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

心力衰竭的精准医学：基因组学在基石药物治疗的疗效和种族差异中的作用

• 批准号: 10382266
• 负责人: Jasmine A Luzum
• 金额: $ 15.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382266
• 关键词: Affect; African; Age; American; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Biological; Biological Factors; Black American; Black Populations; Blood Pressure; Candidate Disease Gene; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Trials; Complex; Computer software; Cox Proportional Hazards Models; Data; Data Analyses; Data Set; Databases; Diabetes Mellitus; EFRAC; Enrollment; Event; Genes; Genetic; Genetic Polymorphism; Genetic study; Genomics; Goals; Grant; Health system; Heart failure; Hospitalization; Hypertension; Individual; Intravenous infusion procedures; K-Series Research Career Programs; Leadership; Mentors; Methods; Michigan; Mission; Outcomes Research; Pathway interactions; Patient Self-Report; Patients; Pharmacotherapy; Population; Race; Registries; Research; Research Personnel; Role; Technology; Testing; Time; Uncertainty; United States National Institutes of Health; Validation; Variant; Writing; clinical practice; differences in access; experience; genetic variant; genome wide association study; genomic data; health care availability; health disparity; improved outcome; mortality; multilevel analysis; novel; patient response; precision medicine; primary outcome; racial disparity; secondary outcome; skills; tool; trait; treatment guidelines; valsartan; whole genome

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.

项目摘要 心力衰竭和射血分数降低（HFrEF）患者的基础药物治疗是血管造影， 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 对于黑人高血压是公认的，也有类似的怀疑种族一致的， ACEI/ARB对HFrEF黑人患者的疗效因此，迫切需要更好地了解 影响ACEI/ARB治疗HFrEF的疗效，特别是对黑人。我的核心假设是基因组学 ACEI/ARB治疗HFrEF疗效和种族差异的重要因素。我的总体思路是-- 用全基因组阵列数据裂解现有的HFrEF临床数据集（用于测试和验证的总n = 2，832; 39%黑人）。以前的研究比较了ACEI/ARB在黑人和白人中与HFrEF的疗效， 他们自我报告的种族，并不能准确地反映出一个基因混合人群的祖先， 美国黑人因此，目的1是确定非洲基因组祖先与ACEI/ARB的关联 自我报告的HFrEF黑人和白人的死亡率获益。我对目标1的假设是， 非洲基因组祖先的比例与HFrEF的ACEI/ARB死亡率获益降低相关。 以前关于ACEI/ARB在HFrEF中疗效的遗传学研究仅集中在通过candi的少数生物学途径上。 最新的基因研究可能会遗漏与ACEI/ARB疗效相关的未知生物学途径。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 HFrEF患者ACEI/ARB死亡率获益的逻辑途径我对目标2的假设是， a GWAS将发现与ACEI/ARB死亡率相关的新的遗传变异和生物学途径， 在HFrEF中有效。先前的研究表明，个体遗传变异通常只能解释一个小的por。 复杂性状的变异性，限制了它们的临床实用性。因此，目标3是确定多变量 基因组评分预测ACEI/ARB对HFrEF患者死亡率的益处。我对目标3的假设是一个多- 变异基因组评分可预测HFrEF患者ACEI/ARB死亡率获益。相对于个人而言， 遗传变异，多变异基因组评分可能具有临床实用性的效应量。预期结果 这项研究的目的是更好地了解基因组学在治疗效果和种族差异中的作用， ACEI/ARB治疗HFrEF。我的长期目标是成为一名专注于精准医疗的独立调查员， 电影和基因组学，利用该技术来改善结果并减少患者的种族差异 心脏衰竭这个职业发展奖将使我掌握基因组学的关键研究技能， 健康差距，赠款写作和领导力。我计划将这些新技能应用到R 01应用程序中，以提高- 密歇根基因组计划中的临床和基因组数据。