Genetic Determinants of Visceral Adiposity

内脏肥胖的遗传决定因素

• 批准号: 8032529
• 负责人: YONGMEI LIU
• 金额: $ 75.52万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032529
• 关键词: Abdomen; Adipose tissue; Adult; African American; Age; Aging; Algorithms; American; Atherosclerosis; Body Composition; Candidate Disease Gene; Cardiovascular Diseases; Childhood; Cholesterol; Chronic; Clinical; Communities; Computer Simulation; DNA; Data; Databases; Deposition; Development; Diabetes Mellitus; Disease; Dyslipidemias; Early identification; Elderly; Environment; Equation; Ethnic Origin; Ethnic group; European; Family; Family Study; Fatty acid glycerol esters; Framingham Heart Study; Functional disorder; Future; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genomics; Genotype; Glucose; Goals; Health; Heart; Heart Diseases; Heritability; Hypertension; Inflammatory; Insulin Resistance; Intervention; Laboratories; Lead; Linear Regressions; Linkage Disequilibrium; Measures; Meta-Analysis; Metabolic; Non obese; Nonesterified Fatty Acids; Obesity; Pathogenesis; Pathway interactions; Persons; Phenotype; Plasma; Play; Population; Population Study; Predisposition; Prevention; Principal Component Analysis; Regression Analysis; Resources; Risk; Risk Factors; Role; Sampling; Screening procedure; Signal Transduction; Single Nucleotide Polymorphism; Staging; Stratification; Technology; Testing; Tissues; Variant; Visceral; X-Ray Computed Tomography; adipokines; adverse outcome; aging gene; base; cohort; cost efficient; design; diabetes risk; emerging adult; follow-up; gene discovery; genetic variant; genome wide association study; high risk; insight; novel; population based; prevent; programs; prospective; therapeutic target

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.

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）的过多沉积与代谢异常（糖尿病和血脂异常）和心血管疾病（CVD）（即使在非肥胖老年人中）更加一致。假设过量的增值税是基础的聚类代谢危险因素，包括血脂异常，血压升高和高血浆葡萄糖。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嵌套在健康衰老和身体组成（健康ABC）研究中的基因组广泛关联（GWA）研究中转变为复制在五个类似型（计算机断层扫描（CT）的五个类似型（CT）验证）独立研究中的最有希望的SNP。具体而言，提出了以下两个目标。目的1：确定来自健康ABC研究（1200名随机选择的欧洲美国人（EA）和1200名非裔美国人（AA））的常见单核苷酸多态性（SNP）（SNP）（SNP）（SNP）和CT测量的Vatamong之间的关联。 1200 EAS和1200 AA将分别使用Illumina 550K和650K芯片进行基因分型。 SNP将使用包含统计显着性的算法，先前的基因组证据（例如，链接研究）和其他优先级指标（例如潜在功能意义）来确定每个种族最有希望的768个增值税相关SNP。目标2：使用两阶段的顺序设计，在五个独立的复制队列中确认或反驳来自健康ABC的最有希望的增值税相关SNP。在第一阶段，两个队列，弗雷明汉心脏研究（FHS，3329 EAS）和杰克逊心脏研究（JHS，4605 AAS）将分别用于跟踪有希望的768 VAT-与Heath ABC的EAS相关的SNP。在第二阶段中，其他三个同龄人，年龄，基因/环境敏感性-Reykjavik（Ages-reykjavik，5764 EAS）研究，动脉粥样硬化的多民族研究（Mesa，787 EAS，787 EAS，411 AAS A），411 AAS A），以及胰岛素抵抗性动脉粥样硬化家庭研究（可能是10-5），可能是5（IRAS），IRAS，IRAS，IRAS，IRAS（IRAS），附近（IRAS），附近（iraS），附近（iraS），附近（iraS），附近（iraS），附近（iraS aas aas aas aas aas aas aas aas aas aas aas aas aas aas aas aas aas aas aas aas aas aas aas）在FHS或JHS中。此外，可用的GWA研究（例如FHS和MESA共享和未来）将允许基于HAPMAP项目的数据直接或通过LD（R2E0.8）捕获的SNP的计算机复制和前瞻性荟萃分析。总体而言，拟议的研究提供了一个独特的机会，可以发现与内脏脂肪积累有关的基因（及其变体），并可能为许多与肥胖相关疾病的病理生理学，预防和有希望的治疗靶标提供新的见解。 公共卫生相关性：腹部脂肪量与糖尿病，异常胆固醇和心脏病有关。我们建议研究决定腹部脂肪量的遗传因素。这些遗传因素的识别可能有助于确定在相对较早的时候，他们面临脂肪相关疾病的风险，需要积极的治疗以防止脂肪相关疾病。