This proposal builds on our team's considerable experience in renal disease epidemiology, genetic epidemiology, and collaborative research. It utilizes the infrastructure of a successful, nationwide cohort study of nearly 1,000 incident ESRD patients in which a DNA bank has been established. We will collaborate with Dialysis Clinic, Inc., a not-for-profit chain that cares for over 10,000 dialysis patients. Drs. Stephen O'Brien and Michael Smith at the Laboratory of Genomic Diversity at the National Cancer will use an innovative technique. Mapping by admixture Linkage Disequilibrium (MALD), to identify genes that increase risk of ESRD. We will extend MALD by also characterizing the haplotypes of the probands. Our study will collect trios (ESRD proband, child, and other biological parent of child) to allow identification of haplotypes to pinpoint the search for the genes controlling risk for ESRD. We will test the following hypotheses: 1. Renal disease susceptibility genes exist which increase the risk of both diabetic and non-diabetic renal disease. 2. Some renal disease susceptibility genes exist which increase the risk of both diabetic and non-diabetic renal disease. 2. Some renal disease susceptibility alleles are present at higher frequency in African-Americans than in whites. 3. Specific regions of the genome in African-Americans on the order of 10-20 cM are in admixture linkage disequilibrium with ESRD susceptibility alleles. To carry out the study we will recruit 1,000 African-Americans trios consisting of cases of diabetic and other types of ESRD, progeny, and the other biological parent of the child. We will utilize a newly developed set of 452 microsatellite markers to perform a whole genome MALD scan. Data from the child and other biological parent will be used to haplotype the proband to identify the gene. We will also screen for polymorphisms and mutations in genes in the region of admixture linkage disequilibrium test (TDT) analysis of the probands and their affected children to test candidate genes. Data collection in ESRD patients can be accomplished very efficiently because the infrastructure is already in place within DCI to collect DNA quickly and cheaply as part of routine care. We have trained study coordinators in 80 dialysis clinics and demonstrated our ability to collect high quality clinical information. The genetic analyses that we propose are innovative and complement more traditional linkage techniques. We look forward to working with other members of the Consortium and contributing our data to provide enhanced power to meet the overall goal of the RFA.
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