ANALYSIS OF CRITICAL RESIDUES OF HLA-DQ6 MOLECULES IN INSULIN-DEPENDENT DIABETES-MELLITUS

Among DQ6 molecules, DQA10102-DQB1*0602 is negatively associated with insulin-dependent diabetes mellitus (IDDM), but DQA10102-DQB1*0604 s hows a neutral to positive association in Swedish children with IDDM. The aim of this study was to identify critical DQB1 residues that may account for the differences in IDDM association observed for these two DQ6 molecules. HLA-DQ genotyping in 425 IDDM patients and 367 matched controls showed DQ6 (B10602) in 1% of patients and 25% of controls ( odds ratio (OR) 0.02). DQ6 (B10604) alone was neutral (9% of patients and 10% of controls) but in combination with DQ8, was positively asso ciated (5% of patients, 1% of controls, OR 9.49). In both these DQ6 mo lecules the alpha-chain is the same but the beta-chain differs at posi tions 9, 30, 57, 70, 86 and 87. DQB10602 has F9, Y30, D57, G70, A86 a nd F87, whereas DQB10604 has Y9, H30, V57, R70, G86 and Y87. Three-di mensional models of the two DQ6 molecules, based on crystal coordinate s of the homologous DR1 molecule, suggest that residue 57 beta will li kely play a critical role in peptide-binding selectivity, whereas resi due 70 beta is probably a major contact site for the T-cell receptor. The effects of these specific polymorphic substitutions in DQ molecule s on peptide binding and T-cell receptor recognition may be significan t in IDDM susceptibility.