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1. Change in cardio-protective medication and health-related quality of life after diagnosis of screen-detected diabetes: Results from the ADDITION-Cambridge cohort

Author

Black, JA, Long, GH, Sharp, SJ, Kuznetsov, L, Boothby, CE, Griffin, SJ, Simmons, RK, Sharp, Stephen [0000-0003-2375-1440], Boothby, Clare [0000-0001-9396-8333], Griffin, Simon [0000-0002-2157-4797], Simmons, Rebecca [0000-0002-7726-8529], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Cardiotonic Agents, Health Status, Endocrinology, Diabetes and Metabolism, Medication, Drug Prescriptions, Article, HRQoL, Cohort Studies, Endocrinology, Surveys and Questionnaires, Internal Medicine, Humans, Mass Screening, Practice Patterns, Physicians', Aged, digestive, oral, and skin physiology, Diabetes, Middle Aged, United Kingdom, Mental Health, Diabetes Mellitus, Type 2, Cardiovascular Diseases, cardiovascular system, Quality of Life, Female, Diabetic Angiopathies, circulatory and respiratory physiology
Abstract

Highlights • We examined individuals with screen-detected diabetes over five years. • Two cardio-protective agents were prescribed at diagnosis, 3 at one year and 4 at five years. • Increases in cardio-protective medication did not impact negatively on HRQoL., Aims Establishing a balance between the benefits and harms of treatment is important among individuals with screen-detected diabetes, for whom the burden of treatment might be higher than the burden of the disease. We described the association between cardio-protective medication and health-related quality of life (HRQoL) among individuals with screen-detected diabetes. Methods 867 participants with screen-detected diabetes underwent clinical measurements at diagnosis, one and five years. General HRQoL (EQ5D) was measured at baseline, one- and five-years, and diabetes-specific HRQoL (ADDQoL-AWI) and health status (SF-36) at one and five years. Multivariable linear regression was used to quantify the association between change in HRQoL and change in cardio-protective medication. Results The median (IQR) number of prescribed cardio-protective agents was 2 (1 to 3) at diagnosis, 3 (2 to 4) at one year and 4 (3 to 5) at five years. Change in cardio-protective medication was not associated with change in HRQoL from diagnosis to one year. From one year to five years, change in cardio-protective agents was not associated with change in the SF-36 mental health score. One additional agent was associated with an increase in the SF-36 physical health score (2.1; 95%CI 0.4, 3.8) and an increase in the EQ-5D (0.05; 95%CI 0.02, 0.08). Conversely, one additional agent was associated with a decrease in the ADDQoL-AWI (−0.32; 95%CI −0.51, −0.13), compared to no change. Conclusions We found little evidence that increases in the number of cardio-protective medications impacted negatively on HRQoL among individuals with screen-detected diabetes over five years.

Published
2015
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2. Adherence to predefined dietary patterns and incident type 2 diabetes in European populations: EPIC-InterAct Study

Author

Kroeger, J, Schulze, MB, Romaguera, D, Guevara, M, Buijsse, B, Boeing, H, Beulens, JWJ, Feskens, EJM, Amiano, P, Ardanaz, E, Agnoli, C, Buckland, G, Clavel-Chapelon, F, Dahm, CC, Fagherazzi, G, Franks, PW, Kaaks, R, Key, TJ, Khaw, KT, Lajous, M, Mattiello, A, Menendez Garcia, V, Navarro, C, Nilsson, PM, Overvad, K, Palli, D, Ricceri, F, Rolandsson, O, Sanchez, M-J, Slimani, N, Spijkerman, AMW, Tjonneland, A, Tumino, R, van der A, DL, Langenberg, C, Sharp, SJ, Forouhi, NG, Riboli, E, Wareham, NJ, and Consortium, I

Subjects
Male, Questionnaires, Health Knowledge, Attitudes, Practice, Nutrition and Disease, Mediterranean diet, Endocrinology, Diabetes and Metabolism, Carbonated Beverages, Type 2 diabetes, Alternative Healthy Eating Index, Risk Factors, Voeding en Ziekte, Surveys and Questionnaires, Vegetables, Medicine, Prospective Studies, Dietary patterns, physical-activity, risk-factors, quality index, Incidence, Reduced rank regression, Middle Aged, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, nutrition, Female, Dietary Proteins, Adult, medicine.medical_specialty, DASH diet, European Continental Ancestry Group, Case-cohort, Diet Surveys, Article, White People, dash diet, insulin-resistance, Beverages, Insulin resistance, Internal medicine, Diabetes mellitus, Dash, Internal Medicine, cancer, Humans, Refined grains, VLAG, Aged, business.industry, mediterranean diet, Feeding Behavior, fatty-acids, medicine.disease, Dietary Fats, Diet, Endocrinology, Diabetes Mellitus, Type 2, Case-Control Studies, Fruit, Sweetening Agents, Dairy Products, Food Habits, Energy Intake, business, chronic disease, Risk Reduction Behavior, Dietary Approaches to Stop Hypertension, Demography
Abstract

Aims/hypothesis Few studies have investigated the relationship between predefined dietary patterns and type 2 diabetes incidence; little is known about the generalisability of these associations. We aimed to assess the association between predefined dietary patterns and type 2 diabetes risk in European populations. Methods From among a case-cohort of 12,403 incident diabetes cases and 16,154 subcohort members nested within the prospective European Prospective Investigation into Cancer and Nutrition study, we used data on 9,682 cases and 12,595 subcohort participants from seven countries. Habitual dietary intake was assessed at baseline with country-specific dietary questionnaires. Two diet-quality scores (alternative Healthy Eating Index [aHEI], Dietary Approaches to Stop Hypertension [DASH] score) and three reduced rank regression (RRR)-derived dietary-pattern scores were constructed. Country-specific HRs were calculated and combined using a random-effects meta-analysis. Results After multivariable adjustment, including body size, the aHEI and DASH scores were not significantly associated with diabetes, although for the aHEI there was a tendency towards an inverse association in countries with higher mean age. We observed inverse associations of the three RRR-derived dietary-pattern scores with diabetes: HRs (95% CIs) for a 1-SD difference were 0.91 (0.86, 0.96), 0.92 (0.84, 1.01) and 0.87 (0.82, 0.92). Random-effects meta-analyses revealed heterogeneity between countries that was explainable by differences in the age of participants or the distribution of dietary intake. Conclusions/interpretation Adherence to specific RRR-derived dietary patterns, commonly characterised by high intake of fruits or vegetables and low intake of processed meat, sugar-sweetened beverages and refined grains, may lower type 2 diabetes risk. Electronic supplementary material The online version of this article (doi:10.1007/s00125-013-3092-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Published
2013
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3. Fruit and vegetable intake and cardiovascular risk factors in people with newly diagnosed type 2 diabetes

Author

Lamb, MJE, Griffin, SJ, Sharp, SJ, Cooper, AJM, Lamb, Maxine [0000-0002-1284-9912], Griffin, Simon [0000-0002-2157-4797], Sharp, Stephen [0000-0003-2375-1440], and Apollo - University of Cambridge Repository

Subjects
Adult, Glycated Hemoglobin, Male, Ascorbic Acid, Middle Aged, Diet Surveys, Risk Assessment, United Kingdom, Diet, Eating, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors, Fruit, Vegetables, Linear Models, Humans, Female, Waist Circumference, Lipoproteins, HDL, Aged, Follow-Up Studies
Abstract

BACKGROUND/OBJECTIVES: The cardiovascular benefit of increasing fruit and vegetable (F&V) intake following diagnosis of diabetes remains unknown. We aimed to describe how quantity and variety of F&V intake, and plasma vitamin C, change after diagnosis of type 2 diabetes and examine whether these changes are associated with improvements in cardiovascular risk factors. SUBJECTS/METHODS: A total of 401 individuals with screen-detected diabetes from the ADDITION-Cambridge study were followed up over 5 years. F&V intake was assessed by food frequency questionnaire and plasma vitamin C at baseline, at 1 year and at 5 years. Linear mixed models were used to estimate associations of changes in quantity and variety of F&V intake, and plasma vitamin C, with cardiovascular risk factors and a clustered cardiometabolic risk score (CCMR), where a higher score indicates higher risk. RESULTS: F&V intake increased in year 1 but decreased by year 5, whereas variety remained unchanged. Plasma vitamin C increased at 1 year and at 5 years. Each s.d. increase (250g between baseline and 1 year and 270g between 1 and 5 years) in F&V intake was associated with lower waist circumference (-0.92 (95% CI: -1.57, -0.27) cm), HbA1c (-0.11 (-0.20, -0.03) %) and CCMR (-0.04 (-0.08, -0.01)) at 1 year and higher high-density lipoprotein (HDL)-cholesterol (0.04 (0.01, 0.06) mmol/l) at 5 years. Increased plasma vitamin C (per s.d., 22.5 μmol/l) was associated with higher HDL-cholesterol (0.04 (0.01, 0.06) mmol/l) and lower CCMR (-0.07 (-0.12, -0.03)) between 1 and 5 years. CONCLUSIONS: Increases in F&V quantity following diagnosis of diabetes are associated with lower cardiovascular risk factors. Health promotion interventions might highlight the importance of increasing, and maintaining increases in, F&V intake for improved cardiometabolic health in patients with diabetes.

Published
2017

4. Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes:systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct

Author

Li, SX, Imamura, F, Ye, Z, Schulze, MB, Zheng, J, Ardanaz, E, Arriola, L, Boeing, H, Dow, C, Fagherazzi, G, Franks, PW, Agudo, A, Grioni, S, Kaaks, R, Katzke, VA, Key, TJ, Khaw, KT, Mancini, FR, Navarro, C, Nilsson, PM, Onland-Moret, NC, Overvad, K, Palli, D, Panico, S, Quirós, JR, Rolandsson, O, Sacerdote, C, Sánchez, MJ, Slimani, N, Sluijs, I, Spijkerman, AM, Tjonneland, A, Tumino, R, Sharp, SJ, Riboli, E, Langenberg, C, Scott, RA, Forouhi, NG, Wareham, NJ, Li, Sherly X., Imamura, Fumiaki, Ye, Zheng, Schulze, Matthias B., Zheng, Jusheng, Ardanaz, Eva, Arriola, Larraitz, Boeing, Heiner, Dow, Courtney, Fagherazzi, Guy, Franks, Paul W., Agudo, Antonio, Grioni, Sara, Kaaks, Rudolf, Katzke, Verena A., Key, Timothy J., Khaw, Kay Tee, Mancini, Francesca R., Navarro, Carmen, Nilsson, Peter M., Onland moret, N. Charlotte, Overvad, Kim, Palli, Domenico, Panico, Salvatore, Quirã³s, J. Ramã³n, Rolandsson, Olov, Sacerdote, Carlotta, Sã¡nchez, Marã­a josã©, Slimani, Nadia, Sluijs, Ivonne, Spijkerman, Annemieke M. W., Tjonneland, Anne, Tumino, Rosario, Sharp, Stephen J., Riboli, Elio, Langenberg, Claudia, Scott, Robert A., Forouhi, Nita G., and Wareham, Nicholas J.

Subjects
Dietary Fiber, Male, Dipeptidases, Interaction, Caveolin 2, Gene-Nutrient Interactions, Macronutrient, Replication, Medicine (miscellaneous), Diabete, Gene, Models, Biological, Dipeptidase, Receptors, Gastrointestinal Hormone, Effect modification, Risk Factors, Diabetes Mellitus, Dietary Carbohydrates, Journal Article, Humans, Dietary Carbohydrate, Dietary Fat, Nutrition and Dietetics, Risk Factor, Diabetes, Diabetes Mellitu, Feeding Behavior, Middle Aged, Dietary Fats, Diet, Europe, Case-Control Studies, Systematic review, Female, Gene-Environment Interaction, Case-Control Studie, Energy Intake, Transcription Factor 7-Like 2 Protein, Human, Meta-Analysis
Abstract

Background Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. Objective We aimed to identify existing evidence for genemacronutrient interactions and T2D and to examine the reported interactions in a large-scale study. Design We systematically reviewed studies reporting genemacronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate countryspecific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Results Thirteen observational studies met the eligibility criteria (n , 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n–3 (v-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7–like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction , 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Conclusions Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.

Published
2017
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5. Effects of vitamin D2 or D3 supplementation on glycaemic control and cardiometabolic risk among people at risk of type 2 diabetes: results of a randomized double-blind placebo-controlled trial

Author

Forouhi, NG, Menon, RK, Sharp, SJ, Mannan, N, Timms, PM, Martineau, AR, Rickard, AP, Boucher, BJ, Chowdhury, TA, Griffiths, CJ, Greenwald, SE, Griffin, SJ, Hitman, GA, Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Griffin, Simon [0000-0002-2157-4797], and Apollo - University of Cambridge Repository

Subjects
vitamin D3, Adult, Male, Risk, vitamin D2, pulse wave velocity, Pulse Wave Analysis, Cohort Studies, Vascular Stiffness, Double-Blind Method, Humans, intervention, Aged, Calcifediol, Cholecalciferol, 25-Hydroxyvitamin D 2, Glycated Hemoglobin, trial, Middle Aged, Diabetes Mellitus, Type 2, England, Cardiovascular Diseases, randomized, Dietary Supplements, Ergocalciferols, placebo, Feasibility Studies, Female, type 2 diabetes, Follow-Up Studies
Abstract

AIMS: To investigate the effect of short-term vitamin D supplementation on cardiometabolic outcomes among individuals with an elevated risk of diabetes. METHODS: In a double-blind placebo-controlled randomized trial, 340 adults who had an elevated risk of type 2 diabetes (non-diabetic hyperglycaemia or positive diabetes risk score) were randomized to either placebo, 100,000 IU vitamin D2 (ergocalciferol) or 100,000 IU vitamin D3 (cholecalciferol), orally administered monthly for 4 months. The primary outcome was change in glycated haemoglobin (HbA1c) between baseline and 4 months, adjusted for baseline. Secondary outcomes included: blood pressure; lipid levels; apolipoprotein levels; C-reactive protein levels; pulse wave velocity (PWV); anthropometric measures; and safety of the supplementation. RESULTS: The mean [standard deviation (s.d.)] 25-hydroxyvitamin D [25(OH)D]2 concentration increased from 5.2 (4.1) to 53.9 (18.5) nmol/l in the D2 group, and the mean (s.d.) 25(OH)D3 concentration increased from 45.8 (22.6) to 83.8 (22.7) nmol/l in the D3 group. There was no effect of vitamin D supplementation on HbA1c: D2 versus placebo: -0.05% [95% confidence interval (CI) -0.11, 0.02] or -0.51 mmol/mol (95% CI -1.16, 0.14; p = 0.13); D3 versus placebo: 0.02% (95% CI -0.04, 0.08) or 0.19 mmol/mol (95% CI -0.46, 0.83; p = 0.57). There were no clinically meaningful effects on secondary outcomes, except PWV [D2 versus placebo: -0.68 m/s (95% CI -1.31, -0.05); D3 versus placebo -0.73 m/s (95% CI -1.42, -0.03)]. No important safety issues were identified. CONCLUSIONS: Short-term supplementation with vitamin D2 or D3 had no effect on HbA1c. The modest reduction in PWV with both D2 and D3 relative to placebo suggests that vitamin D supplementation has a beneficial effect on arterial stiffness.

