Genomic Analysis of Enhanced Response to Heart Failure Therapy in African America

描述(由申请人提供)：与类似的白人队列相比，患有心力衰竭和射血分数(HFrEF)降低的非裔美国人使用固定剂量的硝酸异山梨酯和呋喃西林(FDC I/H)联合治疗的反应得到增强。尽管在非裔美国人心力衰竭试验(AHeFT)中，FDC I/H具有明显的生存益处，但只有25%的黑人受试者可能受益于该药物。就增强的反应而言，种族可能是基因组背景差异的标志。G蛋白β亚单位GNB3的遗传变异因其在高血压中的作用而被广泛研究。825位(T/C)存在多态，该多态在功能上是沉默的，但与导致蛋白质截短的剪接变异体紧密连锁。GNB3T单倍型在黑人中更为普遍，并与低肾素高血压相关。在AHeFT的遗传子研究中对350名受试者的评估表明，在50%的非裔美国人中发现的GNB3TT基因与对FDC I/H的增强治疗反应有关，但在白人中只有10%-15%。这项建议将评估GNB3TT基因是患有HFrEF的非裔美国人对FDC I/H增强治疗反应的标记的假设。这项研究将招募500名患有HFrEF的非裔美国人，开始FDC I/H治疗，并对他们进行长达两年的跟踪调查。受试者将在进入GNB3基因多态时进行基因分型，并将治疗反应按基因进行比较。治疗反应将使用AHeFT的主要终点综合评分来量化，该评分包括死亡率、心力衰竭住院时间和6个月后QOL评分的变化。目的2将以治疗6个月后超声心动图显示的LVEDD或LVEF的改善作为结果指标，对GNB3基因对治疗的反应进行类似的分析。AIM 3将使用混合分析首先确定全球血统(个人的非洲血统DNA百分比)如何影响药物反应的结果衡量标准，以及全球血统如何作为GNB3效果的修饰物。

DESCRIPTION (provided by applicant): The response to therapy with a fixed dose combination of isosorbide dinitrate and hydralazine (FDC I/H) is enhanced in African Americans with heart failure and reduced ejection fraction (HFrEF) when compared to similar white cohorts. Despite the clear survival benefit with FDC I/H in the African American Heart Failure Trial (AHeFT), the drug is prescribed in only 25% of black subjects who would potentially benefit. In terms of the enhanced response, race is likely a marker of differences in genomic background. Genetic variation of the G protein beta sub unit GNB3 has been studied extensively for its role in hypertension. A polymorphism exists at position 825 (T/C) which is functionally silent but tightly linked to a splicing variant resulting in a truncated protein. The GNB3 T haplotype is far more prevalent in blacks and associated with low renin hypertension. Evaluation of 350 subjects in the genetic sub-study of AHeFT suggests that the GNB3 TT genotype, found in 50% of African Americans but only 10-15% of whites, was linked to an enhanced therapeutic response to FDC I/H. This proposal will evaluate the hypothesis that the GNB3 TT genotype is a marker of enhanced therapeutic response to FDC I/H in African Americans with HFrEF. The study will enroll a cohort of 500 African Americans with HFrEF, initiate therapy with FDC I/H and follow them for up to two years. Subjects will be genotyped at entry for the GNB3 polymorphism and response to therapy compared by genotype. Therapeutic response will be quantified using the composite score, the primary endpoint of AHeFT, which incorporates mortality, heart failure hospitalizations, and a change in QoL score at six months. Aim 2 will do a similar analysis of response to therapy by GNB3 genotype using improvement in LVEDD or LVEF by echocardiogram after six months on therapy as the outcomes measure. Aim 3 will use admixture analysis to determine first how global ancestry (the % African ancestral DNA for an individual) impacts on the outcome measures of drug response, and how the global ancestry acts as a modifier for the effect of GNB3.