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: 9904753
• 负责人: Jasmine A Luzum
• 金额: $ 15.55万
• 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/9904753
• 关键词: Affect; African; African American; Age; American; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Biological; Biological Factors; 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; experience; genetic profiling; 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.

项目总结