? End stage renal disease (ESRD) is a major clinical and public health problem, especially in African Americans. This proposal is an ancillary study to the NIH-NIDDK funded Family Investigation of Diabetes and Nephropathy (FIND) and the Choices for Healthy Outcomes in Caring for ESRD patients (CHOICE) studies, ongoing multicenter studies to identify susceptibility genes for nephropathy (FIND), and risk factors for cardiovascular outcomes in ESRD patients (CHOICE). ? The overall objective of this proposal is to identify novel loci, and ultimately genes, that may partially account for excess risk of ESRD in African Americans compared to whites. To achieve this goal, we will employ Mapping by Admixture Linkage Disequilibrium (MALD) analysis, a specialized form of linkage disequilibrium mapping, to perform a genome-wide association study in approximately 2,500 African-American participants who have already been recruited and characterized with respect to renal phenotypes and had DNA collected and isolated. We hypothesize that some renal disease susceptibility alleles are present at higher frequency in African Americans than in whites and that specific regions of the genome in African Americans contain marker alleles that are in ALD with ESRD susceptibility alleles. This hypothesis will be tested by comprehensively evaluating MALD markers in approximately 1,400 African-American cases with ESRD and 750 African-American controls without renal disease. We will: 1) genotype ~3,000 African-American MALD markers (1.2 cM average spacing) in DNA from approximately 2,500 African-American participants (almost 7 million genotypes) using an advanced, high-throughput genotyping system; 2) perform a genome-wide association analysis utilizing a ~1 cM dense genetic map and identify chromosomal loci that are in ALD with ESRD in a case-control design, ESRD attributable to diabetes in a case-control design, and quantitative renal phenotypes amongst 1,100 individuals without ESRD, 3) use closely-spaced SNP markers to fine map putative chromosomal region in ALD with ESRD. ? The proposed genetic analyses are innovative and complementary to the more traditional linkage techniques and not part of the core protocols of the parent studies. This study will provide key insights into the genetic control of susceptibility of ESRD ? ?
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