Cardiorenal Genomics for Risk Prediction in African Descent Populations

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ABSTRACT Hypertension (HTN) and chronic kidney disease (CKD) overburden African Americans (AAs). These disparities translate to higher rates of cardiorenal disease endpoints including stroke, coronary heart disease (CHD), end stage renal disease (ESRD), and death. Blood pressure (BP) lowering with antihypertensive treatment reduces the risk of these outcomes, but the effects of treatment may be variable in different race groups. Studies have demonstrated that AAs respond best to calcium channel blockers and diuretics and not as well to to beta- blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers in comparison to their European American (EA) counterparts. The reasons for differences in cardiorenal health and antihypertensive treatment response are multifactorial and thought to include both environmental and inherited factors. Prior genetic and pharmacogenetic association studies of HTN and BP response to antihypertensive agents have been undertaken in AAs, but these studies have been considerably smaller in scope and sample size compared to those of EA populations. Smaller samples sizes of existing genetic datasets have hindered polygenic risk prediction in this population with the potential to create new health disparities. In order to overcome the limitations of previous research and enable efforts in personalized medicine in AAs, we will leverage data from existing cohorts for one of the largest genomic and pharmacogenomic studies of cardiorenal traits to date. Our pharmacogenetic discovery includes >4000 AAs randomized to chlorthalidone and >2500 randomized to lisinopril from the GenHAT study, an ancillary study of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. We have established an agreement with the International Consortium for Antihypertensives Pharmacogenomics Studies (ICAPS) for validation of our findings. Our genomic discovery is anchored in whole-genome imputed GWAS data from ~12000 REGARDS study AA participants and ~5000 AAs (JHS, Genoa, HyperGEN) with relevant phenotype and genotype data from the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. We will replicate our top variant-association findings in additional populations (~11,000 AAs) with relevant data followed by polygenic risk score testing in other cohorts from TOPMed. Using these rich resources we will derive new screening tools for antihypertensive treatment response and cardiorenal diseases. Polygenic risk score applications are increasing in other populations and this research will substantially improve the available data in underrepresented AAs. .