? End stage renal disease (ESRD) is a major clinical and public health problem, especially in African- Americans. This proposal is a renewal application for the NIH-NIDDK-funded Family Investigation of Diabetes and Nephropathy (FIND), an ongoing multicenter study to identify susceptibility genes for nephropathy. 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 using Mapping by Admixture Linkage Disequilibrium (MALD) analysis. Our central hypothesis is 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 admixture linkage disequilibrium with ESRD susceptibility alleles. ? MALD is a specialized form of linkage disequilibrium mapping and will be used to perform a genome-wide association study in approximately 1,500 African-American cases and 1,300 African-American controls from FIND and 250 similarly phenotyped African-American cases from the CHOICE study, also funded by NIH-NIDDK. In this proposal, we are requesting funds to recruit an additional 300 ESRD cases and 300 controls without renal disease to achieve a final sample size of approximately 3,000 cases and controls. ? The Johns Hopkins center differs from other FIND centers which use either a family-based linkage approach or MALD in Mexican Americans. Furthermore, it is the only FIND study site that has recruited nondiabetic ESRD cases, thus providing an opportunity to examine whether susceptibility genes are similar for diabetic and nondiabetic ESRD. Additional recruitment is justified by the need to have an adequate number of cases with nondiabetic ESRD. Genotyping for this study is funded by an RO-1 to Dr. Kao. ? Since FIND began, our team has developed a dense (about 3,000 markers) genome map of highly informative African-American MALD markers as well as new approaches to statistical analysis. The proposed genetic analyses are innovative and complementary to the more traditional linkage techniques used by other FIND study sites. This study will provide key insights into the genetic susceptibility of ESRD. ? ?
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