Published
2016

6. Association between dietary meat consumption and incident type 2 diabetes: the EPIC-InterAct study

Author

Benedinelli, B, Palli, D, Masala, G, Sharp, Sj, Schulz, Mb, Guevara, M, van der AD, Sera, F, Amiano, P, Balkau, B, Barricarte, A, Boeing, H, Crowe, Fl, Dahm, Cc, Dalmeijer, G, de Lauzon Guillain, B, Egeberg, R, Fagherazzi, G, Franks, Pw, Krogh, V, Huerta, Jm, Jakszyn, P, Khaw, Kt, Li, K, Mattiello, A, Nilsson, Pm, Overvad, K, Ricceri, Fulvio, Rolandsson, O, Sánchez, Mj, Slimani, N, Sluijs, I, Spijkerman, Am, Teucher, B, Tjonneland, A, Tumino, R, van den Berg SW, Forouhi, Ng, Langeberg, C, Feskens, Ej, Riboli, E, Wareham, Nj, and Interact, Consortium

Subjects
Adult, Male, Risk, Meat, Nutrition and Disease, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Cohort Studies, Young Adult, Voeding en Ziekte, Diabetes mellitus, Internal Medicine, Humans, Medicine, Prospective Studies, Prospective cohort study, Aged, Aged, 80 and over, Sex Characteristics, business.industry, Incidence, Case-control study, Middle Aged, medicine.disease, Diet, European Prospective Investigation into Cancer and Nutrition, Europe, Meat Products, Cross-Sectional Studies, Case-cohort study, Diabetes Mellitus, Type 2, Case-Control Studies, Red meat, Female, business, Iron, Dietary, Follow-Up Studies, Demography, Cohort study
Abstract

Aims/hypothesis: A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption. Results: Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants. Conclusions/interpretation: This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.

Published
2012
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7. Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children

Author

Barker, A, Sharp, SJ, Timpson, NJ, Bouatia-Naji, N, Warrington, NM, Kanoni, S, Beilin, LJ, Brage, S, Deloukas, P, Evans, DM, Grontved, A, Hassanali, N, Lawlor, DA, Lecoeur, C, Loos, RJ, Lye, SJ, McCarthy, MI, Mori, TA, Ndiaye, NC, Newnham, JP, Ntalla, I, Pennell, CE, St Pourcain, B, Prokopenko, I, Ring, SM, Sattar, N, Visvikis-Siest, S, Dedoussis, GV, Palmer, LJ, Froguel, P, Smith, GD, Ekelund, U, Wareham, NJ, and Langenberg, C

Subjects
Blood Glucose, Male, Adenylate Cyclase, HOMEOSTASIS, ENDOCRINOLOGY & METABOLISM, Adolescent, VARIANT, Polymorphism, Single Nucleotide, Humans, Child, Glucose Transporter Type 2, Homeodomain Proteins, Science & Technology, INSULIN SENSITIVITY, MTNR1B, Tumor Suppressor Proteins, Fasting, 11 Medical And Health Sciences, Protein-Serine-Threonine Kinases, POLYMORPHISM, Cryptochromes, FASTING PLASMA-GLUCOSE, TWINS, Genetic Loci, Glucose-6-Phosphatase, SECRETION, Female, TYPE-2 DIABETES RISK, Life Sciences & Biomedicine, RESISTANCE, Adenylyl Cyclases, Genome-Wide Association Study, Transcription Factors
Abstract

OBJECTIVE-To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS-A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS-Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level of 0.026 mrnol/L (0.021-0.031) for each unit increase in the score. CONCLUSIONS-Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011

Published
2011
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8. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity

Author

Scott RA, Fall T, Pasko D, Barker A, Sharp SJ, Arriola L, Balkau B, Barricarte A, Barroso I, Boeing H, Clavel Chapelon F, Crowe FL, Dekker JM, Fagherazzi G, Ferrannini E, Forouhi NG, Franks PW, Gavrila D, Giedraitis V, Grioni S, Groop LC, Kaaks R, Key TJ, Kühn T, Lotta LA, Nilsson PM, Overvad K, Palli D, Quirós JR, Rolandsson O, Roswall N, Sacerdote C, Sala N, Sánchez MJ, Schulze MB, Siddiq A, Slimani N, Sluijs I, Spijkerman AM, Tjonneland A, Tumino R, van der A. DL, Yaghootkar H, RISC Study Group, EPIC InterAct Consortium, McCarthy MI, Semple RK, Riboli E, Walker M, Ingelsson E, Frayling TM, Savage DB, Langenberg C, Wareham N.J., PANICO, SALVATORE, Sharp, Stephen [0000-0003-2375-1440], Barroso, Ines [0000-0001-5800-4520], Forouhi, Nita [0000-0002-5041-248X], Semple, Robert [0000-0001-6539-3069], Savage, David [0000-0002-7857-7032], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Scott, Ra, Fall, T, Pasko, D, Barker, A, Sharp, Sj, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel Chapelon, F, Crowe, Fl, Dekker, Jm, Fagherazzi, G, Ferrannini, E, Forouhi, Ng, Franks, Pw, Gavrila, D, Giedraitis, V, Grioni, S, Groop, Lc, Kaaks, R, Key, Tj, Kühn, T, Lotta, La, Nilsson, Pm, Overvad, K, Palli, D, Panico, Salvatore, Quirós, Jr, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sánchez, Mj, Schulze, Mb, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, Am, Tjonneland, A, Tumino, R, van der A., Dl, Yaghootkar, H, RISC Study, Group, EPIC InterAct, Consortium, Mccarthy, Mi, Semple, Rk, Riboli, E, Walker, M, Ingelsson, E, Frayling, Tm, Savage, Db, Langenberg, C, and Wareham, N. J.

Subjects
Adult, Male, Genetic Variation, Alanine Transaminase, gamma-Glutamyltransferase, Glucose Tolerance Test, Middle Aged, Overweight, Polymorphism, Single Nucleotide, Body Mass Index, Cohort Studies, Diabetes Mellitus, Type 2, Insulin Secretion, Body Composition, Glucose Clamp Technique, Body Fat Distribution, Humans, Insulin, Female, Genetic Predisposition to Disease, Obesity, Insulin Resistance, Waist Circumference, Aged
Abstract

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Published
2014

9. The association between a biomarker score for fruit and vegetable intake and incident type 2 diabetes: the EPIC-Norfolk study

Author

Cooper, AJM, Sharp, SJ, Luben, RN, Khaw, K-T, Wareham, NJ, Forouhi, NG, Sharp, Stephen [0000-0003-2375-1440], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Wareham, Nicholas [0000-0003-1422-2993], Forouhi, Nita [0000-0002-5041-248X], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Wales, Incidence, Lutein, Ascorbic Acid, Middle Aged, beta Carotene, Diet Records, Body Mass Index, Diet, Logistic Models, Diabetes Mellitus, Type 2, England, Case-Control Studies, Fruit, Multivariate Analysis, Vegetables, Humans, Female, Prospective Studies, Waist Circumference, Life Style, Biomarkers, Aged
Abstract

BACKGROUND/OBJECTIVES: Biomarkers for a mixed fruit and vegetable (FV) diet are needed to provide a better understanding of the association between FV intake and type 2 diabetes. We aimed to examine the prospective association between a composite score comprised of three biomarkers of FV intake in free-living populations and incident diabetes. SUBJECTS/METHODS: A total of 318 incident diabetes cases and 926 controls from the EPIC (European Prospective Investigation of Cancer)-Norfolk study aged 40-79 years at baseline (1993-1997), completed 7-day prospective food diary and had plasma vitamin C and carotenoid measures. A composite biomarker score (CB-score) comprising the sum of plasma vitamin C, beta-carotene and lutein was derived. Odds ratios (ORs) and 95% confidence intervals (CIs) for incident diabetes were estimated using multivariable logistic regression. RESULTS: A strong inverse association was found between the CB-score and incident diabetes. The ORs (95% CI) of diabetes comparing quartiles Q2, Q3 and Q4 of the CB-score with Q1 (reference category) were 0.70 (0.49, 1.00), 0.34 (0.23, 0.52) and 0.19 (0.12, 0.32), respectively, and 0.49 (0.40, 0.58) per s.d. change in CB-score in a model adjusted for demographic and lifestyle factors. The association was marginally attenuated after additionally adjusting for body mass index and waist circumference (0.60 (0.49 and 0.74) per s.d. change in CB-score). CONCLUSIONS: A combination of biomarkers representing the intake of a mixed FV diet was strongly inversely associated with incident diabetes. These findings provide further support for measuring dietary biomarkers in studies of diet-disease associations and highlight the importance of consuming FV for the prevention of diabetes.

Published
2015

10. Dietary glycemic index, glycemic load, and digestible carbohydrate intake are not associated with risk op type 2 diabetes in eight European countries

Author

Sluijs I, Beulens JW, van der Schouw YT, van der A. DL, Buckland G, Kuijsten A, Schulze MB, Amiano P, Ardanaz E, Balkau B, Boeing H, Gavrila D, Grote VA, Key TJ, Li K, Nilsson P, Overvad K, Palli D, Quir?s JR, Rolandsson O, Roswall N, Sacerdote C, S?nchez MJ, Sieri S, Slimani N, Spijkerman AM, Tj?nneland A, Tumino R, Sharp SJ, Langenberg C, Feskens EJ, Forouhi NG, Riboli E, Wareham NJ, InterAct consortium, PANICO, SALVATORE, Epidemiology and Data Science, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, APH - Health Behaviors & Chronic Diseases, Sluijs, I, Beulens, Jw, van der Schouw, Yt, van der A., Dl, Buckland, G, Kuijsten, A, Schulze, Mb, Amiano, P, Ardanaz, E, Balkau, B, Boeing, H, Gavrila, D, Grote, Va, Key, Tj, Li, K, Nilsson, P, Overvad, K, Palli, D, Panico, Salvatore, Quir?s, Jr, Rolandsson, O, Roswall, N, Sacerdote, C, S?nchez, Mj, Sieri, S, Slimani, N, Spijkerman, Am, Tj?nneland, A, Tumino, R, Sharp, Sj, Langenberg, C, Feskens, Ej, Forouhi, Ng, Riboli, E, Wareham, Nj, and Interact, Consortium

Subjects
Male, Nutrition and Disease, Medicine (miscellaneous), Type 2 diabetes, Gastroenterology, Cohort Studies, prevention, Risk Factors, Surveys and Questionnaires, Voeding en Ziekte, Medicine, Prospective Studies, Nutrition and Dietetics, cohort, Middle Aged, European Prospective Investigation into Cancer and Nutrition, Europe, Glycemic index, nutrition, Population study, Digestion, Female, women, Adult, medicine.medical_specialty, Diabetes risk, life-style, Diabetes mellitus, Internal medicine, Glycemic load, Dietary Carbohydrates, Humans, cancer, Aged, VLAG, Global Nutrition, Wereldvoeding, disease, business.industry, Case-control study, Reproducibility of Results, fiber intake, medicine.disease, Diet, Endocrinology, Diabetes Mellitus, Type 2, Food, Glycemic Index, Case-Control Studies, business, energy-intake, human activities, Follow-Up Studies, mellitus
Abstract

The association of glycemic index (GI) and glycemic load (GL) with the risk of type 2 diabetes remains unclear. We investigated associations of dietary GI, GL, and digestible carbohydrate with incident type 2 diabetes. We performed a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition Study, including a random subcohort (n = 16,835) and incident type 2 diabetes cases (n = 12,403). The median follow-up time was 12 y. Baseline dietary intakes were assessed using country-specific dietary questionnaires. Country-specific HR were calculated and pooled using random effects meta-analysis. Dietary GI, GL, and digestible carbohydrate in the subcohort were (mean +/- SD) 56 +/- 4, 127 +/- 23, and 226 +/- 36 g/d, respectively. After adjustment for confounders, GI and GL were not associated with incident diabetes [HR highest vs. lowest quartile (HRQ4) for GI: 1.05 (95% CI = 0.96, 1.16); HRQ4 for GL: 1.07 (95% CI = 0.95, 1.20)]. Digestible carbohydrate intake was not associated with incident diabetes [HRQ4: 0.98(95% CI = 0.86, 1.10)]. In additional analyses, we found that discrepancies in the GI value assignment to foods possibly explain differences in GI associations with diabetes within the same study population. In conclusion, an expansion of the GI tables and systematic GI value assignment to foods may be needed to improve the validity of GI values derived in such studies, after which GI associations may need reevaluation. Our study shows that digestible carbohydrate intake is not associated with diabetes risk and suggests that diabetes risk with high-GI and -GL diets may be more modest than initial studies suggested. J. Nutr. 143: 93-99, 2013.

