In the current project genetic determinants of diabetic nephropathy and related traits are being sought using techniques of genetic linkage and association analysis. Lymphoblast cell lines have been established from informative pedigrees. DNA is available in other families in nuclear pellets extracted from blood specimens obtained in the epidemiologic studies. An autosomal genome-wide linkage study identified suggestive evidence for linkage to diabetic nephropathy on chromosome 3q and chromosome 7q. Efforts to identify potential causative variants in both of these regions are currently underway using both a systematic analysis of linkage disequilibrium and analyses of candidate genes. Through collaboration with multicenter Family Investigation of Nephropathy (FIND) consortium, additional informative families are being analyzed for linkage. Genome-wide association strategies are also being used.? ? In the last year, the AKR1B1 gene, a strong candidate for nephropathy susceptibility in the linked region on chromosome 7q, was evaluated and it was determined that variants in this gene do not contribute to diabetic nephropathy in this population. A genome-wide linkage study in the first 378 families recruited from the multiethnic FIND consortium identified potential diabetic nephropathy susceptibility loci on chromosomes 7q, 10p, 14q and 18q. A genome-wide association study comparing allele frequencies in pooled DNA from Pimas with end-stage renal disease with pools from individuals with long duration of diabetes without evidence of nephropathy identified the PVT1 gene on chromosome 8q as a strong candidate for susceptibility to diabetic nephropathy.? ? Current efforts are focused on linkage analysis of the full collection families from the FIND consortium. With collaborators dense linkage disequilibrium maps are being generated in the candidate regions on chromosomes 3q and 7q. Replication studies of PVT1 and other candidate genes are also being pursued.
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