Journal
DIABETES
Volume 63, Issue 12, Pages 4360-4368Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db13-1785
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK-46635, DP3-DK-085678]
- JDRF [33-2008-409]
- National Institute of Allergy and Infectious Diseases (NIAID)
- National Human Genome Research Institute (NHGRI)
- National Institute of Child Health and Human Development (NICHD)
- JDRF
- Common Fund of the Office of the Director of the National Institutes of Health
- National Cancer Institute (NCI)
- NHGRI
- National Heart, Lung, and Blood Institute
- National Institute on Drug Abuse
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- NCI/Science Applications International Corporation-Frederick (SAIC-F) [10XS170, 10XS171, X10S172]
- SAIC-F subcontract [10ST1035]
- National Institutes of Health
- [U01-DK-062418]
- [HHSN268201000029C]
- [DA006227]
- [MH090941]
- [MH090951]
- [MH090937]
- [MH090936]
- [MH090948]
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Single nucleotide polymorphisms (SNPs) located in the chromosomal region 16p13.13 have been previously associated with risk for several autoimmune diseases, including type 1 diabetes. To identify and localize specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we resequenced a 455-kb region in type 1 diabetic patients and unaffected control subjects, 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. Forty-eight SNPs, all located in CLEC16A, provided a statistically significant association (P < 5.32 x 10(-5)) with disease, with rs34306440 being most significantly associated (P = 5.74 x 10(-6)). The panel of SNPs used for fine mapping was also tested for association with transcript levels for each of the four genes in the region in B lymphoblastoid cell lines. Significant associations were observed only for transcript levels of DEXI, a gene with unknown function. 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 the risk for type 1 diabetes is through reduced expression of DEXI.
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