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

描述(申请人提供)：肥胖症已经成为美国和世界范围内的流行病。在过去的几年里，全基因组关联研究已经确定了大约50个肥胖症基因座。然而，这些基因座只占肥胖遗传率的一小部分(&lt；5%)，而且目前的GWAS研究几乎没有让我们深入了解这些基因变异是如何与肥胖联系在一起的，以及它们可能如何对环境(饮食和生活方式)的调节做出反应。这项研究的目标是解决这些GWAS的局限性，以提供对肥胖遗传学的系统理解的进一步见解。我们建议应用新开发的基于途径的分析，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)和卫生专业人员后续研究(HPFS)的11577名男性和女性中，通过基因组扫描来识别超出传统GWA的新的肥胖基因座。远程验证将在弗雷明翰心脏研究(N=9,171)和巨型联盟(N=121,600)中进行。我们将通过为期两年的随机饮食干预研究--减重试验，在811名个体中确定新发现的和已确定的肥胖变异。我们将研究基因对两年内体重变化的影响，以响应不同常量营养素组成的减肥饮食。验证将在一个单独资助的为期两年的减肥试验中进行，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的标记物的影响，包括：1)对食物渴望、饱满和饥饿的精神措施；2)能量消耗(静息代谢率[RMR]和总能量消耗[TEE])；3)大脑-肠道-脂肪轴的生化标记物，包括瘦素、胰岛素、葡萄糖、生长激素、GLP-1、脂联素和RBP4；以及4)脂肪基因表达谱。由于全基因组扫描、饮食干预以及能量摄入和支出、脂肪基因表达以及身体成分的测量都是通过其他赠款提供资金，因此拟议的项目将具有极高的成本效益。我们已经组建了一支经验丰富的合作者团队，他们在遗传流行病学、统计学、GGE途径分析、临床试验、肥胖和营养方面具有专业知识。我们相信，该项目中可用的前所未有的资源将提供一个独特的机会来确定导致肥胖的新的遗传因素，并深入了解遗传和饮食因素控制人类长期体重变化的机制。

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.