Genetic underpinnings of cardiorenal risk in Africans and African Americans

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ABSTRACT Hypertension (HTN) has earlier onset and takes on a more severe form in African Americans (AAs) as compared to other U.S. populations, which translates to higher rates of cardiovascular disease (CVD) endpoints including stroke and end stage renal disease. The rates of related comorbidities including type 2 diabetes (T2D) and chronic kidney disease (CKD) are also higher in AAs. These remarkable disparities equate to important consequences for the health of AA communities. Emerging data suggest genetic markers originating in Africa incur disease risk in this population. Prior genetic association studies of HTN, T2D, and CKD have been undertaken in AAs. However, the ancestral genetic variation coverage and sample sizes that have been achieved in genetic studies of European Ancestry populations have not yet been achieved for African ancestry populations. Additionally, a direct comparison of risk alleles between AA and African populations has yet to be made. To address these important research gaps, we propose a study that substantially expands the number of AAs with relevant phenotype and genotype data and dramatically improves the coverage of African specific genetic variation in a large number of AAs belonging to existing cardiovascular epidemiology cohorts. We propose genotyping 8000 AAs from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study and 2000 West Africans from the Human Health and Heredity in Africa (H3A) Kidney Network, newly bringing these 10,000 participants into genetic studies. We will combine these data with existing genotype data from 2000 H3A participants and recently generated high-coverage whole genome sequence (WGS) data on ~6500 AAs, with relevant phenotype data, from the NHLBI’s Trans- Omics for Precision Medicine (TOPMed) program. The TOPMed WGS data will be further used to impute sequence variants into REGARDS, H3A and the ~15,000 previously genotyped AA participants from other NHLBI cohorts. We will use these unprecedented resources to conduct the most comprehensive study of cardiorenal traits (blood pressure, renal function, fasting glucose) in AAs to date. We will follow up our top variant-association findings in an independent replication sample of 11,000 AAs with relevant data. Finally, we will test whether variants associated with these risk factors are also associated with CVD outcomes. Our proposed study, including a total of ~40,500 AAs and 4000 West Africans, will provide us an unprecedented opportunity to evaluate the role of genetic variation, and in particular African-derived genetic variation, in the increased susceptibility to CVD and renal disease in AAs. !