Analysis of critical residues of HLA-DQ6 molecules in insulin-dependent diabetes mellitus

Among DQ6 molecules, DQA1*0102-DQB1*0602 is negatively associated with insulin-dependent diabetes mellitus (IDDM), but DQA1*0102-DQB1*0604 shows 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 (B1*0602) in 1% of patients and 25% of controls (odds ratio (OR) 0.02). DQ6 (B1*0604) alone was neutral (9% of patients and 10% of controls) but in combination with DQ8, was positively associated (5% of patients, 1% of controls, OR 9.49). In both these DQ6 molecules the alpha-chain is the same but the beta-chain differs at positions 9, 30, 57, 70, 86 and 87. DQB1*0602 has F9, Y30, D57, G70, A86 and F87, whereas DQB1*0604 has Y9, H30, V57, R70, G86 and Y87. Three-dimensional models of the two DQ6 molecules, based on crystal coordinates of the homologous DR1 molecule, suggest that residue 57 beta will likely play a critical role in peptide-binding selectivity, whereas residue 70 beta is probably a major contact site for the T-cell receptor. The effects of these specific polymorphic substitutions in DQ molecules on peptide binding and T-cell receptor recognition may be significant in IDDM susceptibility.