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

描述（由申请方提供）：与相似的白色队列相比，患有心力衰竭和射血分数降低（HFrEF）的非裔美国人对硝酸异山梨酯和肼苯哒嗪固定剂量复方制剂（FDC I/H）治疗的反应增强。尽管FDC I/H在非裔美国人心力衰竭试验（AHeFT）中具有明显的生存获益，但该药物仅在25%的黑人受试者中使用。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亚基GNB 3的遗传变异因其在高血压中的作用而被广泛研究。多态性存在于位置825（T/C）处，其在功能上沉默，但与剪接变体紧密连接，导致截短的蛋白质。GNB 3 T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例受试者进行的评价表明，在50%的非洲裔美国人中发现的GNB 3 TT基因型，但仅在10-15%的白人中发现，与FDC I/H的治疗反应增强有关。该提案将评估GNB 3 TT基因型是非裔美国人HFrEF患者对FDC I/H治疗反应增强的标志物这一假设。该研究将招募500名患有HFrEF的非洲裔美国人，开始FDC I/H治疗并随访长达两年。受试者将在入组时进行GNB 3多态性基因分型，并按基因型比较对治疗的反应。将使用综合评分（AHeFT的主要终点，包括死亡率、心力衰竭住院率和6个月时QoL评分的变化）量化治疗反应。目标2将使用治疗6个月后通过超声心动图测定的LVEDD或LVEF改善作为结局指标，通过GNB 3基因型对治疗反应进行类似分析。目标3将使用混合物分析首先确定全球血统（个体的非洲祖先DNA %）如何影响药物应答的结果指标，以及全球血统如何作为GNB 3效应的修饰剂。

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.