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The Role of Chromosomal Region 16p13.13 in Type 1 Diabetes

Tomlinson, Melvin
Thesis/Dissertation; Online
Tomlinson, Melvin
Concannon, Patrick
Type 1 diabetes most frequently results from the autoimmune destruction of the insulin producing pancreatic Beta cells, resulting in dependence on exogenous insulin. The disease is complex and arises due to the effects of both genetic and environmental factors. With the advent of genome-wide association studies (GWAS) over 40 additional loci have been identified that confer low to moderate risks of developing type 1 diabetes (Odds Ratios, OR, ≤1.3). One of these regions identified is located at chromosome 16p13.13 and is associated with type 1 diabetes and several other autoimmune disorders. The specific region of interest on chromosomal region 16p13.13 implicated in autoimmunity spans approximately 530 KB from 10,937,499-11,467,499 base position (bp) (build Hg19) and encompasses four major genes: CIITA, DEXI, CLEC16A and SOCS1. In order to identify specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we re-sequenced the entire region in 192 individuals (128 patients and 64 controls) identifying 93 novel variants. A panel of 939 SNPs, that included 46 of these novel variants, was genotyped in 3,070 multiplex families with type 1 diabetes to identify potential risk variants. After correcting for multiple testing, 48 SNPs provided statistically significant evidence of association with type 1 diabetes (most significant SNP rs34306440 P = 5.74 x 10-6), conditioning on the top SNP found no further significant associations. The panel of SNPs used for fine mapping was also tested for association with variation in the transcript levels of each reported isoform of all genes in the region. Significant associations were observed only for transcript levels of DEXI, a gene originally reported to be unregulated by dexamethasone but whose function is unknown. We also tested novel unreported isoforms of CIITA in our study, but found no association. We examined the relationship between the odds ratio for type 1 diabetes and the magnitude of the effect of DEXI transcript levels for each SNP in the region. Among SNPs significantly associated with type 1 diabetes, the common allele conferred an increased risk for disease, and corresponded to lower DEXI expression. Our results suggest that the primary mechanism by which genetic variation at CLEC16A contributes to risk for type 1 diabetes is through reduced expression of DEXI.
University of Virginia, Department of Biochemistry and Molecular Genetics, PHD, 2013
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