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

描述（由申请人提供）：肥胖已成为美国和世界范围内的流行病。在过去的几年中，全基因组关联研究（GWAS）已经确定了约50个肥胖基因座。然而，这些基因座只占肥胖遗传率的一小部分（<5%），目前的GWAS几乎没有让我们了解这些遗传变异如何与肥胖相关，以及它们如何对环境（饮食和生活方式）调节做出反应。本研究的目的是解决这些GWAS的局限性，以提供进一步的见解，以系统为基础的理解肥胖的遗传学。我们建议应用新开发的基于途径的分析，通过结合功能途径，基因表达遗传学（GGE）分析和基因组扫描，在11，577名来自护士健康研究（NHS）和健康专业人员随访研究（HPFS）的男性和女性中识别出传统GWAS之外的新肥胖基因座。计算机模拟验证将在Fractional Heart研究（N= 9，171）和GIANT联盟（N= 121，600）中进行。我们将在811名来自2年随机饮食干预研究（POUNDS LOST试验）的个体中确定新发现的和已确定的肥胖变异。我们将研究遗传效应对2年体重变化的影响，以应对大量营养素组成不同的减肥饮食。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）。我们还将评估遗传对调节能量摄入和能量消耗的标志物的影响，包括：1）对食物渴望，饱腹感和饥饿感的精神测量; 2）能量消耗（3）脑-肠-脂肪轴的生化指标，包括瘦素、胰岛素、葡萄糖、生长素释放肽、GLP-1、脂联素和RBP 4;脂肪基因表达谱。由于全基因组扫描、饮食干预、能量摄入和支出、脂肪基因表达以及身体组成的测量都是通过其他赠款资助的，因此拟议的项目将具有极高的成本效益。我们聚集了一批经验丰富的合作者，他们在遗传流行病学，统计学，途径GGE分析，临床试验，肥胖和营养方面具有专业知识。我们相信，该项目中前所未有的资源将提供一个独特的机会，以确定肥胖的新遗传因素，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.