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）：与相似的白人队列相比，非裔美国人心力衰竭和射血分数降低（HFrEF）患者对硝酸异山梨酯和肼（FDC I/H）固定剂量联合治疗的反应增强。尽管在非裔美国人心力衰竭试验（AHeFT）中，FDC I/H有明显的生存益处，但只有25%的黑人受试者有潜在的获益。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亚单位GNB3的遗传变异在高血压中的作用已被广泛研究。825位（T/C）存在多态性，该多态性在功能上沉默，但与剪接变异紧密相连，导致蛋白质截断。GNB3 T单倍型在黑人中更为普遍，并与低肾素高血压有关。对AHeFT遗传亚研究中350名受试者的评估表明，GNB3 TT基因型与FDC I/H治疗反应增强有关，该基因型在50%的非裔美国人中发现，但在白人中仅占10-15%。本提案将评估GNB3 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这一假设。该研究将招募500名患有HFrEF的非裔美国人，开始使用FDC I/H治疗，并对他们进行长达两年的随访。受试者将在入院时进行GNB3多态性基因分型，并根据基因型比较对治疗的反应。治疗反应将使用综合评分来量化，AHeFT的主要终点包括死亡率、心力衰竭住院和6个月时生活质量评分的变化。目的2将对GNB3基因型的治疗反应进行类似的分析，在治疗6个月后通过超声心动图检查LVEDD或LVEF的改善情况作为结果衡量。目标3将使用混合分析，首先确定全球祖先（个体的非洲祖先DNA百分比）如何影响药物反应的结果测量，以及全球祖先如何作为GNB3效果的调节剂。