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IDENTIFYING GENES THAT CONTRIBUTE TO TYPE 2 DIABETES SUSCEPTIBILITY IN CAUCASIAN AND AFRICAN AMERICANS

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abstract
The chromosome 20q12-13.1 region is one of the most consistently replicated areas of linkage to T2DM in Caucasian populations. In a dense SNP analysis of this region we observed suggestive evidence of association with T2DM for SNPs within the genes NCOA5, CDH22, and PREX1. We aimed to evaluate these three genes in two independent Caucasian case-control populations. Seventy two SNPs were genotyped in 300 diabetic nephropathy patients and 310 controls. Evidence of association with T2DM was observed in all three candidate genes (additive P-value [Pa] =0.00090-0.045). Six of these associations, all near PREX1, were replicated in an independent population (Pa=0.017-0.042). The combined analysis resulted in the same six SNPs, among others, associated with T2DM (Pa=0.0013-0.041). After testing for association with T2DM while adjusting for body mass index, which resulted in only 2 SNPs remaining nominally associated, association with BMI was observed with 10 SNPs in the PREX1 region (Pa=0.0015-0.029). Stratifying by T2DM status, however, showed that association with BMI was observed solely in cases (Pa=0.0018-0.041) suggesting that BMI may mediate effects of these SNPs on T2DM. Mediation testing revealed the effects of six SNPs were significantly mediated by BMI (30-40% effect). Also as part of this project we evaluated 12 T2DM susceptibility loci identified in genome-wide association analyses of European-derived populations in a large African American population consisting of 993 diabetic cases and 1054 controls. Sixty eight ancestry-informative markers (AIMs) were also genotyped to account for the impact of admixture on association results. Apart from TCF7L2 (rs7903146, Pa=1.59x10-6), we observed little evidence of association with T2DM in AAs. In fact, only rs9300039 in an intragenic region of chromosome 11p12 was associated with T2DM after admixture adjustment (Pd=0.029). The primary objective of this project was to evaluate susceptibility genes in Caucasian and African American populations. In the T2DM-linked region of chromosome 20q13.1 we have identified up to 3 genes that contribute to the formation of T2DM. In addition, evidence suggests variants near PREX1 are mediated by measures of adiposity. In the African American population we observed little evidence of association with T2DM for some of the most highly replicated susceptibility genes in European-derived populations suggesting that some different genetic risk factors may exist between populations. However, risk allele fixation of some of these loci may contribute to the increased overall prevalence of T2DM in the African American population.
subject
Genetics
contributor
Lewis, Joshua (author)
Howard, Timothy (committee chair)
Bowden, Donald (committee member)
Lively, Mark (committee member)
Hawkins, Gregory (committee member)
Antinozzi, Peter (committee member)
date
2009-05-07T18:01:17Z (accessioned)
2010-06-18T18:58:30Z (accessioned)
2009-05-07T18:01:17Z (available)
2010-06-18T18:58:30Z (available)
2009-05-07T18:01:17Z (issued)
degree
Molecular Genetics (discipline)
identifier
http://hdl.handle.net/10339/14769 (uri)
language
en_US (iso)
publisher
Wake Forest University
rights
Release the entire work immediately for access worldwide. (accessRights)
title
IDENTIFYING GENES THAT CONTRIBUTE TO TYPE 2 DIABETES SUSCEPTIBILITY IN CAUCASIAN AND AFRICAN AMERICANS
type
Thesis

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