End-stage renal disease (ESRD) is a late-onset multi-factorial disease that primarily occurs in a subset of patients with diabetes mellitus, hypertension or chronic glomerulonephritis. End-stage renal disease incidence ins rising with an annual mortality of about 20% in incident cases. End-stage renal disease clusters in families and familial aggregation is a more powerful predictor of whether an individual with diabetes mellitus, hypertension or chronic glomerulonephritis will develop ESRD. However, no particular genetic mechanism responsible for the renal function damage that ultimately leads to ESRD as yet been identified. We will recruit 150 affected sib pairs concordant for ESRD and Type 2 diabetes and 200 sib pairs discordant for ESRD (but concordant for Type 2 diabetes mellitus) and 200 additional family members from hemodialysis, peritoneal dialysis and transplant centers as part of a study to identify genetic risk factors for ESRD. We will collect extensive family history and medical history as related to ESRD, on all members of the family recruited into the study. Blood will be obtained from consenting family members. The DNA will be extracted from lymphocytes and candidate genes and other markers will be genotyped. More than half the candidate genes/regions being examined are novel candidates and have not been evaluated for linkages with ESRD before. These include the receptors for the growth factors and the human regions syntenic to ESRD-related loci in rat or mouse models of ESRD. We will also examine regions of human chromosomes 7 and 16, where a genome scan in the Pima Indians shows suggestive evidence for diabetic nephropathy loci. Data will be analyzed using model-free linkage analysis. This dataset is expected to be complex and will have to sub-divide the data by race/ethnicity for analysis. We anticipate that this study will lead to identification of gene(s) for ESRD. This application is intended to provide a core for further, more extensive, acquisition of ESRD phenotype and genotype data. We intend to expand the entire project to include a genome scan and have designed subject collection to accommodate this goal.
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