Analysis of antibody markers, DRB1, DRB5, DQA1 and DQB1 genes and modeling of DR2 molecules in DR2-positive patients with insulin-dependent diabetes mellitus.

Abstract	HLA-DR2 is negatively associated with insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to analyze DR2-positive patients among 425 consecutively diagnosed unrelated Swedish children with IDDM and in 367 matched controls. HLA-DRB, -DQA and -DQB were determined by Taq I restriction fragment length polymorphism analysis. Amplification by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes was done for DQA1, DQB1 and DRB1 and DRB5. DR2 was positive in 11/425 patients (3%) and 101/367 (28%) controls (OR 0.07, p < 0.0001). Of the 11 DR2-positive patients, PCR was done in 10, of whom 8 were positive for DRB11601-DRB50201 compared to 4/96 (4%) controls (OR 92.0: p < 0.001) while the remaining 2 were positive for DRB11501-DRB50101 compared to 92/96 (96%, OR 0.01; p < 0.001). In 2 patients, a recombination between the haplotypes DQB10502-DQA10102 (DQ5)-DRB11601-DRB50201 (DR16 Dw21) and DQB10301-DQA10501 (DQ7)-DRB11602-DRB50202 (DR16 Dw22) was observed resulting in the DQB10301-DQA10501 (DQ7) DRB11601-DRB50201 (DR16 Dw22) haplotypes. The second haplotype was DR3 DQ2 in 6/11 and DR4 DQ8 in 2/11 DR2-positive patients. In all 3 DQB10602-DQA10102-DR15-positive patients the second haplotype was DR4-positive. In order to test whether physicochemical properties of the DR2 molecules were associated with IDDM, we constructed three-dimensional models of the peptide binding and T-cell recognition sites (alpha 1 and beta 1 domains) of five subtypes of DR2-DRB1, based on the published DR1 crystal structure. No correlations were observed for DR molecule physicochemical properties and diabetes susceptibility. Islet cell antibodies, insulin autoantibodies and GAD65 antibodies, were measured in DR2-positive patients (n = 11) and controls (n = 101). Despite the presence of the DR2 haplotype the antibody markers were significantly elevated in the patients compared to the controls (GAD65 3/10 patients and 2/101 controls; ICA 7/11 patients and 1/101 controls and IAA 3/11 patients and 0/101 controls). In conclusion, of the five subtypes of DR2, only one, the DRB11501, DRB50101, DQB10602-DQA10102 haplotype, was negatively associated with IDDM. DQ may therefore confer more protection from the disease than DR.
Authors	C B Sanjeevi, T P Lybrand, M Landin-Olsson, I Kockum, G Dahlquist, W A Hagopian, J P Palmer, A Lernmark
Journal	Tissue antigens (Tissue Antigens) Vol. 44 Issue 2 Pg. 110-9 (Aug 1994) ISSN: 0001-2815 [Print] England
PMID	7817375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References	Antibodies, Monoclonal HLA-DQ Antigens HLA-DQ alpha-Chains HLA-DQ beta-Chains HLA-DQA1 antigen HLA-DQB1 antigen HLA-DR Antigens HLA-DR2 Antigen HLA-DRB1 Chains HLA-DRB5 Chains
Topics	Alleles Animals Antibodies, Monoclonal (immunology) Base Sequence Cricetinae Diabetes Mellitus, Type 1 (genetics, immunology) Disease Susceptibility (immunology) Genes, MHC Class II Genetic Predisposition to Disease HLA-DQ Antigens (genetics) HLA-DQ alpha-Chains HLA-DQ beta-Chains HLA-DR Antigens (genetics) HLA-DR2 Antigen (chemistry, genetics) HLA-DRB1 Chains HLA-DRB5 Chains Haplotypes (genetics) Humans Immunity, Innate (genetics, immunology) Models, Molecular Molecular Sequence Data Polymerase Chain Reaction Polymorphism, Restriction Fragment Length Protein Conformation Recombination, Genetic Sweden

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