The focus of this application is to locate and identify one or more genes that cause hypertension-associated end-stage renal (H-ESRD) disease in the African American population. Hypertensive end-stage renal disease is one of the leading causes of kidney failure in the United States and it disproportionately affects African Americans. This application builds upon a genome scan in 264 African American families containing index cases with H-ESRD and their siblings with end-stage kidney failure. We will perform fine mapping of the regions with the strongest evidence of linkage in the genome scan analysis. Linkage support intervals defined by the fine mapping process will be prioritized based on the evidence for linkage in our sample and other published data. High priority regions will be surveyed for candidate genes that could contribute to hypertension and H-ESRD. These genes will be subjected to a focused high density single nucleotide polymorphism (SNP) mapping effort, block identification and tested for association (e.g., single locus and haplotype) under a case-control design. The case-control sample is independent of the genome scan sample. The signal locus and haplotype analyses should help identify individual polymorphisms and haplotypes that are in linkage disequilibrium with H-ESRD. We anticipate that an intensive genetic analysis for the identification of haplotype blocks will facilitate the search for polymorphisms. Mapping the genes that predispose to hypertensive kidney disease will provide a framework for identifying the pathways that initiate or promote renal failure and could ultimately lead to the development of novel medications to prevent or slow progression of hypertensive kidney failure in African Americans.
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