Genetic Epidemiology of Diabetic Complications

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

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. Mapping studies, using both genetic linkage and association methods, are being used to identify genomic regions containing variants that confer susceptibility to diabetic kidney disease and related traits. Through collaboration with the multicenter Family Investigation of Nephropathy (FIND) consortium, the genetics of diabetic nephropathy and of diabetic retinopathy are also being studied. FIND was initiated as a genome-wide linkage study and is currently using a genome-wide association strategy to identify regions of interest. A genome-wide association study for diabetic nephropathy using 1,000,000 single nucleotide polymorphisms has also been conducted part of the FIND consortium. Initial analyses showed several regions that potentially harbor nephropathy-susceptibility loci. Replication studies in additional samples identified a variant between CNKSR3 and SCAF8 that was associated with nephropathy at genome-wide statistical significance, and across multiple ethnic groups. Recent studies have found that low-frequency variants identified as associated with renal function measures in Hispanic populations had similar frequencies in Indigenous Americans but did not replicate as associated with kidney function. Additional follow-up analyses are currently underway. Current efforts are focused on analysis of genome-wide association in the full collection of samples from the FIND consortium; further genome-wide association studies are being conducted in American Indian studies. With collaborators, dense linkage disequilibrium maps are being generated in candidate regions for linkage with nephropathy and total cholesterol in American Indian. We found that some DNA methylation profiles from peripheral blood observed in East Asians are also predictive in American Indians; further analyses of DNA methylation profiles and replication studies of this are being pursued. Recent analyses have shown that insulin resistance, measured before diabetes onset by the hyperinsulinemic-euglycemic “clamp” technique are predictive of development of severe albuminuria in those who subsequently develop diabetes. In conjunction with collaborators, additional families informative for study of genetics of diabetic nephropathy have been recruited in Micronesia. Genotyping for genome-wide association study has been completed, and analyses are underway. Preliminary analyses of have identified established variants and novel variants strongly associated with lipid levels in Micronesians. Genotyping of additional individuals is planned, as are replication studies.