Published
2013
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11. The prospective association between total and type of fish intake and type 2 diabetes in 8 European countries: EPIC-InterAct Study

Author

Patel PS, Forouhi NG, Kuijsten A, Schulze MB, van Woudenbergh GJ, Ardanaz E, Amiano P, Arriola L, Balkau B, Barricarte A, Beulens JW, Boeing H, Buijsse B, Crowe FL, de Lauzon Guillan B, Fagherazzi G, Franks PW, Gonzalez C, Grioni S, Halkjaer J, Huerta JM, Key TJ, K?hn T, Masala G, Nilsson P, Overvad K, Quir?s JR, Rolandsson O, Sacerdote C, S?nchez MJ, Schmidt EB, Slimani N, Spijkerman AM, Teucher B, Tjonneland A, Tormo MJ, Tumino R, van der A. DL, van der Schouw YT, Sharp SJ, Langenberg C, Feskens EJ, Riboli E, Wareham NJ, InterAct Consortium, PANICO, SALVATORE, Patel, P, Forouhi, Ng, Kuijsten, A, Schulze, Mb, van Woudenbergh, Gj, Ardanaz, E, Amiano, P, Arriola, L, Balkau, B, Barricarte, A, Beulens, Jw, Boeing, H, Buijsse, B, Crowe, Fl, de Lauzon Guillan, B, Fagherazzi, G, Franks, Pw, Gonzalez, C, Grioni, S, Halkjaer, J, Huerta, Jm, Key, Tj, K?hn, T, Masala, G, Nilsson, P, Overvad, K, Panico, Salvatore, Quir?s, Jr, Rolandsson, O, Sacerdote, C, S?nchez, Mj, Schmidt, Eb, Slimani, N, Spijkerman, Am, Teucher, B, Tjonneland, A, Tormo, Mj, Tumino, R, van der A., Dl, van der Schouw, Yt, Sharp, Sj, Langenberg, C, Feskens, Ej, Riboli, E, Wareham, Nj, Interact, Consortium, Epidemiology and Data Science, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, and APH - Health Behaviors & Chronic Diseases

Subjects
Adult, Male, validity, Nutrition and Disease, design, Medicine (miscellaneous), Type 2 diabetes, project, Diabetes mellitus, Environmental health, Voeding en Ziekte, Fatty Acids, Omega-3, Animals, Humans, Medicine, cancer, Prospective Studies, Food science, consumption, Prospective cohort study, omega-3-fatty-acids, Shellfish, Proportional Hazards Models, VLAG, risk, Nutrition and Dietetics, Proportional hazards model, business.industry, Incidence, Incidence (epidemiology), Fishes, Middle Aged, medicine.disease, calibration, Dietary Fats, Diet, European Prospective Investigation into Cancer and Nutrition, Europe, nutrition, Diabetes Mellitus, Type 2, Seafood, Quartile, Female, Energy Intake, business, Follow-Up Studies, mellitus
Abstract

Background: Epidemiologic evidence of an association between fish intake and type 2 diabetes (T2D) is inconsistent and unresolved. Objective: The objective was to examine the association between total and type of fish intake and T2D in 8 European countries. Design: This was a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with 3.99 million person-years of follow-up, 12,403 incident diabetes cases, and a random subcohort of 16,835 individuals from 8 European countries. Habitual fish intake (lean fish, fatty fish, total fish, shellfish, and combined fish and shellfish) was assessed by country-specific dietary questionnaires. HRs were estimated in each country by using Prentice-weighted Cox regression models and pooled by using a random-effects meta-analysis. Results: No overall association was found between combined fish and shellfish intake and incident T2D per quartile (adjusted HR: 1.00; 95% Cl: 0.94, 1.06; P-trend = 0.99). Total fish, lean fish, and shellfish intakes separately were also not associated with T2D, but fatty fish intake was weakly inversely associated with T2D: adjusted HR per quartile 0.97 (0.94, 1.00), with an HR of 0.84 (0.70, 1.01), 0.85 (0.76, 0.95), and 0.87 (0.78, 0.97) for a comparison of the second, third, and fourth quartiles with the lowest quartile of intake, respectively (P-trend = 0.06). Conclusions: These findings suggest that lean fish, total fish, and shellfish intakes are not associated with incident diabetes but that fatty fish intake may be weakly inversely associated. Replication of these findings in other populations and investigation of the mechanisms underlying these associations are warranted. Meanwhile, current public health recommendations on fish intake should remain unchanged. Am J Clin Nutr 2012;95:1445-53

Published
2012
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12. Physical activity, sedentary time and gain in overall and central body fat: 7-year follow-up of the ProActive trial cohort

Author

Golubic, R, Wijndaele, K, Sharp, SJ, Simmons, RK, Griffin, SJ, Wareham, NJ, Ekelund, U, Brage, S, ProActive Study Group, Wijndaele, Katrien [0000-0003-2199-7981], Sharp, Stephen [0000-0003-2375-1440], Simmons, Rebecca [0000-0002-7726-8529], Griffin, Simon [0000-0002-2157-4797], Wareham, Nicholas [0000-0003-1422-2993], Brage, Soren [0000-0002-1265-7355], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Health Knowledge, Attitudes, Practice, Evidence-Based Medicine, Time Factors, Health Promotion, Weight Gain, Cohort Studies, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors, Accelerometry, Humans, Female, Obesity, Sedentary Behavior, Waist Circumference, Exercise, Adiposity, Follow-Up Studies
Abstract

OBJECTIVE: The objective of this study is to examine the independent associations of time spent in moderate-to-vigorous physical activity (MVPA) and sedentary (SED-time), with total and abdominal body fat (BF), and the bidirectionality of these associations in adults at high risk of type 2 diabetes. DESIGN AND SUBJECTS: We measured MVPA (min per day) and SED-time (h per day) by accelerometry, and indices of total (body weight, fat mass (FM), BF% and FM index) and abdominal BF (waist circumference (WC)) using standard procedures in 231 adults (41.3 ± 6.4 years) with parental history of type 2 diabetes (ProActive UK) at baseline, 1-year and 7-year follow-up. Mixed effects models were used to quantify the independent associations (expressed as standardised β-coefficients (95% confidence interval (CI))) of MVPA and SED-time with fat indices, using data from all three time points. All models were adjusted for age, sex, intervention arm, monitor wear time, follow-up time, smoking status, socioeconomic status and MVPA/SED-time. RESULTS: MVPA was inversely and independently associated with all indices of total BF (for example, 1 s.d. higher MVPA was associated with a reduction in FM, β = -0.09 (95% CI: -0.14, -0.04) s.d.) and abdominal BF (for example, WC: β = -0.07 (-0.12, -0.02)). Similarly, higher fat indices were independently associated with a reduction in MVPA (for example, WC: β = -0.25 (-0.36, -0.15); FM: β = -0.27 (-0.36, -0.18)). SED-time was positively and independently associated with most fat indices (for example, WC: β = 0.03 (-0.04, 0.09); FM: β = 0.10 (0.03, 0.17)). Higher values of all fat indices independently predicted longer SED-time (for example, WC: β = 0.10 (0.02, 0.18), FM: β = 0.15 (0.07, 0.22)). CONCLUSIONS: The associations of MVPA and SED-time with total and abdominal BF are bidirectional and independent among individuals at high risk for type 2 diabetes. The association between BF and MVPA is stronger than the reciprocal association, highlighting the importance of considering BF as a determinant of decreasing activity and a potential consequence. Promoting more MVPA and less SED-time may reduce total and abdominal BF.

Published
2015

13. Dietary intakes of individual flavanols and flavonols are inversely associated with incident type 2 diabetes in European populations

Author

Zamora Ros, R, Forouhi, Ng, Sharp, Sj, González, Ca, Buijsse, B, Guevara, M, van der Schouw YT, Amiano, P, Boeing, H, Bredsdorff, L, Fagherazzi, G, Feskens, Ej, Franks, Pw, Grioni, S, Katzke, V, Key, Tj, Khaw, Kt, Kühn, T, Masala, G, Mattiello, A, Molina Montes, E, Nilsson, Pm, Overvad, K, Perquier, F, Redondo, Ml, Ricceri, Fulvio, Rolandsson, O, Romieu, I, Roswall, N, Scalbert, A, Schulze, M, Slimani, N, Spijkerman, Am, Tjonneland, A, Tormo, Mj, Touillaud, M, Tumino, R, van der A., Dl, van Woudenbergh GJ, Langenberg, C, Riboli, E, Wareham, Nj, Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Khaw, Kay-Tee [0000-0002-8802-2903], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Flavonols, Nutritional Status, Motor Activity, White People, Risk Factors, Surveys and Questionnaires, Humans, Nutritional Epidemiology, Proanthocyanidins, Prospective Studies, Life Style, Proportional Hazards Models, Flavonoids, Nutrition and Dietetics, Incidence, Middle Aged, Diet, Europe, Näringslära, Diabetes Mellitus, Type 2, Socioeconomic Factors, Multivariate Analysis, Female, Follow-Up Studies
Abstract

Dietary flavanols and flavonols, flavonoid subclasses, have been recently associated with a lower risk of type 2 diabetes (T2D) in Europe. Even within the same subclass, flavonoids may differ considerably in bioavailability and bioactivity. We aimed to examine the association between individual flavanol and flavonol intakes and risk of developing T2D across European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study was conducted in 8 European countries across 26 study centers with 340,234 participants contributing 3.99 million person-years of follow-up, among whom 12,403 incident T2D cases were ascertained and a center-stratified subcohort of 16,154 individuals was defined. We estimated flavonoid intake at baseline from validated dietary questionnaires using a database developed from Phenol-Explorer and USDA databases. We used country-specific Prentice-weighted Cox regression models and random-effects meta-analysis methods to estimate HRs. Among the flavanol subclass, we observed significant inverse trends between intakes of all individual flavan-3-ol monomers and risk of T2D in multivariable models (all P-trend < 0.05). We also observed significant trends for the intakes of proanthocyanidin dimers (HR for the highest vs. the lowest quintile. 0.81; 95% Cl: 0.71, 0.92; P-trend = 0.003) and trimers (HR: 0.91; 95% Cl: 0.80, 1.04; P-trend = 0.07) but not for proanthocyanidins with a greater polymerization degree. Among the flavonol subclass, myricetin (HR: 0.77; 95% Cl: 0.64, 0.93; P-trend = 0.001) was associated with a lower incidence of T2D. This large and heterogeneous European study showed inverse associations between all individual flavan-3-ol monomers, proanthocyanidins with a low polymerization degree, and the flavonol myricetin and incident T2D. These results suggest that individual flavonoids have different roles in the etiology of T2D.

Published
2014
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14. The association between dietary flavonoid and lignan intakes and incident type 2 diabetes in European populations: the EPIC-InterAct study

Author

Zamora-Ros, R, Forouhi, NG, Sharp, SJ, González, CA, Buijsse, B, Guevara, M, van der Schouw, YT, Amiano, P, Boeing, H, Bredsdorff, L, Clavel-Chapelon, F, Fagherazzi, G, Feskens, EJ, Franks, PW, Grioni, S, Katzke, V, Key, TJ, Khaw, KT, Kühn, T, Masala, G, Mattiello, A, Molina-Montes, E, Nilsson, PM, Overvad, K, Perquier, F, Quirós, JR, Romieu, I, Sacerdote, C, Scalbert, A, Schulze, M, Slimani, N, Spijkerman, AM, Tjonneland, A, Tormo, MJ, Tumino, R, van der A, DL, Langenberg, C, Riboli, E, and Wareham, NJ

Subjects
Flavonoids, Male, Incidence, Nutritional Status, Feeding Behavior, Middle Aged, Lignans, Europe, Diabetes Mellitus, Type 2, Population Surveillance, Humans, Female, Prospective Studies, Epidemiology/Health Services Research, Follow-Up Studies, Original Research
Abstract

OBJECTIVE: To study the association between dietary flavonoid and lignan intakes, and the risk of development of type 2 diabetes among European populations. RESEARCH DESIGN AND METHODS: The European Prospective Investigation into Cancer and Nutrition-InterAct case-cohort study included 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 participants from among 340,234 participants with 3.99 million person-years of follow-up in eight European countries. At baseline, country-specific validated dietary questionnaires were used. A flavonoid and lignan food composition database was developed from the Phenol-Explorer, the U.K. Food Standards Agency, and the U.S. Department of Agriculture databases. Hazard ratios (HRs) from country-specific Prentice-weighted Cox regression models were pooled using random-effects meta-analysis. RESULTS: In multivariable models, a trend for an inverse association between total flavonoid intake and type 2 diabetes was observed (HR for the highest vs. the lowest quintile, 0.90 [95% CI 0.77-1.04]; P value trend = 0.040), but not with lignans (HR 0.88 [95% CI 0.72-1.07]; P value trend = 0.119). Among flavonoid subclasses, flavonols (HR 0.81 [95% CI 0.69-0.95]; P value trend = 0.020) and flavanols (HR 0.82 [95% CI 0.68-0.99]; P value trend = 0.012), including flavan-3-ol monomers (HR 0.73 [95% CI 0.57-0.93]; P value trend = 0.029), were associated with a significantly reduced hazard of diabetes. CONCLUSIONS: Prospective findings in this large European cohort demonstrate inverse associations between flavonoids, particularly flavanols and flavonols, and incident type 2 diabetes. This suggests a potential protective role of eating a diet rich in flavonoids, a dietary pattern based on plant-based foods, in the prevention of type 2 diabetes.

Published
2013
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15. Fruit and vegetable intake and cardiovascular risk factors in people with newly diagnosed type 2 diabetes

Author

Lamb, MJE, Griffin, SJ, Sharp, SJ, and Cooper, AJM

Subjects
Adult, Glycated Hemoglobin, Male, Ascorbic Acid, Middle Aged, Diet Surveys, Risk Assessment, United Kingdom, 3. Good health, Diet, Eating, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors, Fruit, Vegetables, Linear Models, Humans, Female, Waist Circumference, Lipoproteins, HDL, Aged, Follow-Up Studies
Abstract

BACKGROUND/OBJECTIVES: The cardiovascular benefit of increasing fruit and vegetable (F&V) intake following diagnosis of diabetes remains unknown. We aimed to describe how quantity and variety of F&V intake, and plasma vitamin C, change after diagnosis of type 2 diabetes and examine whether these changes are associated with improvements in cardiovascular risk factors. SUBJECTS/METHODS: A total of 401 individuals with screen-detected diabetes from the ADDITION-Cambridge study were followed up over 5 years. F&V intake was assessed by food frequency questionnaire and plasma vitamin C at baseline, at 1 year and at 5 years. Linear mixed models were used to estimate associations of changes in quantity and variety of F&V intake, and plasma vitamin C, with cardiovascular risk factors and a clustered cardiometabolic risk score (CCMR), where a higher score indicates higher risk. RESULTS: F&V intake increased in year 1 but decreased by year 5, whereas variety remained unchanged. Plasma vitamin C increased at 1 year and at 5 years. Each s.d. increase (250g between baseline and 1 year and 270g between 1 and 5 years) in F&V intake was associated with lower waist circumference (-0.92 (95% CI: -1.57, -0.27) cm), HbA1c (-0.11 (-0.20, -0.03) %) and CCMR (-0.04 (-0.08, -0.01)) at 1 year and higher high-density lipoprotein (HDL)-cholesterol (0.04 (0.01, 0.06) mmol/l) at 5 years. Increased plasma vitamin C (per s.d., 22.5 μmol/l) was associated with higher HDL-cholesterol (0.04 (0.01, 0.06) mmol/l) and lower CCMR (-0.07 (-0.12, -0.03)) between 1 and 5 years. CONCLUSIONS: Increases in F&V quantity following diagnosis of diabetes are associated with lower cardiovascular risk factors. Health promotion interventions might highlight the importance of increasing, and maintaining increases in, F&V intake for improved cardiometabolic health in patients with diabetes.

