Racial Genomic Differences and Heart Failure Outcomes

描述(申请人提供)：在心力衰竭的受试者中，基因变异将影响临床结果和治疗反应。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。对于心力衰竭发病机制的几个关键基因，白人和黑人队列中不利等位基因的流行率显著不同。目前的计划将招募1000名因收缩功能障碍而患有心力衰竭的受试者，其中包括500名白人受试者和500名黑人受试者，并将研究遗传背景中的种族差异对左心功能和临床结果的影响。具体目标1将评估遗传背景对500名患有慢性心力衰竭的黑人受试者和500名白人受试者的左心室射血分数(LVEF)和左心室舒张期内径的影响。该提案将侧重于关键心力衰竭介质的不利等位基因，包括ACE缺失、醛固酮合成酶启动子-344C、NOS3 Asp298和Betal Arg389变种。特定的目标2将调查来自目标1的不利等位基因对整个队列以及黑人和白人亚组的存活率的影响。具体目标3将探索基因-基因相互作用，以检查ACE D等位基因的影响是否因GNB3T单倍型的共同遗传而改变。这种多态与α肾上腺素能激活增加和血浆肾素降低有关，并且在黑人人群中更为普遍。具体目标3将在黑人心力衰竭队列中探索通过混合物连锁不平衡(MALD)绘制图谱的使用，该方法利用非洲和欧洲来源的基因组DNA的比较，确定基因组学对明显的种族差异重塑和心力衰竭结局的潜在贡献。 这项建议将解决一个重要的临床问题，并将提供一个理想的计划，指导年轻的研究人员参与遗传学结果研究的方法学。

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.