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.
Current guidelines for the treatment of the approximately 3 million Americans with heart failure and reduced ejection fraction (HFrEF) recommend an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) for all patients (unless contraindicated). However HFrEF patient responses to ACEI/ARB in real-world clinical practice are variable and unpredictable, and evidence suggests that blacks with HFrEF may not benefit as much from ACEI/ARB as whites. This research is relevant to the mission of the NIH because it takes steps toward precision medicine for HFrEF, i.e., using a patient's genetic profile to select the most effective HFrEF therapy.