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

非洲裔美国人对心力衰竭治疗增强反应的基因组分析

• 批准号: 8776074
• 负责人: DENNIS M. MCNAMARA
• 金额: $ 40.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776074
• 关键词: Admixture; African; African American; American; Americas; Blood Pressure; Caliber; Clinical; DNA; Data; Development; Dose; EFRAC; Echocardiography; Effectiveness; Enrollment; Evaluation; GNB3 gene; GNB3 protein; GTP-Binding Proteins; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genomic DNA; Genomics; Genotype; Goals; Haplotypes; Heart failure; Hospitalization; Hydralazine; Hypertension; Individual; Investigation; Isosorbide Dinitrate; Left Ventricular Ejection Fraction; Left Ventricular Function; Link; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Population; Positioning Attribute; Proteins; Quality of life; RNA Splicing; Race; Role; Systolic heart failure; Therapeutic; Variant; base; cohort; genetic analysis; improved; low renin hypertension; mortality; public health relevance; response

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.

描述（由申请人提供）：与类似的白色同学相比，在心力衰竭和射血分数（HFREF）降低的非洲裔美国人中，异氧化二氮和氢化吡疑（FDC I/H）的固定剂量组合对治疗的反应得到了增强。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％的黑人受试者处方了该药物，他们可能会受益。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子单位GNB3的遗传变异已被广泛研究其在高血压中的作用。在825（t/c）的位置存在多态性，该位置在功能上保持沉默，但与剪接变体紧密相关，导致截短的蛋白质。 GNB3 T单倍型在黑色中更为普遍，并且与肾素高压低有关。对AHEFT遗传亚研究者中350名受试者的评估表明，在50％的非裔美国人中发现的GNB3 TT基因型，但只有10-15％的白人与对FDC I/H的治疗反应有关。该提案将评估以下假设：在患有HFREF的非裔美国人中，GNB3 TT基因型是增强对FDC I/H的治疗反应的标志。该研究将招募500名非裔美国人与HFREF一起使用FDC I/H启动治疗，并最多关注两年。 GNB3多态性和对基因型的治疗的反应将在进入时对受试者进行基因分型。将使用复合评分，AHEFT的主要终点来量化治疗反应，该综合评分纳入了死亡率，心力衰竭住院和QOL评分的变化。 AIM 2将对GNB3基因型对治疗的反应进行类似的分析，并在六个月的治疗后通过超声心动图对LVEDD或LVE​​F进行了改进，作为结果测量。 AIM 3将使用混合分析来确定首先确定全球血统（一个非洲祖先DNA的一个人）如何影响药物反应的结果度量，以及全球祖先如何成为GNB3效果的修饰符。