Despite improvements in blood pressure control and the use of angiotensin converting enzyme inhibitors, type 2 diabetes mellitus (T2DM) associated end stage renal disease (ESRD) is the most common and rapidly increasing etiology of chronic renal failure in the United States. Diabetic nephropathy accounts for more than 34% of incident Medicare supported dialysis cases and patients with diabetic ESRD suffer 50% mortality in two years. It remains unclear why only a minority of diabetic patients will ultimately develop renal failure, while the majority of diabetics who have poorly controlled blood sugar and/or hypertension will not. We hypothesize that genes contributing to the development of diabetes-associated ESRD in African Americans exist and can be identified using modern molecular genetic methods. In the first phase of this study we recruited an extensive collection of African American families with T2DM- ESRD. Extensive candidate gene analysis was performed and a genome scan carried out. Analysis of the genome scan results has located several genomic regions inherited with T2DM-ESRD. The focus of this renewal application is to locate and identify one or more of these genes using modern molecular genetic methods. Specifically, targeted linkage studies, i.e. fine mapping, will be carried out for the 6 most likely locations for linkage on chromosomes 3q, 7p, 10q, 12p, 16p, and 18q. One linkage peak will be chosen for a focused, comprehensive search for the underlying T2DM-ESRD gene through construction of a framework haplotype block map of the region, followed by high density genotyping of SNPs across the linkage region, and assessment of association in case-control samples leading to the identification of a specific haplotype block containing the T2DM-ESRD gene. Detailed sequencing and analysis will be used to identify the T2DM-ESRD gene.
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