HLA Class I and Genetic Susceptibility to Type 1 Diabetes
Results From the Type 1 Diabetes Genetics Consortium
- Janelle A. Noble1,
- Ana Maria Valdes2,
- Michael D. Varney3,
- Joyce A. Carlson4,
- Priscilla Moonsamy5,
- Anna Lisa Fear1,
- Julie A. Lane1,
- Eva Lavant4,
- Rebecca Rappner4,
- Anthony Louey3,
- Patrick Concannon6,
- Josyf C. Mychaleckyj6,
- Henry A. Erlich1,5 and
- for the Type 1 Diabetes Genetics Consortium
- 1Children's Hospital Oakland Research Institute, Oakland, California;
- 2Department of Twin Research and Genetic Epidemiology, King's College London, London, U.K.;
- 3Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia;
- 4Clinical Chemistry, University Hospital, Malmö, Sweden;
- 5Roche Molecular Systems, Pleasanton, California;
- 6Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
- Corresponding author: Janelle A. Noble, .
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.
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- Received May 15, 2010.
- Accepted August 13, 2010.
- © 2010 by the American Diabetes Association.
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