16. Effectiveness and cost-effectiveness of the GoActive intervention to increase physical activity among UK adolescents: a cluster randomised controlled trial

Author

Corder, K, Sharp, SJ, Jong, S, Foubister, C, Brown, HE, Wells, EK, Armitage, S, Croxson, CHD, Vignoles, A, Wilkinson, PO, Wilson, ECF, and Van Sluijs, Esther

Subjects
Male, Adolescent, 4. Education, Cost-Benefit Analysis, education, Health Promotion, United Kingdom, 3. Good health, Accelerometry, Humans, Female, 10. No inequality, Exercise, Program Evaluation, School Health Services
Abstract

Background Less than 20% of adolescents globally meet recommenced levels of physical activity, which comes with social disadvantage and rising disease risk at increasingly early ages. The determinants of physical activity in adolescents are multilevel and poorly understood, but the school’s social environment likely plays an important role. We conducted a cluster-randomised controlled trial to assess the effectiveness of a school-based programme (GoActive) to increase moderate-to-vigorous physical activity (MVPA) among adolescents. Methods/Findings Non-fee-paying, co-educational schools including Year 9 students in the UK counties of Cambridgeshire and Essex were eligible for inclusion. Within participating schools (N=16), all Year 9 students were eligible and invited to participate. Participants were 2862 13-14-year-olds (84% of eligible students). After baseline assessment, schools were computer-randomised, stratified by school-level pupil premium (below/above county-specific median) and county (control: 8 schools, 1319 participants, mean (SD) participants per school: n=165 (62); intervention: 8 schools, 1543 participants, n=193 (43)). Measurement staff were blinded to allocation. The iteratively-developed, feasibility-tested 12-week intervention, aligned with Self-Determination Theory, trained older adolescent mentors and in-class-peer-leaders to encourage classes to conduct two new weekly activities. Students and classes gained points and rewards for engaging in any activity in- and out-of-school. The primary outcome was average daily minutes of accelerometer-assessed MVPA at 10-month follow-up; a mixed-methods process evaluation evaluated implementation. Of 2862 recruited participants (52.1% male), 2167 (76%) attended 10-month follow-up measurements; we analysed the primary outcome for 1874 participants (65.5%). At 10-months, there was a mean (SD) decrease in MVPA of 8.3 (19.3) minutes in the control group and 10.4 (22.7) minutes in the intervention group (baseline-adjusted difference [95% confidence interval] -1.91 minutes [-5.53 to 1.70], p=0.316). The programme cost £13 per student compared with control; it was not cost-effective. 62.9% of students and 87.3% of mentors reported that GoActive was fun. Deliverers commented that their roles in programme delivery were unclear. Implementation fidelity was low. The main methodological limitation of this study was the relatively affluent and ethnically homogeneous sample. Conclusions In this study, we observed that a rigorously developed school-based intervention was no more effective than standard school practice at preventing declines in adolescent physical activity. Interdisciplinary research is required to understand educational setting-specific implementation challenges. School-leaders and authorities should be realistic about expectations of effect of school-based physical activity promotion strategies implemented at scale.

17. Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

Author

Lotta, LA, Scott, RA, Sharp, SJ, Burgess, S, Luan, J, Tillin, T, Schmidt, AF, Imamura, F, Stewart, ID, Perry, JRB, Marney, L, Koulman, A, Karoly, ED, Forouhi, NG, Sjögren, RJO, Näslund, E, Zierath, Krook, A, Savage, DB, Griffin, JL, Chaturvedi, N, Hingorani, AD, Khaw, K-T, Barroso, I, McCarthy, MI, O'Rahilly, S, Wareham, NJ, and Langenberg, C

Subjects
Adult, Male, Sweden, Mendelian Randomization Analysis, Middle Aged, 3. Good health, Young Adult, Diabetes Mellitus, Type 2, Risk Factors, Humans, Genetic Predisposition to Disease, Prospective Studies, Amino Acids, Branched-Chain, Aged, Genome-Wide Association Study
Abstract

$\textbf{BACKGROUND}$: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. $\textbf{METHODS AND FINDINGS}$: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. $\textbf{CONCLUSIONS}$: Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.

18. Adiposity and grip strength as long-term predictors of objectively measured physical activity in 93 015 adults: the UK Biobank study

Author

Kim, Y, White, T, Wijndaele, K, Sharp, SJ, Wareham, NJ, and Brage, S

Subjects
2. Zero hunger, Male, Hand Strength, Middle Aged, United Kingdom, Body Mass Index, Predictive Value of Tests, Accelerometry, Ethnicity, Linear Models, Humans, Female, Longitudinal Studies, Prospective Studies, Sedentary Behavior, Waist Circumference, Exercise, Adiposity, Biological Specimen Banks, Follow-Up Studies
Abstract

BACKGROUND/OBJECTIVES: Fatness and fitness are associated with physical activity (PA) but less is known about the prospective associations of adiposity and muscle strength with PA. This study aimed to determine longitudinal associations of body mass index (BMI), waist circumference (WC) and grip strength (GS) with objectively measured PA. SUBJECTS/METHODS: Data are from the UK Biobank study. At baseline (2006-2010), BMI, WC and GS were objectively measured. At follow-up (2013-2015), a sub-sample of 93 015 participants (52 161 women) wore a tri-axial accelerometer on the dominant wrist for 7 days. Linear regression was performed to investigate longitudinal associations of standardised BMI, WC and GS at baseline with moderate-to-vigorous PA (MVPA) and acceleration after a median 5.7-years follow-up (interquartile range: 4.9-6.5 years). RESULTS: Linear regression revealed strong inverse associations for BMI and WC, and positive associations for GS with follow-up PA; in women, MVPA ranges from lowest to highest quintiles of GS were 42-48 min day(-1) in severely obese (BMI⩾35 kg m(-)(2)), 52-57 min day(-1) in obese (30⩽BMI

19. Long-term risk of incident type 2 Diabetes and measures of overall and regional obesity: The EPIC-InterAct Case-Cohort Study

Author

Nicola D. Kerrison, Olov Rolandsson, Joachim Spranger, Nicholas J. Wareham, Kay-Tee Khaw, Luigi Palla, Carlos González, Heiner Boeing, Nita G. Forouhi, Ivonne Sluijs, María José Tormo, Joline W.J. Beulens, Kim Overvad, Matthias B. Schulze, Isabelle Romieu, Beverley Balkau, Francesca L. Crowe, Domenico Palli, María José Sánchez, J. Ramón Quirós, Claudia Langenberg, Yvonne T. van der Schouw, Dora Romaguera, Nadia Slimani, Paul W. Franks, Rosario Tumino, Eva Ardanaz, Göran Hallmans, Stephen J. Sharp, José María Huerta, Anne Tjønneland, Birgit Teucher, H. Bas Bueno-de-Mesquita, Salvatore Panico, Edith J. M. Feskens, Teresa Norat, L. van der A. Daphne, Carlotta Sacerdote, Elio Riboli, Annemieke M.W. Spijkerman, Blandine de Lauzon-Guillan, Peter M. Nilsson, Dagmar Drogan, Timothy J. Key, Sara Grioni, Rudolf Kaaks, Jytte Halkjær, Larraitz Arriola, Amalia Mattiello, Françoise Clavel-Chapelon, The InterAct Consortium, [Langenberg,C, Sharp,SJ, Forouhi,NG, Kerrison,ND, Palla,L, Wareham,NJ] MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom. [Schulze,MB] Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam Rehbruecke, Arthur-Scheunert-Allee, Nuthetal, Germany. [Rolandsson,O, Hallmans,G] Department of Public Health and Clinical Medicine, Umea University, Norrlands Universitetsjukhus, Umea, Sweden. [Overvad,K] Department of Epidemiology, School of Public Health, Aarhus C, Denmark. [Spranger.J] Charité-Universitatsmedizin Berlin, Department of Endocrinology, Diabetes and Nutrition, Berlin, Germany. [Drogan,D, Boeing,H] Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.[Arriola,L, Tormo,MJ] Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain. [Huerta,JM, Arriola,L, Tormo,MJ, Ardanaz,E, Sánchez,MJ] Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pu´ blica), Madrid, Spain . [Arriola,L] Public Health Division of Gipuzkoa, Basque Government, San Sebastian, Spain. Instituto BIO-Donostia, Hospital Donostia, Donostia, Basque Country. [Lauzon-Guillan,B, Balkau,B] INSERM, CESP Centre for Research in Epidemiology and Population Health, U1018: Epidemiology of Diabetes, Obesity and Chronic Kidney Disease over the Lifecourse, Villejuif Cedex, France. University Paris, Villejuif Cedex, France. [Ardanaz,E] Navarre Public Health Institute, Pamplona, Navarra, Spain. [Beulens,JWJ, Sluijs,I, Schouw,T] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. [Bueno-de-Mesquita,HB] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. [Clavel-Chapelon,F] INSERM, CESP Centre for Research in Epidemiology and Population Health,U1018: Nutrition, Hormones and Women’s Health, IGR, Villejuif Cedex, France. [Crowe,FL, Key,TJ] Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford,Richard Doll Building, Roosevelt Drive, Oxford, United Kingdom. [Grioni,S] Fondazione IRCCS Istituto Nazionale Tumori Milan, Milan, Italy. [Halkjaer,J, Tjonneland,A] Danish Cancer Society Research Center, Copenhagen, Denmark. [Kerrison,ND, Teucher,B] German Cancer Research Centre, Heidelberg, Germany. [Khaw,KT] Department of Public Health and Primary Care, University of Cambridge Addenbrooke’s Hospital, Cambridge, United Kingdom. [Mattiello,A] Department of Clinical and Experimental Medicine Federico II University, Naples, Italy. [Nilsson,P, Panico,S] University of Lund, Department of Clinical Sciences Medicine, University Hospital Scania, Malmo, Sweden. [Norat,T, Romaguera,D, Riboli,E] Department of Epidemiology & Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. [Palli,D] Molecular and Nutritional Epidemiology Unit, ISPO Ponte Nuovo, Florence, Italy. [Quirós, JR] Public Health Directorate, Oviedo, Spain. [Romieu,I, Slimani,N] International Agency for Research on Cancer, Lyon Cedex, France. [Sacerdote,C] Center for Cancer Prevention (CPO-Piemonte), Torino, Italy. Human Genetics Foundation (HuGeF), Torino, Italy. [Sánchez,MJ] Andalusian School of Public Health, Granada, Spain. [Spijkerman,AMW, A Daphne,L] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. [Tumino,R] Cancer Registry and Histopathology Unit, ‘‘Civile - M.P. Arezzo’’ Hospital, Dante Ragusa, Italy. [Feskens,EJM] Division of Human Nutrition - Section Nutrition and Epidemiology, University of Wageningen, Wageningen, The Netherlands. [Franks,PW] Department of Clinical Sciences, Clinical Research Center, Ska°ne University Hospital, Lund University, Malmö , Sweden. [Bueno-de-Mesquita,HB] Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands., Funding: EU Integrated Project LSHM-CT-2006-037197. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. InterAct investigators acknowledge funding from the following agencies: KO: Danish Cancer Society, JS: ‘Heisenberg-Professorship (SP716/2-1), clinical research group (KFO218/1), and a research group (Molecular Nutrition to JS) support of the Bundesministerium fu¨ r Bildung und Forschung (BMBF), MJT: Health Research Fund (FIS) of the Spanish Ministry of Health, the CIBER en Epidemiologı´a y Salud Pu´ blica (CIBERESP), Spain, Murcia Regional Government (Nu 6236), JWJB, HBBdM, IS, AMWS, DLvdA, YTvdS: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands, verification of diabetes cases was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht, FLC: Cancer Research UK, PWF: Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, Swedish Heart-Lung Foundation, GH: The county of Va¨sterbotten, RK: German Cancer Aid, Federal Ministry of Education and Research, TJK: Cancer Research UK, KK: Medical Research Council UK, Cancer Research UK, PN: Swedish Research Council, JRQ: Asturias Regional Government, BT: German Cancer Aid, Federal Ministry of Education and Research, AT: Danish Cancer Society, RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government., Epidemiology and Data Science, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, APH - Health Behaviors & Chronic Diseases, Langenberg, C, Sharp, Sj, Schulze, Mb, Rolandsson, O, Overvad, K, Forouhi, Ng, Spranger, J, Drogan, D, Huerta, Jm, Arriola, L, de Lauzon Guillan, B, Tormo, Mj, Ardanaz, E, Balkau, B, Beulens, Jw, Boeing, H, Bueno de Mesquita, Hb, Clavel Chapelon, F, Crowe, Fl, Franks, Pw, Gonzalez, Ca, Grioni, S, Halkjaer, J, Hallmans, G, Kaaks, R, Kerrison, Nd, Key, Tj, Khaw, Kt, Mattiello, A, Nilsson, P, Norat, T, Palla, L, Palli, D, Panico, Salvatore, Quir?s, Jr, Romaguera, D, Romieu, I, Sacerdote, C, S?nchez, Mj, Slimani, N, Sluijs, I, Spijkerman, Am, Teucher, B, Tjonneland, A, Tumino, R, van der A., Dl, van der Schouw, Yt, Feskens, Ej, Riboli, E, Wareham, Nj, and Interact, Consortium

Subjects
Male, Gerontology, Índice de Masa Corporal, Time Factors, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Proportional Hazards Models [Medical Subject Headings], Nutrition and Disease, Epidemiology, Phenomena and Processes::Physical Phenomena::Time::Time Factors [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Anthropometry [Medical Subject Headings], body-mass index, Diabetes Mellitus Tipo 2, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Overweight, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], Body Mass Index, Cohort Studies, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Endocrinology, prevention, Risk Factors, Voeding en Ziekte, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Size::Waist Circumference [Medical Subject Headings], Cumulative incidence, Longitudinal Studies, Prospective Studies, Nutrition and Dietetics, Anthropometry, Incidence, primary-care, Hazard ratio, Absolute risk reduction, Geographicals::Geographic Locations::Europe [Medical Subject Headings], General Medicine, Middle Aged, waist circumference, Europe, Näringslära, nutrition, Cohort, Medicine, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], Female, medicine.symptom, Life Sciences & Biomedicine, Research Article, Cohort study, Clinical Research Design, abdominal adiposity, Check Tags::Male [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Mass Index [Medical Subject Headings], Endocrinology and Diabetes, Medicine, General & Internal, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::Incidence [Medical Subject Headings], General & Internal Medicine, medicine, Humans, cancer, Obesity, Risk factor, Proportional Hazards Models, VLAG, Diabetic Endocrinology, Science & Technology, business.industry, association, nutritional and metabolic diseases, Diabetes Mellitus Type 2, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Diabetes Mellitus, Type 2, Antropometría, Check Tags::Female [Medical Subject Headings], Other Clinical Medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Meta-Analyses, participants, business, Estudios de Cohortes, Body mass index, Demography, mellitus
Abstract

