Genetic Determinants of Visceral Adiposity

描述（由申请人提供）：尽管肥胖与多种慢性健康状况有关，但内脏脂肪组织（VAT）的过度沉积更一致地与代谢异常（糖尿病和血脂异常）和心血管疾病（CVD）相关，即使在非肥胖的老年人中也是如此。过高的VAT被认为是聚集性代谢危险因素的基础，包括血脂异常、血压升高和高血糖。该项目的总体目标是确定内脏肥胖的遗传决定因素。一种分阶段的方法旨在从基因组全关联（GWA）研究（巢在健康衰老和身体组成（Health ABC）研究中）转移到五个相似表型（计算机断层扫描（CT）测量的VAT）独立研究中最有希望的snp的复制。具体而言，提出了以下两个目标。目的1：在健康ABC研究的2400名受试者（随机选择1200名欧洲裔美国人（EA）和1200名非洲裔美国人（AA））中，确定常见单核苷酸多态性（snp）与ct测量的vat1之间的关系。1200个ea和1200个aa将分别使用Illumina 550K和650K芯片进行基因分型。snp将使用结合统计学显著性、先前基因组证据（如连锁研究）和其他优先指标（如潜在功能显著性）的算法进行排序，以确定每个种族群体中最有希望的768个vat相关snp。目的2：采用两阶段序列设计，在五个独立的重复队列中证实或反驳来自Health ABC的最有希望的vat相关snp。在第一阶段，两个队列，Framingham心脏研究（FHS， 3329个ea）和Jackson心脏研究（JHS， 4605个ea），将分别用于跟踪来自Heath ABC的ea和aa的有希望的768个VAT相关snp。在II期，其他三个队列，年龄，基因/环境易感性-雷克雅未克（AGES-Reykjavik， 5764个EAs）研究，动脉粥样硬化多种族研究（MESA， 787个EAs， 411个AAs A）和胰岛素抵抗动脉粥样硬化家族研究（IRAS， 600个AAs），将用于进一步验证在FHS或JHS中复制的snp（可能10-15）。此外，现有的GWA研究（例如FHS和MESA SHARe以及未来的其他研究）将允许对直接或通过LD （r2e0.8）基于HapMap项目数据捕获的snp进行直接的计算机复制和前瞻性meta分析。总的来说，这项研究提供了一个独特的机会来发现参与内脏脂肪积累的基因（及其变异），并可能为许多肥胖相关疾病的病理生理学、预防和有希望的治疗靶点提供新的见解。公共卫生相关性：腹部脂肪量与糖尿病、胆固醇异常和心脏病有关。我们建议研究决定腹部脂肪量的遗传因素。确定这些遗传因素可能有助于在相对较早的年龄确定谁有患脂肪相关疾病的风险，并需要积极治疗以预防脂肪相关疾病。

DESCRIPTION (provided by applicant): Although obesity is associated with a variety of chronic health conditions, excess deposition of visceral adipose tissue (VAT) is more consistently associated with metabolic abnormalities (diabetes and dyslipidemia) and cardiovascular disease (CVD), even in non-obese older adults. Excess VAT is postulated to underlie clustered metabolic risk factors including dyslipidemia, elevated blood pressure and high plasma glucose. The overall goal of this project is to identify genetic determinants of visceral adiposity. A staged approach is designed to move from a genome wide association (GWA) study - nested in the Health Aging and Body Composition (Health ABC) Study - to replication of the most promising SNPs in five similarly-phenotyped (computed tomography (CT)-measured VAT) independent studies. Specifically, the following two aims are proposed. Aim 1: To determine the association between common single nucleotide polymorphisms (SNPs) and CT-measured VATamong a total sample of 2,400 subjects from the Health ABC study (1200 randomly selected European Americans (EA) and 1200 African Americans (AA)). The 1200 EAs and1200 AAs will be genotyped using Illumina 550K and 650K chips, respectively. SNPs will be rank-ordered using an algorithm incorporating statistical significance, prior genomic evidence (e.g., linkage studies), and other indicators of priority (e.g., potential functional significance) to identify the most promising 768 VAT-associated SNPs for each ethnic group. Aim 2: To confirm or refute most promising VAT-associated SNPs from Health ABC in five independent replication cohorts using two-stage sequential design. In Stage I, Two cohorts, the Framingham Heart study (FHS, 3329 EAs) and Jackson Heart study (JHS, 4605 AAs), will be used to follow up the promising 768 VAT- associated SNPs for EAs and AAs from Heath ABC, respectively. In stage II, three other cohorts, the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik, 5764 EAs) Study, the Multi-Ethnic Study of Atherosclerosis (MESA, 787 EAs, 411 AAs A), and the Insulin Resistance Atherosclerosis Family Study (IRAS, 600 AAs), will be used to further validate those SNPs (probably 10-15) replicated in FHS or JHS. In addition, the available GWA studies (e.g. FHS and MESA SHARe and future others) will allow for direct in silico replication and prospective meta-analysis of SNPs captured either directly or through LD (r2e0.8) based on data from the HapMap project. In aggregate, the proposed study provides a unique opportunity to discover genes (and their variants) involved in visceral fat accumulation and may provide novel insights into the pathophysiology, prevention and promising therapeutic targets for a number of obesity-related disorders. PUBLIC HEALTH RELEVANCE: The amount of fat in the abdomen is associated with diabetes, abnormal cholesterol, and heart disease. We propose studying genetic factors that determine the amount of fat in the abdomen. Identification of these genetic factors may help to determine, at a relatively early age, who is at risk of fat related diseases and needs aggressive treatment to prevent the fat related diseases.