Obesity has become an epidemic in the United States and worldwide. During the past few years, genome-wide association studies (GWAS) have identified ~50 loci for obesity. However, those loci only account for small proportion (<5%) of the heritability of obesity, and the current GWAS have given us little insight into how these genetic variants are linked with obesity, and how they may response to environment (diet and lifestyle) modulation. The goal of this study is to address these GWAS limitations to provide further insights into a system-based understanding of the genetics of obesity. We propose to apply newly-developed pathway-based analysis by combining functional pathways, genetics of gene expression (GGE) analysis, and genome scans to identify novel obesity loci beyond conventional GWAS, in 11,577 men and women from the Nurses'Health Study (NHS) and Health Professionals'Follow-up Study (HPFS) with genome scans. The in silico validation will be performed in Framingham Heart Study (N=9,171) and GIANT consortium (N=121,600). We will determine the newly-identified and the established obesity variants in 811 individuals from a 2-year randomized diet intervention study, the POUNDS LOST trial. We will examine genetic effects on the 2-year weight changes in response to weight-loss diets varying in macronutrient compositions. The validation will be conducted in a separately-funded 2-year weight-loss trial, the Dietary Intervention Randomized Controlled Trial (DIRECT, n=322). We will also assess the genetic effects on the markers regulating energy intake and energy expenditure, including: 1) psychiatric measures for food craving, fullness, and hunger;2) energy expenditure (resting metabolic rate [RMR] and total energy expenditure [TEE]);3) biochemical markers of brain-gut- adipose axis, including leptin, insulin, glucose, ghrelin, GLP-1, adiponectin and RBP4;and 4) adipose gene expression profile. Because the genome-wide scans, diet intervention, and measures of energy intakes and expenditure, adipose gene expression, as well as body composition are funded through other grants, the proposed project will be extremely cost-effective. We have assembled a solid group of experienced collaborators with expertise in genetic epidemiology, statistics, pathway GGE analyses, clinical trial, obesity and nutrition. We believe that the unprecedented resources available in this project will provide a unique opportunity to identify novel genetic factors for obesity, and to get insights into the mechanisms of genetic and dietary factors in controlling long-term weight change in humans.

Public Health Relevance

The proposed study integrating novel pathway GGE analyses in large cohorts and comprehensive analyses on the genetic effects on long-term weight loss and mechanisms in response to weight-loss diets in randomized intervention trials would provide extraordinarily important and novel evidence to unravel theetiology of obesity, and have significant public health and clinical implications. Establishing relationship between genetic variants and diets in determining weight change will help identify individuals at high risk for obesity especially when adherent to specific diet. In addition, identifying genes related to energy intakes and expenditure relating to weight change should enable the discovery of new prevention and pharmaceutical treatment for obesity, and could significantly enhance the effectiveness of clinical patient care and assist personalized dietary approaches in prevention of obesity and related metabolic disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Karp, Robert W
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Harvard University
Schools of Public Health
United States
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Xu, Min; Huang, Tao; Lee, Albert W et al. (2016) Ready-to-Eat Cereal Consumption with Total and Cause-Specific Mortality: Prospective Analysis of 367,442 Individuals. J Am Coll Nutr 35:217-23
Wang, T; Huang, T; Zheng, Y et al. (2016) Genetic variation of fasting glucose and changes in glycemia in response to 2-year weight-loss diet intervention: the POUNDS LOST trial. Int J Obes (Lond) 40:1164-9
Ma, Wenjie; Huang, Tao; Zheng, Yan et al. (2016) Weight-Loss Diets, Adiponectin, and Changes in Cardiometabolic Risk in the 2-Year POUNDS Lost Trial. J Clin Endocrinol Metab 101:2415-22
Ma, Wenjie; Li, Yanping; Heianza, Yoriko et al. (2016) Associations of Bowel Movement Frequency with Risk of Cardiovascular Disease and Mortality among US Women. Sci Rep 6:33005
Heianza, Yoriko; Ma, Wenjie; Huang, Tao et al. (2016) Macronutrient Intake-Associated FGF21 Genotype Modifies Effects of Weight-Loss Diets on 2-Year Changes of Central Adiposity and Body Composition: The POUNDS Lost Trial. Diabetes Care 39:1909-1914
Wang, Tiange; Liu, Huikun; Wang, Leishen et al. (2016) Zinc-Associated Variant in SLC30A8 Gene Interacts With Gestational Weight Gain on Postpartum Glycemic Changes: A Longitudinal Study in Women With Prior Gestational Diabetes Mellitus. Diabetes 65:3786-3793
Wang, Tiange; Huang, Tao; Li, Yanping et al. (2016) Low birthweight and risk of type 2 diabetes: a Mendelian randomisation study. Diabetologia 59:1920-7
Zheng, Yan; Xu, Min; Li, Yanping et al. (2016) Gallstones and Risk of Coronary Heart Disease: Prospective Analysis of 270 000 Men and Women From 3 US Cohorts and Meta-Analysis. Arterioscler Thromb Vasc Biol 36:1997-2003
Zheng, Yan; Li, Yanping; Qi, Qibin et al. (2016) Cumulative consumption of branched-chain amino acids and incidence of type 2 diabetes. Int J Epidemiol 45:1482-1492
Zheng, Yan; Ceglarek, Uta; Huang, Tao et al. (2016) Plasma Taurine, Diabetes Genetic Predisposition, and Changes of Insulin Sensitivity in Response to Weight-Loss Diets. J Clin Endocrinol Metab 101:3820-3826

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