A collaborative re-analysis of data from the InterAct case-control study conducted by Claudia Langenberg and colleagues has established that waist circumference is associated with risk of type 2 diabetes, independently of body mass index., Background Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI). Methods and Findings The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5–22.4 kg/m2) with a low WC (102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50–103 per 1,000 person-years in men and 28–74 per 1,000 person-years in women). Conclusions WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action. Please see later in the article for the Editors' Summary, Editors' Summary Background Worldwide, more than 350 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone that the pancreas releases after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest form of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. The long-term complications of diabetes, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes. Why Was This Study Done? A high body mass index (BMI, a measure of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is a strong predictor of type 2 diabetes. Although the risk of diabetes is greatest in obese people (who have a BMI of greater than 30 kg/m2), many of the people who develop diabetes are overweight—they have a BMI of 25–30 kg/m2. Healthy eating and exercise reduce the incidence of diabetes in high-risk individuals, but it is difficult and expensive to provide all overweight and obese people with individual lifestyle advice. Ideally, a way is needed to distinguish between people with high and low risk of developing diabetes at different levels of BMI. Waist circumference is a measure of fat distribution that has the potential to quantify diabetes risk among people with different BMIs because it estimates the amount of fat around the abdominal organs, which also predicts diabetes development. In this case-cohort study, the researchers use data from the InterAct study (which is investigating how genetics and lifestyle interact to affect diabetes risk) to estimate the long-term risk of type 2 diabetes associated with BMI and waist circumference. A case-cohort study measures exposure to potential risk factors in a group (cohort) of people and compares the occurrence of these risk factors in people who later develop the disease and in a randomly chosen subcohort. What Did the Researchers Do and Find? The researchers estimated the association of BMI and waist circumference with type 2 diabetes from baseline measurements of the weight, height, and waist circumference of 12,403 people who subsequently developed type 2 diabetes and a subcohort of 16,154 participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC). Both risk factors were independently associated with type 2 diabetes risk, but waist circumference was a stronger risk factor in women than in men. Obese men (BMI greater than 35 kg/m2) with a high waist circumference (greater than 102 cm) were 22 times more likely to develop diabetes than men with a low normal weight (BMI 18.5–22.4 kg/m2) and a low waist circumference (less than 94 cm); obese women with a waist circumference of more than 88 cm were 31.8 times more likely to develop type 2 diabetes than women with a low normal weight and waist circumference (less than 80 cm). Importantly, among overweight people, waist circumference measurements identified a subgroup of overweight people (those with a high waist circumference) whose 10-year cumulative incidence of type 2 diabetes was similar to that of obese people. What Do These Findings Mean? These findings indicate that, among people of European descent, waist circumference is independently and strongly associated with type 2 diabetes, particularly among women. Additional studies are needed to confirm this association in other ethnic groups. Targeted measurement of waist circumference in overweight individuals (who now account for a third of the US and UK adult population) could be an effective strategy for the prevention of diabetes because it would allow the identification of a high-risk subgroup of people who might benefit from individualized lifestyle advice. Additional Information Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001230. The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health care professionals, and the general public, including detailed information on diabetes prevention (in English and Spanish) The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (including some information in Spanish) The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes, about the prevention of type 2 diabetes, and about obesity; it also includes peoples stories about diabetes and about obesity The charity Diabetes UK also provides detailed information for patients and carers, including information on healthy lifestyles for people with diabetes, and has a further selection of stories from people with diabetes; the charity Healthtalkonline has interviews with people about their experiences of diabetes More information on the InterAct study is available MedlinePlus provides links to further resources and advice about diabetes and diabetes prevention and about obesity (in English and Spanish)

Published
2012
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20. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity

Author

Núria Sala, Nina Roswall, Tilman Kühn, Larraitz Arriola, Dorota Pasko, Elio Riboli, Mark I. McCarthy, Afshan Siddiq, María José Sánchez, Luca A. Lotta, Francesca L. Crowe, Timothy J. Key, Peter M. Nilsson, Anne Tjønneland, Inês Barroso, Guy Fagherazzi, Nita G. Forouhi, Carlotta Sacerdote, Kim Overvad, Aurelio Barricarte, Nicholas J. Wareham, Sara Grioni, Tove Fall, Françoise Clavel-Chapelon, Olov Rolandsson, Heiner Boeing, Jacqueline M. Dekker, Mark Walker, Adam Barker, Vilmantas Giedraitis, Daphne L. van der A, Claudia Langenberg, Diana Gavrila, David B. Savage, Ele Ferrannini, Matthias B. Schulze, Hanieh Yaghootkar, Nadia Slimani, Paul W. Franks, Erik Ingelsson, Annemieke M.W. Spijkerman, Robert A. Scott, Ivonne Sluijs, Rosario Tumino, Stephen J. Sharp, Salvatore Panico, Robert K. Semple, Beverley Balkau, Leif Groop, Domenico Palli, Timothy M. Frayling, J. Ramón Quirós, Rudolf Kaaks, Scott, Ra, Fall, T, Pasko, D, Barker, A, Sharp, Sj, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel Chapelon, F, Crowe, Fl, Dekker, Jm, Fagherazzi, G, Ferrannini, E, Forouhi, Ng, Franks, Pw, Gavrila, D, Giedraitis, V, Grioni, S, Groop, Lc, Kaaks, R, Key, Tj, K?hn, T, Lotta, La, Nilsson, Pm, Overvad, K, Palli, D, Panico, Salvatore, Quir?s, Jr, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, S?nchez, Mj, Schulze, Mb, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, Am, Tjonneland, A, Tumino, R, van der A., Dl, Yaghootkar, H, Mccarthy, Mi, Semple, Rk, Riboli, E, Walker, M, Ingelsson, E, Frayling, Tm, Savage, Db, Langenberg, C, Wareham, Nj, The RISC The study group InterAct, Consortium, Epidemiology and Data Science, and EMGO - Lifestyle, overweight and diabetes

Subjects
Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Type 2 diabetes, Overweight, Polymorphism, Single Nucleotide, Article, Body Mass Index, Cohort Studies, Insulin resistance, Diabetes mellitus, Internal medicine, Insulin Secretion, Internal Medicine, medicine, Body Fat Distribution, Humans, Insulin, Genetic Predisposition to Disease, Obesity, Aged, 2. Zero hunger, Glucose tolerance test, medicine.diagnostic_test, business.industry, nutritional and metabolic diseases, Genetic Variation, Alanine Transaminase, gamma-Glutamyltransferase, Glucose clamp technique, Glucose Tolerance Test, Middle Aged, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Body Composition, Glucose Clamp Technique, Female, medicine.symptom, Insulin Resistance, Waist Circumference, business
Abstract

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp– and oral glucose tolerance test–based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], −0.03 [−0.04, −0.01]; P = 0.004). This score was associated with lower BMI (−0.01 [−0.01, −0.0]; P = 0.02) and gluteofemoral fat mass (−0.03 [−0.05, −0.02; P = 1.4 × 10−6) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Published
2016
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21. Association of plasma phospholipid n-3 and n-6 polyunsaturated fatty acids with type 2 diabetes: The EPIC-InterAct case-cohort study

Author

Forouhi, N, Imamura, F, Sharp, S, Koulman, A, Schulze, M, Zheng, J, Ye, Z, Sluijs, I, Guevara, M, Huerta, J, Kröger, J, Wang, L, Summerhill, K, Griffin, J, Feskens, E, Affret, A, Amiano, P, Boeing, H, Dow, C, Fagherazzi, G, Franks, P, Gonzalez, C, Kaaks, R, Key, T, Khaw, K, Kühn, T, Mortensen, L, Nilsson, P, Overvad, K, Pala, V, Palli, D, Panico, S, Quirós, J, Rodriguez-Barranco, M, Rolandsson, O, Sacerdote, C, Scalbert, A, Slimani, N, Spijkerman, A, Tjonneland, A, Tormo, M, Tumino, R, van der A, D, van der Schouw, Y, Langenberg, C, Riboli, E, Wareham, N, Forouhi, Nita G, Imamura, Fumiaki, Sharp, Stephen J, Koulman, Albert, Schulze, Matthias B, Zheng, Jusheng, Ye, Zheng, Sluijs, Ivonne, Guevara, Marcela, Huerta, José María, Kröger, Janine, Wang, Laura Yun, Summerhill, Keith, Griffin, Julian L, Feskens, Edith J. M, Affret, Aurélie, Amiano, Pilar, Boeing, Heiner, Dow, Courtney, Fagherazzi, Guy, Franks, Paul W, Gonzalez, Carlo, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay Tee, Kühn, Tilman, Mortensen, Lotte Maxild, Nilsson, Peter M, Overvad, Kim, Pala, Valeria, Palli, Domenico, Panico, Salvatore, Quirós, J. Ramón, Rodriguez Barranco, Miguel, Rolandsson, Olov, Sacerdote, Carlotta, Scalbert, Augustin, Slimani, Nadia, Spijkerman, Annemieke M. W, Tjonneland, Anne, Tormo, Maria Jose, Tumino, Rosario, van der A, Daphne L, van der Schouw, Yvonne T, Langenberg, Claudia, Riboli, Elio, Wareham, Nicholas J., Apollo - University of Cambridge Repository, [Forouhi,NG, Imamura,F, Sharp,SJ, Zheng,J, Ye,Z, Langenberg,C, Wareham,NJ] MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom. [Koulman,A, Wang,LY, Summerhill,K, Griffin,JL] MRC Human Nutrition Research, Cambridge, UK. [Schulze,MB, Kröger,J, Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany. [Sluijs,I, van der Schouw,YT] University Medical Center Utrecht, Utrecht, the Netherlands. [Guevara,M] Navarre Public Health Institute (ISPN), Pamplona, Spain. [Guevara,M, Huerta,JM, Amiano,P, Rodriguez-Barranco,M, Tormo,M] CIBER Epidemiología y Salud Pública (CIBERESP), Spain. [Huerta,M, Tormo,M] Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain. [Feskens,EJM] Wageningen University, The Netherlands. [Affret,A, Dow,C, Fagherazzi,G] Inserm, CESP, U1018, Villejuif, France. Univ Paris-Sud, Villejuif, France, Gustave Roussy Institute, Villejuif, France. [Amiano,P] Public Health Division of Gipuzkoa, San Sebastian, Spain. Instituto BIO-Donostia, Basque Government, San Sebastian, Spain. [Boeing,H] German Institute of Human Nutrition Potsdam-Rehbruecke, Germany. [Franks,PW, Nilsson,PM] Lund University, Malmö, Sweden. [Franks,PW, Rolandsson,O] Umeå University, Umeå, Sweden. [Gonzalez,C] Catalan Institute of Oncology (ICO), Barcelona, Spain. [Kaaks,R, Kühn1,T] German Cancer Research Centre (DKFZ), Heidelberg, Germany. [Key1,TJ] University of Oxford, Oxford, United Kingdom. [Khaw,KT] University of Cambridge, Cambridge, United Kingdom. [Mortensen,M] Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark. [Mortensen,M, Overvad,K] Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark. [Overvad,K] Aalborg University Hospital, Aalborg, Denmark. [Pala,V] Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Palli,D] Cancer Research and Prevention Institute (ISPO), Florence, Italy. [Panico,S] Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy. [Quirós,JR] Public Health Directorate, Asturias, Spain. [Rodriguez-Barranco,M] Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain. [Sacerdote,C] Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Turin, Italy. Human Genetics Foundation (HuGeF), Turin, Italy. [Scalbert,A, Slimani,N] International Agency for Research on Cancer, Lyon, France. [Spijkerman,AMW, van der A,DL] National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. [Tjonneland,A] Danish Cancer Society Research Center, Copenhagen, Denmark. [Tormo,MJ] Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain. [Tumino,R] Cancer Registry and Histopathology Unit, Civic and M.P.Arezzo Hospital, ASP Ragusa, Italy. [Riboli,E] School of Public Health, Imperial College London, London, United Kingdom., Funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197)., Imamura, Fumiaki [0000-0002-6841-8396], Sharp, Stephen J [0000-0003-2375-1440], Koulman, Albert [0000-0001-9998-051X], Sluijs, Ivonne [0000-0001-7758-4911], Guevara, Marcela [0000-0001-9242-6364], Huerta, José María [0000-0002-9637-3869], Rodriguez-Barranco, Miguel [0000-0002-9972-9779], Tormo, Maria-Jose [0000-0003-1474-5233], van der Schouw, Yvonne T [0000-0002-4605-435X], Langenberg, Claudia [0000-0002-5017-7344], and Wareham, Nicholas J [0000-0003-1422-2993]

Subjects
Male, Physiology, Social Sciences, Diabetes Mellitus Tipo 2, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Fatty Acids, Omega-6::Linoleic Acids [Medical Subject Headings], Anatomy::Fluids and Secretions::Body Fluids::Blood::Plasma [Medical Subject Headings], Biochemistry, Plasma, Mathematical and Statistical Techniques, Endocrinology, Sociology, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Fatty Acids, Omega-3 [Medical Subject Headings], Plant Products, Estudios prospectivos, Medicine and Health Sciences, Fosfolípidos, Ácidos grasos omega 3, Phospholipids, Medicine(all), Schools, Fatty Acids, Geographicals::Geographic Locations::Europe [Medical Subject Headings], food and beverages, Agriculture, Ácido eicosapentaenoico, 11 Medical And Health Sciences, Hematology, Middle Aged, Lipids, Type 2 Diabetes, Body Fluids, Blood, Ácidos Grasos Omega-6, Ácido 8,11,14-eicosanoico, Endokrinologi och diabetes, Physical Sciences, Fatty Acids, Unsaturated, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], Medicine, Dieta, lipids (amino acids, peptides, and proteins), Anatomy, Europa, Statistics (Mathematics), Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Arachidonic Acids [Medical Subject Headings], Research Article, Cromatografía de gases, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies [Medical Subject Headings], Endocrine Disorders, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Eicosanoids::8,11,14-Eicosatrienoic Acid [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet [Medical Subject Headings], Endocrinology and Diabetes, Research and Analysis Methods, Vegetable Oils, Blood Plasma, Education, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Fatty Acids, Omega-3::Docosahexaenoic Acids [Medical Subject Headings], General & Internal Medicine, Fatty Acids, Omega-6, Fatty Acids, Omega-3, Ácidos docosahexaenoicos, Diabetes Mellitus, Journal Article, Humans, Statistical Methods, Chemicals and Drugs::Lipids::Phospholipids [Medical Subject Headings], Ácido araquidónico, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Chromatography::Chromatography, Gas [Medical Subject Headings], Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Fatty Acids, Omega-6 [Medical Subject Headings], Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Fatty Acids, Omega-3::Eicosapentaenoic Acid [Medical Subject Headings], Ácidos Grasos Insaturados, Biology and Life Sciences, Ácido linoleico, Agronomy, Diabetes Mellitus, Type 2, Metabolic Disorders, Case-Control Studies, Oils, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated [Medical Subject Headings], Mathematics, Meta-Analysis, Crop Science
Abstract

Background Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations. Methods and Findings Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88–0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77–0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85–0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs. Conclusions These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class., Using a large European cohort, Nita Forouhi and colleagues investigate the association between the concentration of polyunsaturated fatty acids measured in plasma and risk of developing type 2 diabetes., Author Summary Why Was This Study Done? Most dietary guidelines recommend the consumption of polyunsaturated fatty acids for cardiovascular health, but it is unclear whether or how n-3 and n-6 types of polyunsaturated fatty acids are related to type 2 diabetes. Health concerns have been raised previously about a diet high in linoleic acid (n-6 fatty acid), but its association with type 2 diabetes is unclear. Major limitations in previous studies have included the error-prone subjective assessment of the habitual consumption of polyunsaturated fatty acids when dietary intakes were evaluated and a small number of type 2 diabetes cases (n = 71 to 673) when objective biomarkers of polyunsaturated fatty acids were measured. What Did the Researchers Do and Find? We measured circulating individual polyunsaturated fatty acids in the blood samples of individuals within a large study from across eight countries of Europe among a reference sample of 15,919 individuals as well as 12,132 individuals who subsequently developed diabetes. Individuals were followed up for an average of approximately 10 y. We investigated the association between individual polyunsaturated fatty acids and the risk of future type 2 diabetes using statistical analyses that accounted for factors that could be potential alternative explanations for any observed associations. We found that higher levels of blood alpha-linolenic acid, a plant-origin n-3 fatty acid, and n-6 linoleic acid, the most abundant type of polyunsaturated fatty acid, were associated with a lower risk of future type 2 diabetes. In contrast, higher levels of four other minor individual n-6 fatty acids were associated with higher type 2 diabetes risk, while the blood marine-origin n-3 fatty acids were not associated with future diabetes. What Do These Findings Mean? Our findings show that it is important to consider individual circulating polyunsaturated fatty acids for association with type 2 diabetes risk, rather than placing emphasis on the class of circulating polyunsaturated fatty acids. We found that blood n-6 linoleic acid, the most abundant polyunsaturated fatty acid, is inversely associated with type 2 diabetes. We found no evidence that blood total n-6 polyunsaturated fatty acids may elevate the risk of type 2 diabetes, but several individual minor blood n-6 polyunsaturated fatty acids were associated with increased type 2 diabetes risk, highlighting the importance of polyunsaturated fatty acid metabolism in the development of type 2 diabetes.

