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

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk Analysis of the Type 1 Diabetes Genetics Consortium Families Henry Erlich 1 2 , Ana Maria Valdes 2 , Janelle Noble 2 , Joyce A. Carlson 3 , Mike Varney 4 , Pat Concannon 5 , Josyf C. Mychaleckyj 5 , John A. Todd 6 , Persia Bonella 2 , Anna Lisa Fear 2 , Eva Lavant 3 , Anthony Louey 4 , Priscilla Moonsamy 1 and for the Type 1 Diabetes Genetics Consortium 1 Roche Molecular Systems, Alameda, California 2 Children's Hospital Oakland Research Institute, Oakland, California 3 Clinical Chemistry, University Hospital, Malmö, Sweden 4 Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia 5 Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 6 Juvenile 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 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 (