The HLA-DPB1–Associated Component of the IDDM1 and Its Relationship to the Major Loci HLA-DQB1, -DQA1, and -DRB1

• Published in: Diabetes (New York, N.Y.) Vol. 50; no. 5; pp. 1200 - 1205
• Main Authors: CUCCA, Francesco, DUDBRIDGE, Frank, GILCHRIST, Frances, CORDELL, Heather, WELSH, Ken, TODD, John A, LODDO, Miriam, MULARGIA, Anna P, LAMPIS, Rosannna, ANGIUS, Efisio, DE VIRGILIIS, Stefano, KOELEMAN, Bobby P. C, BAIN, Stephen C, BARNETT, Anthony H
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2001
• Subjects: Alleles; Antigens; Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, Pair 6; Confidence Intervals; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Familial diseases; Genes; Genetic aspects; Genetic polymorphisms; Genetic Predisposition to Disease - genetics; Genetic Variation; Haplotypes; HLA-DP Antigens - genetics; HLA-DP beta-Chains; HLA-DQ alpha-Chains; HLA-DQ Antigens - genetics; HLA-DQ beta-Chains; HLA-DR Antigens - genetics; HLA-DRB1 Chains; Humans; Insulin; Italy; Major histocompatibility complex; Medical research; Medical sciences; Physiological aspects; Polymerase chain reaction; Type 1 diabetes; United Kingdom; Italy; United Kingdom; Sardinia; Europe; United States; United Kingdom > UK; Endocrinopathy; Human; Immunopathology; HLA-System; Association; Major histocompatibility system; Insulin dependent diabetes; Autoimmune disease; Genetics; Polymorphism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.50.5.1200

The HLA-DPB1 –Associated Component of the IDDM1 and Its Relationship to the Major Loci HLA-DQB1 , -DQA1 , and - DRB1 Francesco Cucca 1 , Frank Dudbridge 3 , Miriam Loddo 1 2 , Anna P. Mulargia 1 2 , Rosannna Lampis 1 , Efisio Angius 2 , Stefano De Virgiliis 1 , Bobby P.C. Koeleman 3 , Stephen C. Bain 4 , Anthony H. Barnett 4 , Frances Gilchrist 5 , Heather Cordell 2 , Ken Welsh 6 and John A. Todd 3 1 Department of Biomedical Science and Biotechnology, University of Cagliari 2 Pediatric Diabetes Unit, G. Brotzu Hospital, Via Peretti, Cagliari, Sardinia, Italy 3 Wellcome Trust Center for Molecular Mechanisms in Disease, University of Cambridge, Addenbrooks Hospital, Cambridge 4 Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Birmingham 5 Royal Brompton Hospital, Fulham Road, London 6 Transplant Immunology, Oxford Transplant Centre, Churchill Hospital, Oxford, U.K. Abstract The major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes ( IDDM1 ). Common allelic variants at the class II HLA-DRB1 , -DQA1 , and -DQB1 loci account for the major part of IDDM1 . Previous studies suggested that other MHC loci are likely to contribute to IDDM1 , but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen–presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1 , DQA1 , and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1 . Footnotes Address correspondence and reprint requests to the following authors: Francesco Cucca, Dipartimento di Scienze Biomediche e Biotecnologie, University of Cagliari, Via Jenner, Cagliari 09121, Italy. E-mail: fcucca{at}mcweb.unica.it . John Todd, Wellcome Trust Centre for Molecular Mechanisms in Disease, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, U.K. E-mail: john.todd{at}cimr.cam.ac.uk . Received for publication 30 June 2000 and accepted in revised form AFBAC, affected family-based control subject; ETDT, extended transmission/disequilibrium test; HM, haplotype method; MHC, major histocompatibility complex; ORT, odds ratio for transmission; PCR, polymerase chain reaction; PW, pairwise; SSP, sequence-specific primer.