HLA Class I and Genetic Susceptibility to Type 1 Diabetes

Results From the Type 1 Diabetes Genetics Consortium

  1. for the Type 1 Diabetes Genetics Consortium
  1. 1Children's Hospital Oakland Research Institute, Oakland, California;
  2. 2Department of Twin Research and Genetic Epidemiology, King's College London, London, U.K.;
  3. 3Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia;
  4. 4Clinical Chemistry, University Hospital, Malmö, Sweden;
  5. 5Roche Molecular Systems, Pleasanton, California;
  6. 6Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
  1. Corresponding author: Janelle A. Noble, jnoble{at}chori.org.

Abstract

OBJECTIVE We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study.

RESEARCH DESIGN AND METHODS Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients.

RESULTS Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes–associated alleles were B*5701 (odds ratio 0.19; P = 4 × 10−11) and B*3906 (10.31; P = 4 × 10−10). Other significantly type 1 diabetes–associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class II. Other class I type 1 diabetes associations appear to be specific to individual class II haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403).

CONCLUSIONS These data indicate that HLA class I alleles, in addition to and independently from HLA class II alleles, are associated with type 1 diabetes.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Received May 15, 2010.
  • Accepted August 13, 2010.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 59 no. 11 2972-2979
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