Luan, J. A.; Chan, K. P.; Wareham, N. J. (2003) The detection of gene-environment interaction for continuous traits: should we deal with measurement error by bigger studies or better measurement? Int J Epidemiol, 32 (1),51-7 [Journal Article] Online
Abstract: BACKGROUND: The search for biologically relevant gene-environment interactions has been facilitated by technological advances in genotyping. The design of studies to detect interactions on continuous traits such as blood pressure and insulin sensitivity is attracting increasing attention. We have previously described power calculations for such studies, and this paper describes the extension of those calculations to take account of measurement error. METHODS: The model considered in this paper is a simple linear regression relating a continuous outcome to a continuously distributed exposure variable in which the ratio of slopes for each genotype is considered as the interaction parameter. The classical measurement error model is used to describe the uncertainty in measurement in the outcome and the exposure. The sample size to detect differing magnitudes of interaction with varying frequencies of the minor allele are calculated for a given main effect observed with error both in the exposure and the outcome. The sample size to detect a given interaction for a given minor allele frequency is calculated for differing degrees of measurement error in the assessment of the exposure and the outcome. RESULTS: The required sample size is dependent upon the magnitude of the interaction, the allele frequency and the strength of the association in those with the common allele. As an example, we take the situation in which the effect size in those with the common allele was a quarter of a standard deviation change in the outcome for a standard deviation change in the exposure. If a minor allele with a frequency of 20% leads to a doubling of that effect size, then the sample size is highly dependent upon the precision with which the exposure and outcome are measured. rho(Tx) and rho(Ty) are the correlation between the measured exposure and outcome, respectively and the true value. If poor measures of the exposure and outcome are used, (e.g. rho(Tx) = 0.3, rho(Ty) = 0.4), then a study size of 150 989 people would be required to detect the interaction with 95% power at a significance level of 10(-4). Such an interaction could be detected in study samples of under 10 000 people if more precise measurements of exposure and outcome were made (e.g. rho(Tx) = 0.7, rho(Ty) = 0.7), and possibly in samples of under 5000 if the precision of estimation were enhanced by taking repeated measurements. CONCLUSIONS: The formulae for calculating the sample size required to study the interaction between a continuous exposure and a genetic factor on a continuous outcome variable in the face of measurement error will be of considerable utility in designing studies with appropriate power. These calculations suggest that smaller studies with repeated and more precise measurement of the exposure and outcome will be as powerful as studies even 20 times bigger, which necessarily employ less precise measures because of their size. Even though the cost of genotyping is falling, the magnitude of the effect of measurement error on the power to detect interaction on continuous traits suggests that investment in studies with better measurement may be a more appropriate strategy than attempting to deal with error by increasing sample sizes.
Keywords: Environmental Exposure *Epidemiologic Methods Gene Frequency *Genetic Predisposition to Disease Genotype Human Linear Models *Models, Statistical *Quantitative Trait, Heritable Regression Analysis Research Design Sample Size Support, Non-U.S. Gov't
PubMed Accession Number :: 12690008.

Yuyun, M. F.; Dinneen, S. F.; Edwards, O. M.; Wood, E.; Wareham, N. J. (2003) Absolute level and rate of change of albuminuria over 1 year independently predict mortality and cardiovascular events in patients with diabetic nephropathy Diabet Med, 20 (4),277-82 [Journal Article] Online
Abstract: AIMS: To determine the nature of the association between baseline albuminuria and risk of all-cause mortality and cardiovascular disease, and to determine if the rate of change of albuminuria from baseline over 1 year predicts these endpoints in patients with diabetic nephropathy. METHODS: Cohort study of 427 patients (161 Type 1 and 266 Type 2) with diabetic nephropathy defined as urinary albumin excretion (UAE) > or = 30 mg/24 h at baseline (mean age 53.4 years). Patients were recruited at the time of referral to a diabetic nephropathy clinic and followed up annually for an average of 5 years. UAE rate was re-measured at 1 year and the rate of change from baseline calculated. RESULTS: All-cause mortality and cardiovascular disease increased significantly and continuously across quintiles of baseline UAE (P for linear trend < 0.001 in both outcomes). The rate of change of albuminuria over 1 year (log10) independently predicted all-cause mortality (hazard ratio (95% confidence interval) 1.76 (1.39, 3.11)) and cardiovascular mortality (1.57 (1.13, 5.22)). Taken as a categorical variable, a rate of change of albuminuria > or = 30% independently predicted mortality and cardiovascular events (2.07 (1.5, 4.30) and 1.89 (1.33, 4.06), respectively). CONCLUSIONS: The rate of change of albuminuria over 1 year independently predicts mortality and cardiovascular disease in diabetic nephropathy and may have clinical utility as a risk marker in identifying a subgroup of patients at particular risk. The risk of these outcomes is continuous across the range of baseline albuminuria in patients with diabetic nephropathy.
Keywords: Adult Albuminuria/*etiology Cardiovascular Diseases/*complications Cohort Studies Diabetic Neuropathies/*complications/mortality/urine Female Human Male Middle Aged Predictive Value of Tests
PubMed Accession Number :: 12675640.

Shohaimi, S.; Luben, R.; Wareham, N.; Day, N.; Bingham, S.; Welch, A.; Oakes, S.; Khaw, K. T. (2003) Residential area deprivation predicts smoking habit independently of individual educational level and occupational social class. A cross sectional study in the Norfolk cohort of the European Investigation into Cancer (EPIC-Norfolk) J Epidemiol Community Health, 57 (4),270-6 [Journal Article] Online
Abstract: OBJECTIVES: To investigate the independent association between individual and area based measures of socioeconomic status and cigarette smoking habit. DESIGN AND SETTING: Cross sectional, population based study. Participants and methods: 12 579 men and 15 132 women aged 39-79 years living in the general community participating in the EPIC-Norfolk Study in 1993-1997. The association between social class, educational status, Townsend residential deprivation level, and cigarette smoking status was examined. MAIN OUTCOME MEASURES: Cigarette smoking status at baseline survey. RESULTS: Social class, educational level, and residential deprivation level independently related to cigarette smoking habit in both men and women. Multivariate age adjusted odds ratios for current smoking in men were 1.62 (95% CI 1.45 to 1.81) for manual compared with non-manual social class, 1.32 (95% CI 1.17 to 1.48) for those with educational level less than O level compared with those with O level qualifications or higher and 1.84 (95% CI 1.62 to 2.08) for high versus low area deprivation level. For women, the odds ratios for current smoking for manual social class were 1.14 (95% CI 1.03 to 1.27); 1.31 (95% CI 1.18 to 1.46) for low educational level and 1.68 (95% CI 1.49 to 1.90) for high residential deprivation respectively. CONCLUSIONS: Residential deprivation level using the Townsend score, individual social class, and educational level all independently predict smoking habit in both men and women. Efforts to reduce cigarette smoking need to tackle not just individual but also area based factors. Understanding the specific factors in deprived areas that influence smoking habit may help inform preventive efforts.
Keywords: Adult Aged Cross-Sectional Studies Educational Status England/epidemiology Female Human Male Middle Aged Occupations Odds Ratio Poverty *Poverty Areas Risk Factors Smoking/*epidemiology *Social Class Socioeconomic Factors Support, Non-U.S. Gov't
PubMed Accession Number :: 12646543.

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