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. Analysis of the candidate genes, ELMO1 and CNDP1, showed little evidence for an association with diabetic nephropathy in American Indians. Markers were genotyped for the full collection of families from the FIND consortium and linkage analyses were completed for both diabetes and diabetic nephropathy;several regions of suggestive linkage were identified for both traits. Fine-mapping of these regions is being planned. In addition, a genome-wide association study for diabetic nephropathy using 1,000,000 single nucleotide polymorphisms has been conducted part of the FIND consortium. Initial analyses showed several regions that potentially harbor nephropathy-susceptibility loci, although none reached genome-wide significance. Additional follow-up studies are currently underway. Current efforts are focused on analysis of 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, additional families informative for study of genetics of diabetic nephropathy have been recruited in Micronesia and in Phoenix. Genotyping of additional individuals is planned for replication.
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