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J Diabetes. 2011 Sep;3(3):238-47. doi: 10.1111/j.1753-0407.2011.00131.x.

Replication and further characterization of a Type 1 diabetes-associated locus at the telomeric end of the major histocompatibility complex.

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  • 1Barbara Davis Center for Childhood Diabetes, University of Colorado-Denver, 1775 Aurora Ct., Aurora, CO 80045, USA.

Abstract

BACKGROUND:

We recently reported an association between Type 1 diabetes and the telomeric major histocompatibility complex (MHC) single nucleotide polymorphism (SNP) rs1233478. As further families have been analyzed in the Type 1 Diabetes Genetics Consortium (T1DGC), we tested replication of the association and, with more data, analyzed haplotypic associations.

METHODS:

An additional 2717 case and 1315 control chromosomes have been analyzed from the T1DGC, with human leukocyte antigen (HLA) typing and data for 2837 SNPs across the MHC region.

RESULTS:

We confirmed the association of rs1233478 (new data only: P=2.2E-5, OR=1.4). We also found two additional SNPs nearby that were significantly associated with Type 1 diabetes (new data only rs3131020: P=8.3E-9, OR=0.65; rs1592410: P=2.2E-8, OR=1.5). For studies of Type 1 diabetes in the MHC region, it is critical to account for linkage disequilibrium with the HLA genes. Logistic regression analysis of these new data indicated that the effects of rs3131020 and rs1592410 on Type 1 diabetes risk are independent of HLA alleles (rs3131020: P=2.3E-3, OR=0.73; rs1592410: P=2.1E-3, OR=1.4). Haplotypes of 12 SNPs (including the three highly significant SNPs) stratify diabetes risk (high risk, protective, and neutral), with high-risk haplotypes limited to approximately 20,000 bp in length. The 20,000-bp region is telomeric of the UBD gene and contains LOC729653, a hypothetical gene.

CONCLUSIONS:

We believe that polymorphisms of the telomeric MHC locus LOC729653 may confer risk for Type 1 diabetes.

© 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

PMID:
21631897
[PubMed - indexed for MEDLINE]
PMCID:
PMC3610173
Free PMC Article
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