Published
2016
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22. Consumption of fatty foods and incident type 2 diabetes in populations from eight European countries

Author

Nita G. Forouhi, Kim Overvad, Stephen J. Sharp, Salvatore Panico, Giovanna Masala, M-J Sanchez, Peter M. Nilsson, Annemieke M.W. Spijkerman, Pilar Amiano, Kay-Tee Khaw, Dagmar Drogan, B. de Lauzon-Guillain, Paul W. Franks, Guy Fagherazzi, José María Huerta, Matthias B. Schulze, Valeria Pala, Olov Rolandsson, Elio Riboli, Edith J. M. Feskens, Heiner Boeing, Brian Buijsse, Ivonne Sluijs, Timothy J. Key, Anne Tjønneland, Aurelie Moskal, Claudia Langenberg, Y. T. van der Schouw, Françoise Clavel-Chapelon, Ana Fonseca-Nunes, Marianne Uhre Jakobsen, Fulvio Ricceri, Aurelio Barricarte, María-Luisa Redondo, Rudolf Kaaks, R. Tumino, Nicholas J. Wareham, Buijsse, B, Boeing, H, Drogan, D, Schulze, Mb, Feskens, Ej, Amiano, P, Barricarte, A, Clavel Chapelon, F, de Lauzon Guillain, B, Fagherazzi, G, Fonseca Nunes, A, Franks, Pw, Huerta, Jm, Jakobsen, Mu, Kaaks, R, Key, Tj, Khaw, Kt, Masala, G, Moskal, A, Nilsson, Pm, Overvad, K, Pala, V, Panico, Salvatore, Redondo, Ml, Ricceri, F, Rolandsson, O, Sánchez, Mj, Sluijs, I, Spijkerman, Am, Tjonneland, A, Tumino, R, van der A., Dl, van der Schouw, Yt, Langenberg, C, Sharp, Sj, Forouhi, Ng, Riboli, E, Wareham, Nj, and Interact, C. o. n. s. o. r. t. i. u. m.

Subjects
Male, saturated fat, Nutrition and Disease, Saturated fat, nut consumption, Medicine (miscellaneous), Type 2 diabetes, MEAT CONSUMPTION, Body Mass Index, chemistry.chemical_compound, SATURATED FAT, Risk Factors, Voeding en Ziekte, Surveys and Questionnaires, Nuts, Food science, Prospective Studies, Non-U.S. Gov't, physical-activity, METABOLIC SYNDROME, Nutrition and Dietetics, INSULIN SENSITIVITY, Research Support, Non-U.S. Gov't, Incidence, POSTPRANDIAL GLYCEMIA, Europe, epic-interact, Female, Adult, Trans fat, Research Support, DIETARY-FAT, metabolic syndrome, Diabetes mellitus, medicine, Journal Article, insulin sensitivity, Humans, Plant Oils, CORONARY-HEART-DISEASE, Life Style, meat consumption, VLAG, Proportional Hazards Models, dietary-fat, business.industry, Unsaturated fat, Case-control study, medicine.disease, postprandial glycemia, Dietary Fats, Margarine, Diet, PHYSICAL-ACTIVITY, Nutrition Assessment, chemistry, Diabetes Mellitus, Type 2, Case-Control Studies, Mental Recall, Butter, NUT CONSUMPTION, EPIC-INTERACT, Metabolic syndrome, business, coronary-heart-disease, Energy Intake, Energy Metabolism, Body mass index, Follow-Up Studies
Abstract

Background/Objectives:Diets high in saturated and trans fat and low in unsaturated fat may increase type 2 diabetes (T2D) risk, but studies on foods high in fat per unit weight are sparse. We assessed whether the intake of vegetable oil, butter, margarine, nuts and seeds and cakes and cookies is related to incident T2D.Subjects/Methods:A case-cohort study was conducted, nested within eight countries of the European Prospective Investigation into Cancer (EPIC), with 12 403 incident T2D cases and a subcohort of 16 835 people, identified from a cohort of 340 234 people. Diet was assessed at baseline (1991-1999) by country-specific questionnaires. Country-specific hazard ratios (HRs) across four categories of fatty foods (nonconsumers and tertiles among consumers) were combined with random-effects meta-analysis.Results:After adjustment not including body mass index (BMI), nonconsumers of butter, nuts and seeds and cakes and cookies were at higher T2D risk compared with the middle tertile of consumption. Among consumers, cakes and cookies were inversely related to T2D (HRs across increasing tertiles 1.14, 1.00 and 0.92, respectively; P-trend

Published
2014
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23. Different in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study

Author

Matthias B. Schulze, Nita G. Forouhi, Carlos González, Kim Overvad, María José Tormo, Fumiaki Imamura, Domenico Palli, J. Ramón Quirós, Yvonne T. van der Schouw, José María Huerta, Francesca L. Crowe, Joline W.J. Beulens, Geertruida J. van Woudenbergh, Valeria Pala, Françoise Clavel-Chapelon, Stephen J. Sharp, Daphne L. van der A, Claudia Langenberg, Edith J. M. Feskens, Marcela Guevara, Keith Summerhill, Pilar Amiano, Tilman Kühn, Kay-Tee Khaw, Guy Fagherazzi, Elio Riboli, Rosario Tumino, María José Sánchez, Nicholas J. Wareham, Nina Roswall, Rudolf Kaaks, Amalia Mattiello, Marianne Uhre Jakobsen, Timothy J. Key, Julian L. Griffin, L. Wang, Janine Kröger, Olov Rolandsson, Laureen Dartois, Annemieke M.W. Spijkerman, Carlotta Sacerdote, Heiner Boeing, Anne Tjønneland, Albert Koulman, Nadia Slimani, Paul W. Franks, Peter M. Nilsson, Epidemiology and Data Science, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, APH - Health Behaviors & Chronic Diseases, [Forouhi,NG] MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. [Koulman,A, Wang,L, Summerhill,K, Griffin,JL] MRC Human Nutrition Research, Cambridge, UK. [Sharp,SJ, Imamura,F, Langenberg,C, Wareham,NJ] MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. [Kröger,J, Schulze,MB, Boeing,H] German Institute of Human Nutrition Potsdam-Rehbruecke, Potsdam, Germany. [Crowe,FL, Key,TJ] Nuffield Department of Medicine, University of Oxford, Oxford, UK. [Huerta,JM] Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain, CIBER Epidemiología y Salud Pública (CIBERESP), Murcia, Spain. [Guevara,M] CIBER Epidemiología y Salud Pública (CIBERESP), Murcia, Spain, Navarre Public Health Institute (ISPN), Pamplona, Spain. [Beulens,JW, van der Schouw,YT] University Medical Center Utrecht, Utrecht, Netherlands. [van Woudenbergh,GJ, Feskens,EJ] Wageningen University, Wageningen, Netherlands. [Amiano,P] CIBER Epidemiología y Salud Pública (CIBERESP), Murcia, Spain, Public Health Division of Gipuzkoa, San Sebastian, Spain, Instituto BIO-Donostia, Basque Government, San Sebastian, Spain. [Clavel-Chapelon,F, Dartois L, Fagherazzi,G] Inserm, CESP, Villejuif, France, Univ Paris-Sud, Villejuif, France, Gustave Roussy Institute, Villejuif, France. [Franks,PW] Lund University, Malmö, Sweden, Umeå University, Umeå, Sweden. [Gonzalez,C] Catalan Institute of Oncology (ICO), Barcelona, Spain. [Jakobsen,MU] Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark. [Kaaks,R, Kühn,T] German Cancer Research Centre (DKFZ), Heidelberg, Germany. [Khaw,KT] Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Mattiello,A] Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy. [Nilsson,PM] Lund University, Malmö, Sweden. [Overvad,K] Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark, Aalborg University Hospital, Aalborg, Denmark. [Pala,V] Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Palli,D] Cancer Research and Prevention Institute (ISPO), Florence, Italy. [Quirós,JR] Public Health Directorate, Asturias, Spain. [Rolandsson,O] Umeå University, Umeå, Sweden. [Roswall,N] Danish Cancer Society, Copenhagen, Denmark. [Sacerdote,C] Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Centre for Cancer Prevention (CPO), Turin, Italy, Human Genetics Foundation (HuGeF), Turin, Italy. [Sánchez,MJ] CIBER Epidemiología y Salud Pública (CIBERESP), Murcia, Spain, Andalusian School of Public Health, Granada, Spain, Instituto de Investigación Biosanitaria de Granada (Granada.ibs), Granada, Spain. [Slimani,N] International Agency for Research on Cancer, Lyon, France. [Spijkerman,AM, van der A,DL] National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands. [Tjonneland,A] Danish Cancer Society Research Center, Copenhagen, Denmark. [Tormo,MJ] Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain, CIBER Epidemiología y Salud Pública (CIBERESP), Murcia, Spain, Department of Health and Social Sciences, Universidad de Murcia, Spain. [Tumino,R] Associazione Italiana Registri Tumori, Dipartimento di Prevenzione Medica, Azienda Sanitaria Provinciale, Ragusa, Italy, Aire Onlus, Ragusa, Italy. [Riboli,E] School of Public Health, Imperial College London, London, UK., and EU FP6 programme, Medical Research Council Epidemiology Unit, Medical Research Council Human Nutrition Research, and Cambridge Lipidomics Biomarker Research Initiative.

Subjects
Male, Nutrition and Disease, 030309 nutrition & dietetics, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Pentadecanoic acid, Palmitic acid, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, project, Voeding en Ziekte, Estudios prospectivos, Fosfolípidos, Prospective Studies, humans, risk-factors, Ácidos grasos, Phospholipids, 2. Zero hunger, 0303 health sciences, Estudios de casos y controles, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Fatty Acids, de-novo lipogenesis, Articles, Chemicals and Drugs::Lipids::Fatty Acids [Medical Subject Headings], Middle Aged, 3. Good health, Endokrinologi och diabetes, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], biomarker, dietary, Heptadecanoic acid, Female, Stearic acid, medicine.medical_specialty, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies [Medical Subject Headings], Diabetes Mellitus tipo 2, Lignoceric acid, Check Tags::Male [Medical Subject Headings], 030209 endocrinology & metabolism, Endocrinology and Diabetes, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, cancer, Chemicals and Drugs::Lipids::Phospholipids [Medical Subject Headings], VLAG, Mediana edad, disease, business.industry, medicine.disease, dairy product intake, chemistry, Check Tags::Female [Medical Subject Headings], Diabetes Mellitus, Type 2, Case-Control Studies, Odd-chain fatty acid, business, mellitus
Abstract

Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't; BACKGROUND Conflicting evidence exists regarding the association between saturated fatty acids (SFAs) and type 2 diabetes. In this longitudinal case-cohort study, we aimed to investigate the prospective associations between objectively measured individual plasma phospholipid SFAs and incident type 2 diabetes in EPIC-InterAct participants. METHODS The EPIC-InterAct case-cohort study includes 12,403 people with incident type 2 diabetes and a representative subcohort of 16,154 individuals who were selected from a cohort of 340.234 European participants with 3·99 million person-years of follow-up (the EPIC study). Incident type 2 diabetes was ascertained until Dec 31, 2007, by a review of several sources of evidence. Gas chromatography was used to measure the distribution of fatty acids in plasma phospholipids (mol%); samples from people with type 2 diabetes and subcohort participants were processed in a random order by centre, and laboratory staff were masked to participant characteristics. We estimated country-specific hazard ratios (HRs) for associations per SD of each SFA with incident type 2 diabetes using Prentice-weighted Cox regression, which is weighted for case-cohort sampling, and pooled our findings using random-effects meta-analysis. FINDINGS SFAs accounted for 46% of total plasma phospholipid fatty acids. In adjusted analyses, different individual SFAs were associated with incident type 2 diabetes in opposing directions. Even-chain SFAs that were measured (14:0 [myristic acid], 16:0 [palmitic acid], and 18:0 [stearic acid]) were positively associated with incident type 2 diabetes (HR [95% CI] per SD difference: myristic acid 1·15 [95% CI 1·09-1·22], palmitic acid 1·26 [1·15-1·37], and stearic acid 1·06 [1·00-1·13]). By contrast, measured odd-chain SFAs (15:0 [pentadecanoic acid] and 17:0 [heptadecanoic acid]) were inversely associated with incident type 2 diabetes (HR [95% CI] per 1 SD difference: 0·79 [0·73-0·85] for pentadecanoic acid and 0·67 [0·63-0·71] for heptadecanoic acid), as were measured longer-chain SFAs (20:0 [arachidic acid], 22:0 [behenic acid], 23:0 [tricosanoic acid], and 24:0 [lignoceric acid]), with HRs ranging from 0·72 to 0·81 (95% CIs ranging between 0·61 and 0·92). Our findings were robust to a range of sensitivity analyses. INTERPRETATION Different individual plasma phospholipid SFAs were associated with incident type 2 diabetes in opposite directions, which suggests that SFAs are not homogeneous in their effects. Our findings emphasise the importance of the recognition of subtypes of these fatty acids. An improved understanding of differences in sources of individual SFAs from dietary intake versus endogenous metabolism is needed. FUNDING EU FP6 programme, Medical Research Council Epidemiology Unit, Medical Research Council Human Nutrition Research, and Cambridge Lipidomics Biomarker Research Initiative. Yes

