Genetic Mechanisms of Arteriosclerosis in Hypertensive Sibships

简介（由申请人提供）：动脉病变遗传流行病学网络（GENOA）成立于1995年，旨在研究兄弟姐妹中高血压及其动脉硬化并发症的遗传学。心脏、大脑、肾脏和外周动脉的动脉硬化（即动脉粥样硬化和小动脉硬化）会导致靶器官损伤和临床后遗症，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，我们建议进行全外显子组关联研究（Aim 1）和转录组分析（Aim 2），作为识别和研究1020名热那亚非洲裔和非西班牙裔白人兄弟姐妹（N=2912）的功能变异的成本效益方法，这些人有发生各种动脉硬化临床结果的高风险。热那亚队列提供了一个独特的机会来评估在兄弟姐妹中自然复制的罕见变异的表型影响，但即使在大型流行病学人群中也可能不会再看到。热那亚社区高血压兄弟姐妹抽样明确设计用于研究多种迟发性动脉硬化疾病的遗传学

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.