Racial Genomic Differences and Heart Failure Outcomes

描述（由申请人提供）：在心力衰竭受试者中，遗传变异会影响临床结果和对治疗的反应。心力衰竭是一种多基因疾病，特定基因多态性的影响会受到遗传背景的影响。对于一些对心力衰竭发病机制至关重要的基因，在白人和黑人人群中，不良等位基因的患病率存在显著差异。目前的提案将招募1000名因收缩功能障碍而心力衰竭的受试者，包括500名白人受试者和500名黑人受试者，并将检查遗传背景的种族差异对左心室功能和临床结果的影响。特异性目的1将评估遗传背景对500名黑人慢性心力衰竭患者和500名白人患者左室射血分数（LVEF）和左室舒张直径的影响。该提案将重点关注关键心力衰竭介质的不良等位基因，包括ACE缺失、醛固酮合成酶启动子-344C、NOS3 Asp298和betal Arg389变体。特异性目标2将调查目标1中的不良等位基因对整个队列以及黑人和白人亚群生存的影响。具体目标3将探讨基因-基因相互作用，以检查ACE D等位基因的影响是否被GNB3 T单倍型的共遗传修饰。这种多态性与α -肾上腺素能激活增加和血浆肾素低有关，在黑人人群中更为普遍。特异性目标3将在黑人心力衰竭队列中探索混合连锁不平衡（MALD）制图的使用，该方法利用非洲和欧洲起源的基因组DMA进行比较，以确定基因组学对重塑和心力衰竭结果的明显种族差异的潜在贡献。

DESCRIPTION (provided by applicant): In subjects with heart failure, genetic variation will affect clinical outcomes and the response to therapy. Heart failure is a polygenic disorder, and the impact of specific genetic polymorphisms will be influenced by genetic background. For several genes critical to heart failure pathogenesis, the prevalence of adverse alleles differs significantly between white and black cohorts. The current proposal will enroll one thousand subjects with heart failure due to systolic dysfunction including 500 white subjects and 500 black subjects, and will examine the impact of racial differences in genetic background on left ventricular function and clinical outcomes. Specific Aim 1 will evaluate the impact of genetic background on left ventricular ejection fraction (LVEF) and LV diastolic diameter in 500 black subjects with chronic heart failure and a matched cohort of 500 white subjects. The proposal will focus on adverse alleles of key heart failure mediators including the ACE deletion, aldosterone synthase promoter -344C, NOS3 Asp298, and betal Arg389 variants. Specific Aim 2 will investigate the impact of the adverse alleles from aim 1 on survival in the overall cohort and separately in the black and white subsets. Specific aim 3 will explore gene-gene interactions to examine whether the impact of the ACE D allele is modified by coinheritance of the GNB3 T haplotype. This polymorphism is linked to increased alpha adrenergic activation and low plasma renin and is far more prevalent in black cohorts. Specific Aim 3 will explore in the black heart failure cohort the use of Mapping by Admixture Linkage Disequilibrium (MALD), which utilizes comparisons of genomic DMA of African and European orgin, to determine the potential contributions of genomics to apparent racial differences in remodeling and heart failure outcomes. This proposal will address an important clinical question and will provide an ideal program for mentoring young investigators in the methodologies involved in genetics outcomes research.