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. Markers were genotyped for the full collection of families from the FIND consortium and linkage analyses were completed;several regions of suggestive linkage were identified for nephropathy and related quantitative traits. Fine-mapping of these regions is being 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. A genome-wide association study for diabetic nephropathy in individual DNA is currently underway as part of the FIND consortium. 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 is underway in Micronesia.
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