Genetic analysis fo metabolic syndrome by admixture mapping in African Americans

描述（由申请人提供）：代谢综合征是一系列心血管风险因素，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。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，估计影响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。非洲裔美国人往往比欧洲裔美国人具有更大的胰岛素抵抗和更高的血压;相反，欧洲裔美国人具有更多的致动脉粥样硬化脂质谱。在非裔美国人中，一些代谢综合征特征与非洲血统相关（胰岛素抵抗，血压），其他特征与欧洲血统相关（内脏脂肪，低HDL胆固醇，高甘油三酯），这表明调节这些特征的不同遗传变异已从两个祖先人群中遗传。我们假设，在非裔美国人中，代谢综合征特征的遗传位点可以通过混合作图来确定。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，其在祖先群体之间具有高等位基因频率差异。混合位点共享连锁不平衡与祖先的信息标记在大的基因组片段，可以使用相对较少的遗传标记进行映射，相比全基因组关联研究。我们建议对来自心血管健康研究（CHS）和健康、衰老和身体成分研究（HABC）的2000名非洲裔美国人的联合队列中的所有代谢综合征特征进行混合映射。我们将通过与来自杰克逊心脏研究（JHS）的混合标测结果的联合分析来验证我们的发现。我们将对以下定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以及血压。我们将特别关注腹部内脏脂肪在代谢综合征中的作用，通过比较在调整和不调整内脏脂肪负荷的情况下绘制MetS性状的结果。内脏脂肪测量在HABC和JHS中是唯一可用的，HABC和JHS之间的合作将提供一个新颖而独特的机会，以确定影响代谢综合征特征的遗传位点，而不受内脏脂肪的深刻影响。我们将在两个独立队列的联合分析中验证结果。我们的最终目标是在分析的性状中对4-6个最有希望的候选位点进行精细定位，以确定潜在的致病变异。在一个大型的混合家系队列中分析代谢综合征特征的遗传影响，将阐明代谢综合征特征和患病率的人群差异的病因，并为研究人群特异性管理和治疗奠定基础。 公共卫生相关性：代谢综合征是一种日益普遍的健康问题，影响着四分之一的美国人，患有腹部肥胖、高胆固醇和葡萄糖水平以及高血压，并增加了患糖尿病、中风和心脏病的风险。我们将通过非裔美国人的遗传图谱来识别与代谢综合征相关的基因，这些非裔美国人从他们的非洲和欧洲祖先那里继承了不同的遗传变异;这些遗传模式使得更容易找到与疾病相关的遗传变化。我们的工作将提高对基因和生活方式对不同种族人群中代谢综合征发病、进展和风险的影响的理解，并在未来帮助开发特定的疾病管理和治疗方法，以减轻代谢综合征对健康的负面影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: People with metabolic syndrome, an increasingly common health problem affecting a quarter of all Americans, have abdominal obesity, high blood cholesterol and glucose levels and high blood pressure, and have increased risk of diabetes, stroke and heart disease. We will identify genes related to metabolic syndrome by genetic mapping in African Americans, who have inherited different genetic variants from their African and European ancestors; these inheritance patterns make it easier to find genetic changes associated with disease. Our work will improve understanding of the effects of genes and lifestyle on the onset, progression and risks of Metabolic Syndrome in different ethnic groups, and, in the future, help develop specific disease management and treatment approaches to lessen the negative impact of Metabolic Syndrome on health.