Published
2014
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24. Non-invasive risk scores for prediction of type 2 diabetes (EPIC-InterAct):A validation of existing models

Author

Aurelio Barricarte, Olov Rolandsson, Laureen Dartois, Matthias B. Schulze, J. Ramón Quirós, Yvonne T. van der Schouw, Timothy J. Key, Diederick E. Grobbee, Larraitz Arriola, Kay-Tee Khaw, Elio Riboli, Kristin Mühlenbruch, María José Tormo, Carlotta Sacerdote, Andre Pascal Kengne, Annemieke M.W. Spijkerman, Luigi Palla, Thure Filskov Overvad, Peter M. Nilsson, Anne Tjønneland, José María Huerta, Giovanna Tagliabue, Rosario Tumino, Rudolf Kaaks, Nadia Slimani, Paul W. Franks, Daphne L. van der A, Domenico Palli, Simon J. Griffin, Nicholas J. Wareham, Françoise Clavel-Chapelon, Heiner Boeing, Karel G.M. Moons, Nina Roswall, María José Sánchez, Claudia Langenberg, Nita G. Forouhi, Joline W.J. Beulens, Kim Overvad, Noël C. Barengo, Catalina Bonet, Kuanrong Li, Guy Fagherazzi, Linda M. Peelen, Stephen J. Sharp, Salvatore Panico, Kengne, Ap, Beulens, Jw, Peelen, Lm, Moons, Kg, van der Schouw, Yt, Schulze, Mb, Spijkerman, Am, Griffin, Sj, Grobbee, De, Palla, L, Tormo, Mj, Arriola, L, Barengo, Nc, Barricarte, A, Boeing, H, Bonet, C, Clavel Chapelon, F, Dartois, L, Fagherazzi, G, Franks, Pw, Huerta, Jm, Kaaks, R, Key, Tj, Khaw, Kt, Li, K, M?hlenbruch, K, Nilsson, Pm, Overvad, K, Overvad, Tf, Palli, D, Panico, Salvatore, Quir?s, Jr, Rolandsson, O, Roswall, N, Sacerdote, C, S?nchez, Mj, Slimani, N, Tagliabue, G, Tj?nneland, A, Tumino, R, van der A., Dl, Forouhi, Ng, Sharp, Sj, Langenberg, C, Riboli, E, Wareham, Nj, Epidemiology and Data Science, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, APH - Health Behaviors & Chronic Diseases, Department of Public Health, and Hjelt Institute (-2014)

Subjects
Male, Gerontology, EXTERNAL VALIDATION, LIFE-STYLE INTERVENTIONS, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Body Mass Index, Cohort Studies, MELLITUS, 0302 clinical medicine, Endocrinology, TOOL, Medicine, 030212 general & internal medicine, 10. No inequality, media_common, education.field_of_study, Age Factors, Middle Aged, 3. Good health, Cohort, Female, IDENTIFYING INDIVIDUALS, Waist Circumference, Risk assessment, Cohort study, Waist, education, Population, 030209 endocrinology & metabolism, Models, Biological, Risk Assessment, White People, 03 medical and health sciences, Sex Factors, Internal Medicine, Humans, media_common.cataloged_instance, COHORT, VALIDITY, European union, METAANALYSIS, business.industry, medicine.disease, PREVENTION, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, FOLLOW-UP, business, Body mass index, Demography
Abstract

Background: The comparative performance of existing models for prediction of type 2 diabetes across populations has not been investigated. We validated existing non-laboratory-based models and assessed variability in predictive performance in European populations. Methods: We selected non-invasive prediction models for incident diabetes developed in populations of European ancestry and validated them using data from the EPIC-InterAct case-cohort sample (27 779 individuals from eight European countries, of whom 12 403 had incident diabetes). We assessed model discrimination and calibration for the first 10 years of follow-up. The models were first adjusted to the country-specific diabetes incidence. We did the main analyses for each country and for subgroups defined by sex, age (2 vs ≥25 kg/m2), and waist circumference (men heterogeneityheterogeneity>0·05) except for three models. However, two models overestimated risk, DPoRT by 34% (95% CI 29-39%) and Cambridge by 40% (28-52%). Discrimination was always better in individuals younger than 60 years or with a low waist circumference than in those aged at least 60 years or with a large waist circumference. Patterns were inconsistent for BMI. All models overestimated risks for individuals with a BMI of 2. Calibration patterns were inconsistent for age and waist-circumference subgroups. Interpretation: Existing diabetes prediction models can be used to identify individuals at high risk of type 2 diabetes in the general population. However, the performance of each model varies with country, age, sex, and adiposity. Funding: The European Union.

Published
2014
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25. The amount and type of dairy product intake and incident type 2 diabetes:results from the EPIC-InterAct Study

Author

Peter M. Nilsson, Rudolf Kaaks, Jytte Halkjær, Anne Tjønneland, Nita G. Forouhi, Domenico Palli, Kim Overvad, María José Sánchez, Blandine de Lauzon-Guillain, Aurelio Barricarte, Françoise Clavel-Chapelon, Claudia Langenberg, Yvonne T. van der Schouw, H. Bas Bueno-de-Mesquita, Edith J. M. Feskens, Elio Riboli, Annemieke M.W. Spijkerman, María José Tormo, Nadia Slimani, Larraitz Arriola, Paul W. Franks, Olov Rolandsson, Daphne L. van der A, Beverley Balkau, Carlos González, Heiner Boeing, José Ramón Quirós, Nicholas J. Wareham, Francesca L. Crowe, Carlotta Sacerdote, Claudia Agnoli, Fulvio Ricceri, Joline W.J. Beulens, Ivonne Sluijs, Stephen J. Sharp, Salvatore Panico, Sabina Rinaldi, Dagmar Drogan, Aurelie Moskal, Birgit Teucher, Diana Gavrila, Rosario Tumino, Epidemiology and Data Science, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, APH - Health Behaviors & Chronic Diseases, Sluijs, I, Forouhi, Ng, Beulens, Jw, van der Schouw, Yt, Agnoli, C, Arriola, L, Balkau, B, Barricarte, A, Boeing, H, Bueno de Mesquita, Hb, Clavel Chapelon, F, Crowe, Fl, de Lauzon Guillain, B, Drogan, D, Franks, Pw, Gavrila, D, Gonzalez, C, Halkjær, J, Kaaks, R, Moskal, A, Nilsson, P, Overvad, K, Palli, D, Panico, Salvatore, Quirós, Jr, Ricceri, F, Rinaldi, S, Rolandsson, O, Sacerdote, C, Sánchez, Mj, Slimani, N, Spijkerman, Am, Teucher, B, Tjonneland, A, Tormo, Mj, Tumino, R, van der A., Dl, Sharp, Sj, Langenberg, C, Feskens, Ej, Riboli, E, Wareham, Nj, on behalf of The InterAct, C. o. n. s. o. r. t. i. u. m., Halkjaer, J, Quir?s, Jr, S?nchez, Mj, and Interact, Consortium

Subjects
Adult, Male, medicine.medical_specialty, Nutrition and Disease, vitamin-d, Medicine (miscellaneous), metabolic risk-factors, Type 2 diabetes, EPIC, Cohort Studies, Risk Factors, Voeding en Ziekte, Environmental health, Internal medicine, Diabetes mellitus, Surveys and Questionnaires, medicine, Humans, consumption, Product (category theory), Prospective Studies, dietary assessment methods, VLAG, Proportional Hazards Models, Nutrition and Dietetics, business.industry, Incidence, Follow up studies, cohort, Middle Aged, medicine.disease, myocardial-infarction, Diet, Europe, nutrition, Endocrinology, Diabetes Mellitus, Type 2, milk-fat, Milk fat, insulin-resistance syndrome, Female, Dairy Products, energy-intake, business, Energy Intake, Follow-Up Studies
Abstract

Background: Dairy product intake may be inversely associated with risk of type 2 diabetes, but the evidence is inconclusive for total dairy products and sparse for types of dairy products. Objective: The objective was to investigate the prospective association of total dairy products and different dairy subtypes with incidence of diabetes in populations with marked variation of intake of these food groups. Design: A nested case-cohort within 8 European countries of the European Prospective Investigation into Cancer and Nutrition Study (n = 340,234; 3.99 million person-years of follow-up) included a random subcohort (n = 16,835) and incident diabetes cases (n = 12,403). Baseline dairy product intake was assessed by using dietary questionnaires. Country-specific Prentice-weighted Cox regression HRs were calculated and pooled by using a random-effects meta-analysis. Results: Intake of total dairy products was not associated with diabetes (HR for the comparison of the highest with the lowest quintile of total dairy products: 1.01; 95% CI: 0.83, 1.34; P-trend = 0.92) in an analysis adjusted for age, sex, BMI, diabetes risk factors, education, and dietary factors. Of the dairy subtypes, cheese intake tended to have an inverse association with diabetes (HR: 0.88; 95% CI: 0.76, 1.02; P-trend = 0.01), and a higher combined intake of fermented dairy products (cheese, yogurt, and thick fermented milk) was inversely associated with diabetes (HR: 0.88; 95% CI: 0.78, 0.99; P-trend = 0.02) in adjusted analyses that compared extreme quintiles. Conclusions: This large prospective study found no association between total dairy product intake and diabetes risk. An inverse association of cheese intake and combined fermented dairy product intake with diabetes is suggested, which merits further study.

Published
2012
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26. A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans

Author

Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, DIAGRAM Consortium, MAGIC Investigators, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie CY, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, Van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex SF, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul RV, Jørgensen, Torben, Kao, Wen HL, Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Perry, John RB, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, Van Dam, Rob M, Van Haeften, Timon W, Van Herpt, Thijs, Van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Mohlke, Karen L, Morris, Andrew D, Palmer, Colin NA, Pramstaller, Peter P, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Hu, Frank B, Meigs, James B, Pankow, James S, Pedersen, Oluf, Wichmann, H-Erich, Barroso, Inês, Florez, Jose C, Frayling, Timothy M, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, Van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Johnson, Toby, Elliott, Paul, Rybin, Denis, Henneman, Peter, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Egan, Josephine M, Lajunen, Taina, Doney, Alex, Kanoni, Stavroula, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan JM, Cooper, Matthew N, Crisponi, Laura, Day, Ian NM, De Geus, Eco JC, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Frants, Rune, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hicks, Andrew A, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Jula, Antti, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Manning, Alisa K, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Oostra, Ben A, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Perola, Markus, Pfeiffer, Andreas FH, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Psaty, Bruce M, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sijbrands, Eric JG, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tanaka, Toshiko, Tönjes, Anke, Uitterlinden, André G, Van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline CM, Yarnell, John WG, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, Borecki, Ingrid B, Loos, Ruth JF, Meneton, Pierre, Magnusson, Patrik KE, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Salomaa, Veikko, Smith, George Davey, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Dedoussis, George V, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, WH Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Siscovick, David S, Penninx, Brenda WJH, Boomsma, Dorret I, Deloukas, Panos, Spector, Timothy D, Ferrucci, Luigi, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Waterworth, Dawn M, Vollenweider, Peter, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, Center for Liver, Digestive and Metabolic Diseases (CLDM), Palmer, Nd, Mcdonough, Cw, Hicks, Pj, Roh, Bh, Wing, Mr, An, S, Hester, Jm, Cooke, Jn, Bostrom, Ma, Rudock, Me, Talbert, Me, Lewis, Jp, Diagram, Consortium, Magic, Investigator, Ferrara, A, Lu, L, Ziegler, Jt, Sale, Mm, Divers, J, Shriner, D, Adeyemo, A, Rotimi, Cn, Ng, Mc, Langefeld, Cd, Freedman, Bi, Bowden, Dw, Voight, Bf, Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Langenberg, C, Hofmann, Om, Dupuis, J, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Couper, Dj, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Perry, Jr, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, Nj, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Meigs, Jb, Pankow, J, Pedersen, O, Wichmann, He, Barroso, I, Florez, Jc, Frayling, Tm, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Johnson, T, Elliott, P, Rybin, D, Henneman, P, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Egan, Jm, Lajunen, T, Kanoni, S, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Frants, R, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hicks, Aa, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Jula, A, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Manning, Ak, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Oostra, Ba, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Perola, M, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Psaty, Bm, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tanaka, T, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Borecki, Ib, Loos, Rj, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Salomaa, V, Smith, Gd, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Dedoussis, Gv, Serrano Ríos, M, Lind, L, Palmer, Lj, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Buchanan, Ta, Valle, Tt, Rotter, Ji, Siscovick, D, Penninx, Bw, Boomsma, Di, Deloukas, P, Spector, Td, Ferrucci, L, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Waterworth, Dm, Vollenweider, P, Peltonen, L, Mooser, V, Sladek, R., Medical Research Council (MRC), Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, Langenberg, Claudia [0000-0002-5017-7344], Griffin, Simon [0000-0002-2157-4797], Wareham, Nicholas [0000-0003-1422-2993], Soranzo, Nicole [0000-0003-1095-3852], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Apollo - University of Cambridge Repository, DIAGRAM Consortium, MAGIC Investigators, Johnson, T., Bergman, S., Bochud, M., Waeber, G., and Vollenweider, P.

