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DR- and DQ-Associated Protection from Type 1A Diabetes: Comparison of DRB1¹1401 and DQA1^,10102-DQB1^,10602^,1

Barbara Davis Center for Childhood Diabetes (M.J.R., E.K., C.L.M., G.S.E.) and Department of Medicine (B.M.F.), University of Colorado Health Sciences Center, Denver, Colorado 80262; Children’s Hospital Oakland Research Institute (J.A.N., H.A.E.), Oakland, California 94609; Department of Human Genetics, Inc. (J.A.N., H.A.E.), Roche Molecular Systems, Alameda, California 94501; Institute of Immunology (B.A.L., E.T., D.E.U.), The National Hospital, University of Oslo, 0027 Oslo, Norway; and Section of Epidemiology (K.S.R.), National Institute of Public Health, N-0403 Oslo, Norway

Address correspondence and requests for reprints to: George S. Eisenbarth, M.D., Ph.D., Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Avenue, B-140, Denver, Colorado 80262. E-mail: george.eisenbarth{at}UCHSC.edu

The transmission disequilibrium test was used to analyze haplotypes for association and linkage to diabetes within families from the Human Biological Data Interchange type 1 diabetes repository (n = 1371 subjects) and from the Norwegian Type 1 Diabetes Simplex Families study (n = 2441 subjects). DQA1*0102-DQB1*0602 was transmitted to 2 of 313 (0.6%) affected offspring (P < 0.001, vs. the expected 50% transmission). Protection was associated with the DQ alleles rather than DRB1*1501 in linkage disequilibrium with DQA1*0102-DQB1*0602: rare DRB1*1501 haplotypes without DQA1*0102-DQB1*0602 were transmitted to 5 of 11 affected offspring, whereas DQA1*0102-DQB1*0602 was transmitted to 2 of 313 affected offspring (P < 0.0001). Rare DQA1*0102-DQB1*0602 haplotypes without DRB1*1501 were never transmitted to affected offspring (n = 6).

The DQA1*0101-DQB1*0503 haplotype was transmitted to 2 of 42 (4.8%) affected offspring (P < 0.001, vs. 50% expected transmission). Although DRB1*1401 is in linkage disequilibrium with DQB1*0503, neither of the two affected children who carried DQA1*0101-DQB1*0503 had DRB1*1401. However, all 13 nonaffected children who inherited DQA1*0101-DQB1*0503 had DRB1*1401. In a case-control comparison of patients from the Barbara Davis Center, DQA1*0101-DQB1*0503 was found in 5 of 110 (4.5%) controls compared with 3 of 728 (0.4%) patients (P < 0.005). Of the three patients with DQB1*0503, only one had DRB1*1401. Our data suggest that both DR and DQ molecules (the DRB1*1401 and DQA1*0102-DQB1*0602 alleles) can provide protection from type 1A diabetes.

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