Obesity Genes, Energy Regulation in Response to Weight-Loss Diets

描述（由申请人提供）：肥胖在美国和世界范围内已经成为一种流行病。在过去的几年中，全基因组关联研究（GWAS）已经确定了大约50个与肥胖有关的基因座。然而，这些基因座只占肥胖遗传率的一小部分（<5%），目前的GWAS对这些遗传变异如何与肥胖联系以及它们如何对环境（饮食和生活方式）调节作出反应知之甚少。本研究的目的是解决这些GWAS的局限性，为肥胖遗传学的系统理解提供进一步的见解。我们建议应用新发展的基于途径的分析，结合功能途径、基因表达遗传学（GGE）分析和基因组扫描，在来自护士健康研究（NHS）和卫生专业人员随访研究（HPFS）的11,577名男性和女性中，识别传统GWAS之外的新型肥胖位点。计算机验证将在Framingham Heart Study （N= 9171）和GIANT consortium （N=121,600）中进行。我们将从一项为期2年的随机饮食干预研究（POUNDS lose试验）中确定811名个体中新发现的和已确定的肥胖变异。我们将研究基因对2年体重变化的影响，以应对减肥饮食中不同的宏量营养素组成。验证将在一项单独资助的2年减肥试验中进行，即饮食干预随机对照试验（DIRECT, n=322）。我们还将评估基因对调节能量摄入和能量消耗标记的影响，包括：1)对食物渴望、饱腹感和饥饿的精神病学测量；2)能量消耗（静息代谢率[RMR]和总能量消耗[TEE]）；3)脑肠脂肪轴生化指标：瘦素、胰岛素、葡萄糖、胃饥饿素、GLP-1、脂联素、RBP4；4)脂肪基因表达谱。由于全基因组扫描、饮食干预、能量摄入和消耗、脂肪基因表达以及身体成分的测量都是通过其他资助资助的，因此拟议的项目将极具成本效益。我们在遗传流行病学、统计学、通路GGE分析、临床试验、肥胖和营养方面拥有丰富的经验。我们相信，这个项目中前所未有的资源将为识别肥胖的新遗传因素提供一个独特的机会，并深入了解遗传和饮食因素在控制人类长期体重变化中的机制。

DESCRIPTION (provided by applicant): 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.