Project Summary / Abstract Heart failure (HF) affects ~6.2 million Americans and is one of the leading causes of hospitalization in the U.S. Hospitalizations for heart failure (HHF) account for 80% of HF costs since 83% of HF patients are hospitalized at least once and 43% at least four times. About 30% of HF patients die within one year of being hospitalized. Black HF patients experience higher hospitalization rates over time compared to White HF patients. Angiotensin Inhibitors prevent HHF. Although these drugs are most effective in patients with reduced ejection fraction (HFrEF), HHF patients remain high, suggesting that drug response differs between individuals. Race seems to be a critical factor in angiotensin inhibitor response because White HF patients experienced a 44% reduction in the risk of HHF on these drugs, while this effect was not seen in Black HF patients. Although this difference in responsiveness to angiotensin inhibitors is not yet fully understood, these drugs are guideline- recommended for all HFrEF patients. Given the increasing frequency, costs, and grave outcomes, there is a critical need to understand the factors underlying racial disparity in the angiotensin inhibitor-associated reduction of HFrEF hospitalizations. Race is a complex construct of social and genomic variables, and both may play a role in this racial disparity. Our central hypothesis is social variables better explain this racial disparity. Therefore, the overall objective is to understand the effects of self-identified race, genomics, and social variables in the racial disparity of angiotensin inhibitor-associated reductions in HFrEF hospitalizations. Pharmacogenomic (PGx) studies often rely on self-identified race instead of genomic ancestry, and findings of genetic variants responsible for differences in HF treatment outcomes are inconsistent. Aim 1 overcomes this limitation with a diverse cohort of HFrEF patients (N=575 Black, N=547 White) in the Henry Ford Heart Failure PGx registry (HFPGR) with whole-genome data, allowing for ancestral quantification and access to electronic medical records. Many studies investigating racial disparities in HHF are outdated, given current knowledge on access to care that can influence HHF. Aim 2 overcomes this limitation with access to a more contemporary dataset where patients have similar health care access and quality. Studies investigating the effects of social determinants of health (SDoH) on HHF found cumulative increases of specific social variables were associated with an increased risk of HHF but did not investigate drug-specific social variables. Aim 3 overcomes this limitation by testing for interactions using self-identified race, genomic ancestry, and social variables specifically related to angiotensin inhibitor benefit in HFrEF hospitalizations. The overall approach is to analyze an existing clinical and genomics dataset (HFPGR) with HHF as the primary outcome. This research is feasible by leveraging an...