Genetic analysis fo metabolic syndrome by admixture mapping in African Americans

项目总结/摘要 代谢综合征是一系列心血管危险因素，包括腹部肥胖， 致动脉粥样硬化性血脂异常、高血压、胰岛素抵抗以及促炎和促血栓形成状态。一 代谢综合征是2型糖尿病和早发性心血管疾病的主要危险因素， 估计有25%的美国人。代谢综合征的特征在不同的种族群体之间存在差异。非裔美国人倾向于 有更大的胰岛素抵抗和更高的血压比欧洲裔美国人;相反，欧洲- 美国人有更多的致动脉粥样硬化的血脂谱。在非裔美国人中， 与非洲血统相关（胰岛素抵抗，血压），其他特征与欧洲血统相关 祖先（内脏脂肪，低HDL胆固醇，高甘油三酯），这表明不同的遗传变异， 调节这些性状的基因是从两个祖先群体遗传而来的。我们假设基因 代谢综合征特征的基础基因座可以通过非洲人的混合作图来鉴定， 美国人混合作图是一种全基因组的方法，用于识别疾病相关的遗传 变异，在祖先群体之间具有高等位基因频率差异。混合位点份额 连锁不平衡与祖先信息标记跨越大的基因组片段，并可以映射 与全基因组关联研究相比，使用相对较少的遗传标记。 我们建议在一个联合队列中对所有代谢综合征特征进行混合作图 来自心血管健康研究（CHS）和健康，衰老和身体的2000名非洲裔美国人 组成研究（HABC）。我们将通过混合映射结果的联合分析来验证我们的发现 来自杰克逊心脏研究（JHS）。我们将对以下数量性状进行混合作图， 单独和主成分分析后：腹部脂肪，肥胖，空腹血糖和胰岛素， 甘油三酯、HDL和LDL胆固醇、血清炎症和血栓形成标志物和血压。 我们将特别关注腹部内脏脂肪在代谢综合征中的作用， 结果从映射MetS性状有和没有调整内脏脂肪负荷。内脏脂肪测定 在HABC和JHS中是独一无二的，HABC和JHS之间的合作将提供一种新颖的， 独特的机会，以确定影响代谢综合征性状的基因位点，独立于 内脏脂肪的影响我们将在两个独立队列的联合分析中验证结果。 我们的最终目标是对性状中最有希望的4-6个候选位点进行精细定位 分析以确定潜在的致病变量。 在一个大的混合祖先队列中剖析遗传对代谢综合征特征的影响， 阐明代谢综合征特征和患病率的人群差异的病因， 研究特定人群管理和治疗的基础。

Project Summary/Abstract Metabolic syndrome is a constellation of cardiovascular risk factors including abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, and a pro-inflammatory and pro-thrombotic state. A major risk factor for type 2 diabetes and early-onset cardiovascular disease, metabolic syndrome affects an estimated 25% of Americans. Metabolic syndrome traits differ among ethnic groups. African-Americans tend to have greater insulin-resistance and higher blood pressure than European-Americans; conversely, European- Americans have more atherogenic lipid profiles. In African-Americans, some metabolic syndrome traits correlate with African ancestry (insulin resistance, blood pressure), and others traits correlate with European ancestry (visceral fat, low HDL cholesterol, high triglycerides), suggesting that distinct genetic variants modulating these traits have been inherited from the two ancestral populations. We hypothesize that genetic loci underlying metabolic syndrome traits can be identified by admixture mapping in African- Americans. Admixture mapping is a genome-wide approach for identifying disease-associated genetic variants, which have a high allele frequency difference between ancestral populations. Admixture loci share linkage disequilibrium with ancestry-informative markers across large genomic segments and can be mapped using relatively few genetic markers, compared to genome-wide association studies. We propose to perform admixture mapping for all metabolic syndrome traits in a combined cohort of 2000 African-Americans from the Cardiovascular Health Study (CHS) and the Health, Aging and Body Composition Study (HABC). We will validate our findings via joint analyses with admixture mapping results from the Jackson Heart Study (JHS). We will perform admixture mapping for the following quantitative traits, individually and after principal component analysis: abdominal fat, obesity, fasting glucose and insulin, triglycerides, HDL and LDL cholesterol, serum inflammatory and thrombotic markers, and blood pressure. We will specifically focus on the role of abdominal visceral fat in metabolic syndrome by comparing results from mapping MetS traits with and without adjusting for visceral fat burden. Visceral fat measurement is uniquely available in HABC and JHS, and the collaboration between HABC and JHS will provide a novel and unique opportunity to identify genetic loci affecting metabolic syndrome traits independently of the profound effect of visceral fat. We will validate findings in joint analyses of the two independent cohorts. Our final goal is to perform fine mapping for the 4-6 most promising candidate loci among the traits analyzed to identify the underlying causative variants. Dissection of genetic influences on metabolic syndrome traits in a large ancestry-admixed cohort will illuminate the etiology of population differences in metabolic syndrome characteristics and prevalence and lay the foundation for research into population-specific management and treatment.