Genetic Determinants of Visceral Adiposity

内脏肥胖的遗传决定因素

基本信息

批准号：
8220801
负责人：
YONGMEI LIU
金额：
$ 83.26万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/8220801
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

项目摘要

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）：虽然肥胖与多种慢性健康状况相关，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。据推测，过高的增值税是导致血脂异常、血压升高和高血糖等代谢危险因素的基础。该项目的总体目标是确定内脏肥胖的遗传决定因素。分阶段的方法旨在从全基因组关联 (GWA) 研究（嵌套在健康老龄化和身体成分 (Health ABC) 研究中）转向在五个相似表型（计算机断层扫描 (CT)）中复制最有希望的 SNP测量增值税）独立研究。具体而言，提出以下两个目标。目标 1：在 Health ABC 研究的 2,400 名受试者（随机选择的 1200 名欧洲裔美国人 (EA) 和 1200 名非裔美国人 (AA)）的总样本中，确定常见单核苷酸多态性 (SNP) 与 CT 测量的 VAT 之间的关联。 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 SNP 进行排序，该算法结合了统计显着性、先前的基因组证据（例如连锁研究）和其他优先指标（例如潜在的功能显着性），以确定每个种族群体中最有希望的 768 个与 VAT 相关的 SNP。目标 2：使用两阶段序贯设计在五个独立的复制队列中确认或反驳来自 Health ABC 的最有希望的 VAT 相关 SNP。在第一阶段，两个队列中，Framingham Heart 研究（FHS，3329 EA）和 Jackson Heart 研究（JHS，4605 AA）将分别用于追踪来自 Heath ABC 的 EA 和 AA 有希望的 768 个与 VAT 相关的 SNP 。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-雷克雅未克，5764 个 EA）研究、动脉粥样硬化多种族研究（MESA、787 个 EA、411 个 AA）和胰岛素抵抗动脉粥样硬化家庭研究（IRAS，600 AA），将用于进一步验证 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）将允许基于 HapMap 项目的数据直接或通过 LD (r2e0.8) 捕获的 SNP 进行直接计算机复制和前瞻性荟萃分析。总的来说，拟议的研究提供了一个独特的机会来发现与内脏脂肪积累有关的基因（及其变体），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。公众健康相关性：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。这些遗传因素的识别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。