Subjects
Netherlands Twin Register (NTR), Male, Adult, African Americans/genetics, Aged, Case-Control Studies, Cohort Studies, Diabetes Mellitus, Type 2/ethnology, Diabetes Mellitus, Type 2/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Validation Studies as Topic, Medicin och hälsovetenskap, Linkage disequilibrium, Genetic Screens, endocrine system diseases, lcsh:Medicine, Genome-wide association study, Medical and Health Sciences, 0302 clinical medicine, Endocrinology, Genome Sequencing, lcsh:Science, Medicine(all), Genetics, African Americans, 0303 health sciences, education.field_of_study, INSULIN-RESISTANCE, Multidisciplinary, Agricultural and Biological Sciences(all), LARGE-SCALE ASSOCIATION, STAGE RENAL-DISEASE, COMMON VARIANTS, Genomics, Medicine, Research Article, SUSCEPTIBILITY LOCI, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, DIAGRAM Consortium, 03 medical and health sciences, MAGIC Investigators, SDG 3 - Good Health and Well-being, Genetic linkage, MD Multidisciplinary, Genome-Wide Association Studies, SNP, ddc:610, education, Genotyping, 030304 developmental biology, Diabetic Endocrinology, LINKAGE ANALYSIS, Biochemistry, Genetics and Molecular Biology(all), lcsh:R, TCF7L2 GENE, Case-control study, Computational Biology, nutritional and metabolic diseases, Human Genetics, Diabetes Mellitus Type 2, Stage renal-disease, large-scale association, Susceptibility loci, Insulin-resistance, Fasting glucose, Tissue factor, Homeodomain protein, Linkage analysis, Common variants, TCF7L2 gene, Black or African American, Diabetes Mellitus, Type 2, TISSUE FACTOR, Genetics of Disease, HOMEODOMAIN PROTEIN, Genetic Polymorphism, lcsh:Q, Genome Expression Analysis, 030217 neurology & neurosurgery, Population Genetics, FASTING GLUCOSE
Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Published
2012
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27. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women

Author

Amelie Bonnefond, Nancy Heard-Costa, Eleftheria Zeggini, Anna Gloyn, LAURA CRISPONI, Eco De Geus, Michael Weedon, Torben Jørgensen, Jaakko Kaprio, Iva Miljkovic, Amanda Bennett, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Christian Dina, Sophie Visvikis-Siest, Udo Seedorf, Vilmundur Gudnason, Michael Marmot, Mika Kivimaki, Mary Feitosa, Danielle Posthuma, Claudia Langenberg, Stavroula Kanoni, Cyrus Cooper, Meena Kumari, Peter Kovacs, Debbie A Lawlor, Inga Prokopenko, Rafn Benediktsson, Stephen Kritchevsky, Philippe Froguel, Cornelia Van Duijn, Nita Forouhi, Anne B. Newman, Ko Willems van Dijk, John Carr, Reedik Mägi, Sutapa Mukherjee, Lyle John Palmer, Francois Pattou, L. Adrienne Cupples, Paul Franks, Paul Elliott, Albert Vernon Smith, MANUELA UDA, Kirsten Ohm Kyvik, Manuel Serrano Ríos, Richard Bergman, Gonneke Willemsen, Cecilia Lindgren, Igor Rudan, Human genetics, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Institute for Molecular Medicine Finland, Research Group Ripatti Samuli, Hjelt Institute (-2014), Department of Public Health, Biostatistics Helsinki, Complex Disease Genetics, Genetic Epidemiology, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, GIANT Consortium, MAGIC Consortium, GLGC Consortium, Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, AU., Wheeler, E., Glazer, NL., Bouatia-Naji, N., Gloyn, AL., Lindgren, CM., Mägi, R., Morris, AP., Randall, J., Johnson, T., Elliott, P., Rybin, D., Thorleifsson, G., Steinthorsdottir, V., Henneman, P., Grallert, H., Dehghan, A., Hottenga, JJ., Franklin, CS., Navarro, P., Song, K., Goel, A., Perry, JR., Egan, JM., Lajunen, T., Grarup, N., Sparsø, T., Doney, A., Voight, BF., Stringham, HM., Li, M., Kanoni, S., Shrader, P., Cavalcanti-Proença, C., Kumari, M., Qi, L., Timpson, NJ., Gieger, C., Zabena, C., Rocheleau, G., Ingelsson, E., An, P., O'Connell, J., Luan£££Jian'an£££ J., Elliott, A., McCarroll, SA., Payne, F., Roccasecca, RM., Pattou, F., Sethupathy, P., Ardlie, K., Ariyurek, Y., Balkau, B., Barter, P., Beilby, JP., Ben-Shlomo, Y., Benediktsson, R., Bennett, AJ., Bergmann, S., Bochud, M., Boerwinkle, E., Bonnefond, A., Bonnycastle, LL., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, SJ., Charpentier, G., Chen, YD., Chines, P., Clarke, R., Coin, LJ., Cooper, MN., Cornelis, M., Crawford, G., Crisponi, L., Day, IN., de Geus EJ., Delplanque, J., Dina, C., Erdos, MR., Fedson, AC., Fischer-Rosinsky, A., Forouhi, NG., Fox, CS., Frants, R., Franzosi, MG., Galan, P., Goodarzi, MO., Graessler, J., Groves, CJ., Grundy, S., Gwilliam, R., Gyllensten, U., Hadjadj, S., Hallmans, G., Hammond, N., Han, X., Hartikainen, AL., Hassanali, N., Hayward, C., Heath, SC., Hercberg, S., Herder, C., Hicks, AA., Hillman, DR., Hingorani, AD., Hofman, A., Hui, J., Hung, J., Isomaa, B., Johnson, PR., Jørgensen, T., Jula, A., Kaakinen, M., Kaprio, J., Kesaniemi, YA., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, KO., Lathrop, GM., Lawlor, DA., Le Bacquer, O., Lecoeur, C., Li, Y., Lyssenko, V., Mahley, R., Mangino, M., Manning, AK., Martínez-Larrad£££María Teresa£££ MT., McAteer, JB., McCulloch, LJ., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, BD., Morken, MA., Mukherjee, S., Naitza, S., Narisu, N., Neville, MJ., Oostra, BA., Orrù, M., Pakyz, R., Palmer, CN., Paolisso, G., Pattaro, C., Pearson, D., Peden, JF., Pedersen, NL., Perola, M., Pfeiffer, AF., Pichler, I., Polasek, O., Posthuma, D., Potter, SC., Pouta, A., Province, MA., Psaty, BM., Rathmann, W., Rayner, NW., Rice, K., Ripatti, S., Rivadeneira, F., Roden, M., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, AA., Scheet, P., Scott, LJ., Seedorf, U., Sharp, SJ., Shields, B., Sigurðsson, G., Sijbrands, EJ., Silveira, A., Simpson, L., Singleton, A., Smith, NL., Sovio, U., Swift, A., Syddall, H., Syvänen, AC., Tanaka, T., Thorand, B., Tichet, J., Tönjes, A., Tuomi, T., Uitterlinden, AG., van Dijk KW., van Hoek, M., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, PJ., Walley, A., Walters, GB., Ward, KL., Watkins, H., Weedon, MN., Wild, SH., Willemsen, G., Witteman, JC., Yarnell, JW., Zeggini, E., Zelenika, D., Zethelius, B., Zhai, G., Zhao, JH., Zillikens, MC., Borecki, IB., Loos, RJ., Meneton, P., Magnusson, PK., Nathan, DM., Williams, GH., Hattersley, AT., Silander, K., Salomaa, V., Smith, GD., Bornstein, SR., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, AR., Cooper, C., Dedoussis, GV., Serrano-Ríos, M., Morris, AD., Lind, L., Palmer, LJ., Hu, FB., Franks, PW., Ebrahim, S., Marmot, M., Kao, WH., Pankow, JS., Sampson, MJ., Kuusisto, J., Laakso, M., Hansen, T., Pedersen, O., Pramstaller, PP., Wichmann, HE., Illig, T., Rudan, I., Wright, AF., Stumvoll, M., Campbell, H., Wilson, JF., Hamsten, A., Bergman, RN., Buchanan, TA., Collins, FS., Mohlke, KL., Tuomilehto, J., Valle, TT., Altshuler, D., Rotter, JI., Siscovick, DS., Penninx, BW., Boomsma, ID., Deloukas, P., Spector, TD., Frayling, TM., Ferrucci, L., Kong, A., Thorsteinsdottir, U., Stefansson, K., van Duijn CM., Aulchenko, YS., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, MR., Waterworth, DM., Vollenweider, P., Peltonen, L., Mooser, V., Abecasis, RG., Wareham, NJ., Sladek, R., Froguel, P., Watanabe, RM., Meigs, JB., Groop, L., Boehnke, M., McCarthy, MI., Florez, JC., Barroso£££Inês£££ I., Feitosa, Mary [0000-0002-0933-2410], Heard-Costa, Nancy [0000-0001-9730-0306], Newman, Anne B [0000-0002-0106-1150], Miljkovic, Iva [0000-0002-3155-9777], Kritchevsky, Stephen B [0000-0003-3336-6781], Carr, J Jeffrey [0000-0002-4398-8237], Gudnason, Vilmunder [0000-0001-5696-0084], Cupples, L Adrienne [0000-0003-0273-7965], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)

Subjects
Male, Netherlands Twin Register (NTR), Cancer Research, Adipose tissue, Genome-wide association study, QH426-470, FTO gene, Body Mass Index, 0302 clinical medicine, Genetics (clinical), TISSUE DISTRIBUTION, GENE-EXPRESSION, 2. Zero hunger, ATHEROSCLEROSIS MESA, 0303 health sciences, INSULIN-RESISTANCE, Sex Characteristics, MAGIC Consortium, Adult, Aged, Cytokines/genetics, European Continental Ancestry Group, Female, Genome-Wide Association Study, HapMap Project, Humans, Intra-Abdominal Fat, Lysophospholipase/genetics, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proteins/genetics, Subcutaneous Fat, Abdominal, 3142 Public health care science, environmental and occupational health, CARDIOVASCULAR-DISEASE, OBESITY, Cytokines, Medicine, Lysophospholipase, Research Article, medicine.medical_specialty, Waist, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 030209 endocrinology & metabolism, HIP RATIO, Biology, White People, GLGC Consortium, 03 medical and health sciences, Insulin resistance, Internal medicine, GIANT Consortium, medicine, Genetics, CORONARY-HEART-DISEASE, ddc:610, Molecular Biology, PERICARDIAL FAT, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0604 Genetics, Proteins, nutritional and metabolic diseases, medicine.disease, Obesity, Endocrinology, RISK-FACTORS, Body mass index, Developmental Biology
Abstract

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits., Author Summary Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. We quantified subcutaneous and visceral fat in more than 10,000 women and men who also had genome-wide association data available. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, near the THNSL2 gene. These findings were not observed in men. We also interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed for 7 of these loci, most notably for VAT/SAT ratio. We conclude that genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not uncovered in large-scale GWAS of anthropometric traits.

Published
2012
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28. Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Author

Seppo Koskinen, Christian Herder, Daniel I. Chasman, Andrew R. Wood, Jonna L. Grimsby, J.F. Wilson, Day Inm., Massimo Mangino, Gonneke Willemsen, Robert W. Mahley, Cristian Pattaro, Nicole L. Glazer, T.B. Harris, Irene Pichler, M S Sandhu, D. van Heemst, Christine Proença, Martha Ganser, Robert A. Hegele, Richa Saxena, Eleftheria Zeggini, Markku Laakso, Peter Kraft, Judith B. Borja, Karen L. Mohlke, J B Richards, de Geus Ejc., Robert Sladek, Cristen J. Willer, Samy Hadjadj, S.M. Boekholdt, Gina M. Peloso, Kijoung Song, Sutapa Mukherjee, Gudmar Thorleifsson, Winston Hide, Mark I. McCarthy, Ruth E. Pakyz, Marian Beekman, Ayellet V. Segrè, Inga Prokopenko, Ping An, George Dedoussis, Danielle Posthuma, Jeanette Erdmann, Simon J. Griffin, Nilesh J. Samani, Inke R. König, Frank B. Hu, Lokki M-L., David M. Evans, Xiaohui Li, Valgerdur Steinthorsdottir, Aimo Ruokonen, A Pouta, Kerrin S. Small, Cecilia M. Lindgren, O Le Bacquer, Xijing Han, Florian Kronenberg, E Katsareli, Christian Dina, S. Gabriel, Jochen Spranger, James S. Pankow, M. Kloppenburg, Penninx Bwjh., Torben Hansen, Josh Smith, Jennie Hui, Gordon H. Williams, Mark Seielstad, Ingrid B. Borecki, Weihua Zhang, Peter P. Pramstaller, Stephen J. Sharp, Neil R. Robertson, Zee Ryl., Mike Sampson, Angela Silveira, C.M. van Duijn, Anders Hamsten, Peter Shrader, Denis Rybin, Chen Y-Di., Gunnar Sigurdsson, Michael Stumvoll, Russel Tracy, Mark O. Goodarzi, Göran Hallmans, Michael R. Erdos, Valeriya Lyssenko, Juha Saharinen, Sven Bergmann, Jeffrey R. O'Connell, Debbie A Lawlor, Thomas Meitinger, Yvonne Böttcher, Jérôme Delplanque, Sarah G. Buxbaum, Silvia Naitza, Shah Ebrahim, Graham A. Hitman, Angelo Scuteri, Aroon D. Hingorani, Heribert Schunkert, François Pattou, Claudia Lamina, A L Elliott, Sekar Kathiresan, Dawn M. Waterworth, Jennifer A. Brody, Thomas Quertermous, Leena Peltonen, Josephine M. Egan, Daniel J. Rader, J F Peden, Yarnell Jwg., Daniel S. 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Subjects
Netherlands Twin Register (NTR), Male, Insulin Resistance/genetics, VARIANTS, 0302 clinical medicine, POPULATION, African Americans, blood/genetics, 0303 health sciences, education.field_of_study, Adiponectin/blood, Adiponectin/genetics, Asian Continental Ancestry Group, Cholesterol, HDL/genetics, Diabetes Mellitus, Type 2/genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Global B Pgen Consortium, MAGIC investigators, 3. Good health, Cholesterol, Medicine, Adiponectin, Type 2, medicine.medical_specialty, HDL, Biolääketieteet - Biomedicine, Single-nucleotide polymorphism, DIAGRAM Consortium, White People, Molecular Genetics, GLGC Consortium, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, GIANT Consortium, Diabetes Mellitus, Genetics, DIAGRAM+ Consortium, GENOME-WIDE ASSOCIATION, Polymorphism, education, Biology, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, Science & Technology, GLGC Investigators, nutritional and metabolic diseases, ta3121, medicine.disease, Obesity, Black or African American, blood/genetics, African Americans, Asian Continental Ancestry Group, Cholesterol, genetics, Diabetes Mellitus, genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, genetics, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Endocrinology, Diabetes Mellitus, Type 2, Developmental Biology, Type 2/genetics, Cancer Research, Type 2 diabetes, QH426-470, 030204 cardiovascular system & hematology, LIPID CONCENTRATIONS, GENETICS & HEREDITY, Genetics (clinical), RISK, 2. Zero hunger, INSULIN-RESISTANCE, Glucose tolerance test, medicine.diagnostic_test, MAGIC Consortium, Single Nucleotide, ADIPOSE-TISSUE, CORONARY-ARTERY-DISEASE, Life Sciences & Biomedicine, Research Article, Clinical Research Design, GENETIC-BASIS, Population, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, ddc:610, 030304 developmental biology, RECEPTOR, Cholesterol, HDL, Human Genetics, HDL/genetics, 3121 General medicine, internal medicine and other clinical medicine, MuTHER Consortium, 3111 Biomedicine, Procardis Consortium, Insulin Resistance
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p, Author Summary Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.

Published
2012
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