Genetic Determinants of Visceral Adiposity

描述(申请人提供)：虽然肥胖与各种慢性健康状况有关，但内脏脂肪组织(VAT)的过度沉积与代谢异常(糖尿病和血脂异常)和心血管疾病(CVD)更一致，即使在非肥胖的老年人中也是如此。过高的增值税被认为是聚集的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症的遗传决定因素。设计了一种分阶段的方法，从嵌套在健康老龄化和身体成分(Health ABC)研究中的全基因组关联(GWA)研究转移到五项类似表型(计算机断层扫描(CT)测量VAT)的独立研究中复制最有希望的SNPs。具体地说，提出了以下两个目标。目的：从Health 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(SNPs)与CT测量的维生素A(VAT)的相关性。1200个EA和1200个AA将分别使用Illumina 550K和650K芯片进行基因分型。将使用一种算法对SNPs进行排序，该算法结合了统计意义、先前的基因组证据(例如，连锁研究)和其他优先指标(例如，潜在的功能意义)，以确定每个种族群体中最有希望的768个与增值税相关的SNPs。目的2：采用两阶段序贯设计在5个独立的重复队列中证实或驳斥来自Health ABC的最有希望的增值税相关SNPs。在第一阶段，将使用两个队列，即弗雷明翰心脏研究(FHS，3329个EAs)和杰克逊心脏研究(JHS，4605个AAs)，分别跟踪Heath ABC的768个与增值税相关的SNPs，分别用于EAs和AAs。在第二阶段，另外三个队列，年龄、基因/环境易感性-雷克雅未克(AGEs-Reykjavik，5764 EAs)研究、动脉粥样硬化多种族研究(MESA，787 EAs，411 AAs)和胰岛素抵抗动脉粥样硬化家族研究(IRAs，600 AAs)将被用于进一步验证在FHS或JHS中复制的SNPs(可能是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)将允许直接进行电子复制，并根据HapMap项目的数据对直接或通过LD(r2e0.8)捕获的SNPs进行预期荟萃分析。总而言之，这项拟议的研究为发现与内脏脂肪积累有关的基因(及其变体)提供了一个独特的机会，并可能为一些肥胖相关疾病的病理生理学、预防和有前景的治疗目标提供新的见解。公共卫生相关性：腹部脂肪的数量与糖尿病、异常胆固醇和心脏病有关。我们建议研究决定腹部脂肪含量的遗传因素。识别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.