Genetic ancestry and antihypertensive medication responses in African Americans

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PROJECT SUMMARY/ABSTRACT Hypertension (HTN) is the leading modifiable cause of cardiovascular disease (CVD) in the US, affecting 80 million Americans and costing over $45 billion annually. HTN has profound, disproportionate effects on African Americans (AAs). My goal in seeking a Mentored Research Career Development Award is to acquire the necessary training, practical experience, and knowledge to develop a research career as a principal investigator focused on reducing health disparities through scientific discoveries made using the combination of pharmacoepidemiology (medication effects in populations) and pharmacogenomics (genetic causes of variable medication effects). To continue my progress towards this goal, the objective of this project is to determine the association between genetic ancestry, including individual genetic variants, with blood pressure control, antihypertensive medication responses, and CVD outcomes in AAs. Given the observed racial differences in antihypertensive medication response, the central hypothesis is that the racial disparities in HTN control and long-term sequelae are related to genetic differences in the response to antihypertensive medications, particularly angiotensin converting enzyme inhibitors. The rationale for this project is that genetic ancestry will identify genetic factors accounting for racial differences in antihypertensive medication responses and provide a framework for the development of personalized approaches to antihypertensive treatment. At the same time, it will provide the means to place me on a trajectory towards a research career as a principal investigator focused on reducing health disparities using the combination of pharmacoepidemiology and pharmacogenomics. To test the central hypothesis and accomplish the objectives for this application, I will pursue the following three specific aims: 1) Establish the association of genetic ancestry and blood pressure control in AAs by medication class; 2) Determine if genetic ancestry modifies the effect of antihypertensive medications on CVD events in AAs; and 3) Identify opportunities to improve blood pressure control among African American Veterans. I will utilize three cohorts of AAs: (1) Jackson Heart Study (JHS): a large exclusively African American cohort study (n=5,301) with detailed genetic, clinical, and socioeconomic status (SES) variables, (2) Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): a large (n=42,419) randomized trial (RCT) comparing the efficacy of four antihypertensive medications on CVD events, and (3) Veterns Administration Informatics and Computing Infrastructure (VINCI): a database with patient data including medication claims, electronic health records, and administrative claims for all Veterans (n=~9 million). This contribution is a significant first step in a continuum of research that characterizes the role of genetic ancestry, including individual genetic variants, in HTN treatment. This is significant because it may transform how AAs are initially treated, (e.g., guiding the choice of initial antihypertensive medication[s]), resulting in reduced racial disparities in HTN outcomes and aligning with federal investments in population-based, precision medicine approaches to improve health equity. The proposed research is innovative in its focuses on the use of genetic ancestry to characterize differences in antihypertensive medication responses and outcomes among AAs. The vast majority of research to date identified differences in response between self-reported AAs and Caucasians. Examining differences in drug response within AAs across ranges of genetic ancestry has received far less attention, with no studies in HTN to date. This work represents a shift in the research approach to understanding racial differences in antihypertensive medication treatment responses and outcomes. In order to obtain my long-term goal and the objective of this proposal, I will require training and mentorship in: (1) genetic ancestry analyses, (2) analysis of genetic sub-studies of RCTs, (3) cardiovascular pharmacoepidemiology, (4) health disparities, and (5) leadership skills for principal investigators. Such training, which complements existing expertise in cardiovascular pharmacogenetics and clinical pharmacy, will be achieved through a combination of highly focused coursework, significant research experience, and active mentoring. The Candidate's mentoring team is all internationally recognized experts with long and successful track records of funding and trainee mentorship who possess all the necessary knowledge and skills, for success. My mentorship team includes experts in genetics and admixture (Drs. Lynn Jorde, Rick Kittles), pharmacoepidemiology and HTN (Drs. Paul Muntner and Rachel Hess), pharmacogenetics (Dr. Donna Arnett) and biostatistics (Dr. Tom Greene). My team has the breadth of expertise to help me obtain critical multidisciplinary skills and successfully implement my research aims. The environment at the University of Utah is an ideal setting for me to transition to independence. In summary, my previous training and experience, innovative research plan, high-quality training plan, first-rate mentorship team, and supportive research environment give me the highest likelihood of success to research independence with the proposed K01 award.