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HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk: Analysis of the Type 1 Diabetes Genetics Consortium Families

¹Roche Molecular Systems, Alameda, CA
²Children's Hospital Oakland Research Institute, Oakland, CA, USA
³Clinical Chemistry, University Hospital, S-205 02 Malmö, Sweden
⁴Victorian Transplantation & Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia
⁵University of Virginia, Center for Public Health Genomics, Charlottesville, VA
⁶Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 OXY, UK

Objective: The Type 1 Diabetes Genetics Consortium (T1DGC) has collected worldwide T1D families for genetic analysis. The major genetic determinants of type 1 diabetes are alleles at the HLA-DRB1 and DQB1 loci, with both susceptible and protective DR-DQ haplotypes present in all human populations. The aim of this study is to estimate the risk conferred by specific DR-DQ haplotypes and genotypes.

Research Design and Methods: 607 Caucasian families and 38 Asian families were typed at high resolution for the DRB1, DQA1, and DQB1 loci. The association analysis was performed by comparing the frequency of DR-DQ haplotypes among the chromosomes transmitted to an affected child with the frequency of chromosomes not transmitted to any affected child.

Results: A number of susceptible, neutral, and protective DR-DQ haplotypes have been identified and a statistically significant hierarchy of T1D risk has been established. The most susceptible haplotypes are the DRB1*0301-DQA1*0501-DQB1*0201 (OR = 3.64) and the DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB*0302, and DRB1*0402-DQA1*0301-DQB1*0302 haplotypes (ORs = 11.37, 8.39, and 3.63), followed by the DRB1*0404-DQA1*0301-DQB1*0302 (OR = 1.59) and the DRB1*0801-DQB1*0401-DQB1*0402 (OR = 1.25). The most protective haplotypes are the DRB1*1501-DQA1*0102-DQB1*0602 (OR = 0.03), DRB1*1401-DQA1*0101-DQB1*0503 (OR= 0.02) and DRB1*0701-DQA1*0201-DQB1*0303 (OR = 0.02).

Conclusions: Specific combinations of alleles at the DRB1,DQA1, and DQB1 loci determine the extent of haplotypic risk. The comparison of closely related DR-DQ haplotype pairs with different T1D risks allowed identification of specific amino acid positions critical in determining disease susceptibility. These data also indicate that the risk associated with specific HLA haplotypes can be influenced by the genotype context and, that the trans-complementing heterodimer encoded by DQA1*0501 and DQB1*0302 confers very high risk.

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