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 from 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, 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. Several regions linked with quantitative measures of renal function were also identified. Markers were genotyped for the full collection of families from the FIND consortium and linkage analyses are currently underway. A genome-wide association study in these families was planned. In addition, 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 analysis of linkage and genome-wide association in 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. Additional American Indian families informative for linkage and association studies of diabetic nephropathy continue to be recruited. In conjunction with collaborators, further recruitment of families for these studies has been initiated in Micronesia.

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