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The Genetics of Type 2 Diabetic End-Stage Renal Disease in African Americans

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abstract
A genome wide linkage scan for type 2 diabetes (T2DM) associated end-stage renal disease (ESRD) (T2DM-ESRD) in African Americans was performed using 206 affected sibling pairs. Following ordered subset analysis (OSA), evidence for linkage was found on chromosomes 3q, 7p, and 18q. On chromosome 18, linkage was observed at 100.5cM in families with an earlier age at diabetes diagnosis (maximized LOD = 3.72; 64% of pedigrees). This region had been previously linked to diabetic nephropathy in other populations. To identify genes which contribute to T2DM-ESRD in African Americans on chromosome 18q21.1-23, candidate gene analysis, fine mapping, and dense SNP mapping methods were used. Using a candidate gene approach, the carnosinase genes (CNDP1 and CNDP2) were evaluated for their role in diabetic nephropathy susceptibility in African Americans. After a sequencing study and an initial genotyping phase, 12 SNPs and one microsatellite marker were genotyped in a large African American case-control population, with T2DM-ESRD cases, and non-diabetic, non-nephropathy controls. Association was seen with 1 SNP in CNDP2 and 1 SNP in CNDP1, additional association was seen with 2- and 3-marker haplotypes in both genes. A fine mapping study was conducted in the 18q21.1-23 region by adding 49 additional markers to the region, and increasing the family population to 270 affected sibling pairs. Continued evidence of linkage on chromosome 18 was observed through OSA with an earlier age of T2DM diagnosis at 90.1cM (maximized LOD = 3.90; 50% of pedigrees). In order to further refine this region, a dense SNP map was constructed across the 17.5 Mb LOD-1 interval; 2,814 SNPs were genotyped in AA cases with T2DM-ESRD and AA controls. NEDD4L and SERPINB7 were identified as T2DM-ESRD candidate genes in AA. In order to evaluate genetic variations across the entire genome that may contribute to T2DM-ESRD risk in AAs, a genome-wide association study (GWAS) was conducted. Following a replication phase and a trait discrimination phase, SASH1, RPS12, AUH, LIMK2, and SFI1 were strong candidate genes for T2DM-ESRD susceptibility in AAs. In addition, LIMK2 and SFI1 were identified as candidate genes for all-cause ESRD. These studies have found evidence of association in the carnosinase genes, CNDP1 and CNDP2, with T2DM-ERSD in African Americans. In addition, these studies have identified novel genes that could contribute to T2DM-ESRD risk in African Americans: NEDD4L, SERPINB7, SASH1, RPS12, AUH, LIMK2, and SFI1. Overall, this work has discovered genetic polymorphisms that contribute to the susceptibility of T2DM-ESRD in African Americans.
subject
Human Genetics
Diabetic Nephropathy
Type 2 Diabetes
End-Stage Renal Disease
contributor
McDonough, Caitrin W. (author)
Freedman, Barry I. (committee chair)
Bowden, Donald W. (committee member)
Howard, Timothy D. (committee member)
Hawkins, Gregory A. (committee member)
Antinozzi, Peter A. (committee member)
Divers, Jasmin (committee member)
date
2010-05-05T12:44:52Z (accessioned)
2010-06-18T18:59:29Z (accessioned)
2010-05-05T12:44:52Z (available)
2010-06-18T18:59:29Z (available)
2010-05-05T12:44:52Z (issued)
degree
Molecular Medicine (discipline)
identifier
http://hdl.handle.net/10339/14859 (uri)
language
en_US (iso)
publisher
Wake Forest University
rights
Release the entire work for access only to the Wake Forest University system for one year from the date below. After one year, release the entire work for access worldwide. (accessRights)
title
The Genetics of Type 2 Diabetic End-Stage Renal Disease in African Americans
type
Dissertation

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