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

Henry Erlich; Ana Maria Valdes; Janelle Noble; Joyce A. Carlson; Mike Varney; Pat Concannon; Josyf C. Mychaleckyj; John A. Todd; Persia Bonella; Anna Lisa Fear; Eva Lavant; Anthony Louey; Priscilla Moonsamy

doi:10.2337/db07-1331

Genetics

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk

Analysis of the Type 1 Diabetes Genetics Consortium Families

Henry Erlich1,2,
Ana Maria Valdes2,
Janelle Noble2,
Joyce A. Carlson3,
Mike Varney4,
Pat Concannon5,
Josyf C. Mychaleckyj5,
John A. Todd6,
Persia Bonella2,
Anna Lisa Fear2,
Eva Lavant3,
Anthony Louey4,
Priscilla Moonsamy1 and
for the Type 1 Diabetes Genetics Consortium

¹Roche Molecular Systems, Alameda, California
²Children's Hospital Oakland Research Institute, Oakland, California
³Clinical Chemistry, University Hospital, Malmö, Sweden
⁴Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia
⁵Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
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, U.K

Address correspondence and reprint requests to Henry A. Erlich, PhD, Roche Molecular Systems, 1145 Atlantic Ave., Alameda, CA 94501. E-mail: Henry.Erlich{at}Roche.com

Diabetes 2008 Apr; 57(4): 1084-1092. https://doi.org/10.2337/db07-1331

Abstract

OBJECTIVE—The Type 1 Diabetes Genetics Consortium has collected type 1 diabetic families worldwide 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:—Six hundred and seven 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 type 1 diabetes risk has been established. The most susceptible haplotypes are the DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [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) haplotypes. The most protective haplotypes are 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 type 1 diabetes 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.