Genetic Mechanisms of Arteriosclerosis in Hypertensive Sibships

描述（由申请人提供）：动脉病遗传流行病学网络（GENOA）于1995年启动，旨在研究同胞中高血压及其动脉并发症的遗传学。动脉炎（即，动脉粥样硬化和小动脉硬化）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、慢性肾病和跛行。在本申请中，我们建议进行外显子组范围的关联研究（目标1）和转录组学分析（目标2）作为识别和研究1020个GENOA非洲裔美国人和非西班牙裔白色同胞（N=2912）的功能变异的成本效益的方法，这些同胞具有发展广泛动脉炎临床结局的高风险。GENOA队列提供了一个独特的机会来评估罕见变异的表型影响，这些变异在亲缘关系中自然复制，但即使在大的流行病学人群中也可能不会再次出现。GENOA以社区为基础的高血压同胞抽样明确旨在研究多种迟发性动脉炎疾病的遗传学， 通常只有在家族的上一代才变得临床明显。为了最终确定“处于风险中”的个体并估计两个美国人群中遗传风险等位基因的累积负担（目标3），我们将估计遗传风险评分并评估由这些新的遗传变异解释的表型变异的可归因分数。

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.