Genetic Mechanisms of Arteriosclerosis in Hypertensive Sibships

描述(申请人提供)：动脉病遗传流行病学网络(Genoa)成立于1995年，目的是研究兄弟姐妹中高血压及其动脉硬化并发症的遗传学。心、脑、肾和外周动脉的动脉硬化(即动脉硬化和动脉硬化)会导致靶器官损害和临床后遗症，如心脏病发作、心力衰竭、中风、痴呆、慢性肾脏疾病和跛行。在这项应用中，我们建议进行外显子组范围的关联研究(目标1)和转录谱分析(目标2)，作为识别和研究1020名热那亚非裔美国人和非西班牙裔白人同胞(N=2912)功能变异的经济有效的方法，这些人具有发展成广泛动脉硬化性临床结果的高风险。热那亚队列提供了一个独特的机会来评估稀有变异的表型影响，这些变异在兄弟姐妹关系中自然复制，但即使在大规模流行病学人群中也可能不会再次出现。热那亚社区高血压同胞抽样明确设计用于研究多种迟发性动脉硬化性疾病的遗传学。 通常在临床上只在上一代家庭中表现明显。为了最终识别“风险”个体并估计两个美国群体(目标3)的遗传风险等位基因的累积负担，我们将估计遗传风险分数，并评估这些新的遗传变异所解释的表型变异的可归因性。

DESCRIPTION (provided by applicant): The Genetic Epidemiology Network of Arteriopathy (GENOA) was initiated in 1995 to study the genetics of hypertension and its arteriosclerotic complications in sibships. Arteriosclerosis (i.e., atherosclerosis and arteriolosclerosis) of the cardiac, cerebral, renal, and peripheral arteries leads to target organ damage and clinical sequelae such as heart attack, heart failure, stroke, dementia, chronic kidney disease, and claudication. In this application, we propose to conduct an exome-wide association study (Aim 1) and transcriptomic profiling (Aim 2) as cost-effective methods of identifying and studying functional variations in the 1020 GENOA African-American and non-Hispanic White sibships (N=2912) who are at high risk of developing a wide range of arteriosclerotic clinical outcomes. The GENOA cohort provides a unique opportunity to assess the phenotypic impact of rare variants that naturally replicate within a sibship, but may not be seen again even in large epidemiological populations. The GENOA community-based sampling of hypertensive sibships was explicitly designed to study the genetics of multiple late-onset arteriosclerotic diseases that typically become clinically apparent only in the upper generations of families. In order to ultimately identify "at risk" individuals and estimate the cumulative burden of genetic risk allele in two U.S. populations (Aim 3) we will estimate genetic risk scores and assess the attributable fraction of phenotypic variation explained by these new genetic variations.