Precision Medicine for Heart Failure: The Role of Genomics in the Efficacy and Racial Disparity of Cornerstone Pharmacotherapy

项目总结 心力衰竭和射血分数降低患者的基石药物治疗是一种... 血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂(ACEI/ARB)。然而，具有里程碑意义的HFrEF ACEI/ARB临床试验主要招募白人。ACEI/ARB疗效的显著种族差异 对于患有高血压的黑人来说，这一点是公认的，对于种族一致性也存在类似的怀疑 ACEI/ARB对患有HFrEF的黑人的疗效。因此，迫切需要更好地了解这些因素 影响ACEI/ARB对HFrEF的疗效，特别是对黑人。我的中心假设是基因组学 ACEI/ARB在HFrEF中的疗效和种族差异的显著因素。我的总体思路是分析- 利用全基因组阵列数据来裂解现有的HFrEF临床数据集(总计n=2,832，用于测试和验证； 39%的黑人)。以前比较ACEI/ARB和HFrEF在黑人和白人中的疗效的研究使用的是PA-PA。 帝王的自我报告的种族，这不能准确地反映基因混合的种群中的祖先，比如 美国黑人。因此，目标1是确定非洲基因组祖先与ACEI/ARB的关联 患有HFrEF的自我报告的黑人和白人的死亡率受益。我对目标1的假设是 非洲基因组祖先的比例与HFrEF的ACEI/ARB死亡率降低相关。 以往关于血管紧张素转换酶/ARB在HFrEF中作用的遗传学研究仅集中在通过CANDI/ARB途径的几个生物学途径上。 Date基因研究，这可能会遗漏与ACEI/ARB疗效有关的意外生物学途径。因此 在目标2中，我将进行全基因组关联研究(Gwas)，以发现新的遗传变异和生物多样性。 与ACEI/ARB死亡率相关的逻辑路径在HFrEF患者中受益。我对目标2的假设是 一个GWAS将发现与ACEI/ARB死亡率相关的新的遗传变异和生物途径。 在HFrEF中退出。先前的研究表明，个别基因变异通常只解释一小部分- 复杂性状的变异性降低，限制了它们的临床应用。因此，目标3是确定一种多变种 预测ACEI/ARB死亡率的基因组评分在HFrEF患者中受益。我对目标3的假设是一个多- 不同的基因组评分将预测HFrEF患者的ACEI/ARB死亡率受益。与单独的GE- 变异体，多变型的基因组评分可能具有临床应用的效应大小。预期的结果 这项研究的目的是更好地理解基因组学在高血压的疗效和种族差异中的作用。 ACEI/ARB用于HFrEF。我的长期目标是成为一名专注于精准医学的独立调查员- 电影和基因组学，利用这项技术来改善结果并减少患者的种族差异 并伴有心力衰竭。这个职业发展奖将让我掌握基因组学方面的关键研究技能， 健康差距、拨款申请和领导力。我计划将这些新技能应用到R01应用程序中，该应用程序- 对密歇根基因组学计划中的临床和基因组数据进行老化。

PROJECT SUMMARY Cornerstone pharmacotherapy for patients with heart failure and reduced ejection fraction (HFrEF) is an angio- tensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB). However, the landmark HFrEF ACEI/ARB clinical trials predominantly enrolled whites. A significant racial disparity in the efficacy of ACEI/ARB for blacks with hypertension is well recognized, and there are parallel doubts about racially consistent ACEI/ARB efficacy for blacks with HFrEF. Therefore there is a critical need to better understand the factors affecting the efficacy of ACEI/ARB for HFrEF, particularly for blacks. My central hypothesis is that genomics is a significant factor in the efficacy and racial disparity for ACEI/ARB in HFrEF. My overall approach is to ana- lyze existing HFrEF clinical datasets with whole genome array data (total n = 2,832 for testing and validation; 39% blacks). Previous studies comparing ACEI/ARB efficacy in blacks and whites with HFrEF used the pa- tients' self-reported race, which does not accurately reflect ancestry in a genetically admixed population like black Americans. Therefore Aim 1 is to determine the association of African genomic ancestry with ACEI/ARB mortality benefit in self-reported blacks and whites with HFrEF. My hypothesis for Aim 1 is that an increased proportion of African genomic ancestry is associated with decreased ACEI/ARB mortality benefit for HFrEF. Previous genetic studies of ACEI/ARB efficacy in HFrEF focused on only a few biological pathways via candi- date gene studies, which can miss unsuspected biological pathways involved in ACEI/ARB efficacy. Therefore in Aim 2, I will perform a genome-wide association study (GWAS) to discover novel genetic variants and bio- logical pathways associated with ACEI/ARB mortality benefit in HFrEF patients. My hypothesis for Aim 2 is that a GWAS will discover novel genetic variants and biological pathways associated with ACEI/ARB mortality ben- efit in HFrEF. Previous research has shown that individual genetic variants typically explain only a small por- tion of the variability in complex traits, limiting their clinical utility. Therefore Aim 3 is to identify a multi-variant genomic score that predicts ACEI/ARB mortality benefit in HFrEF patients. My hypothesis for Aim 3 is a multi- variant genomic score will predict ACEI/ARB mortality benefit in HFrEF patients. In contrast to individual ge- netic variants, a multi-variant genomic score may have an effect size with clinical utility. The expected outcome of this research is a better understanding of the role of genomics in the efficacy and racial disparity of ACEI/ARB for HFrEF. My long-term goal is to become an independent investigator focused on precision medi- cine and genomics, leveraging that technology to improve outcomes and reduce racial disparities in patients with heart failure. This career development award will allow me to master critical research skills in genomics, health disparities, grant-writing, and leadership. I plan to apply those new skills to a R01 application that lever- ages the clinical & genomic data in the Michigan Genomics Initiative.