Combination of HLA-A and HLA class II alleles controls the susceptibility to rheumatoid arthritis

Two hundred and four unrelated Japanese patients with rheumatoid arthritis (RA) were typed for HLA by serological typing and DNA typing. The serological typing revealed that frequencies of HLA-A11, DR4, DR53 and DQ4 were increased and those of DR8 and DQ1 were decreased in the patients. The DNA typing has precisely defined the disease-associated HLA class II alleles; DRB1*0405, DQA1*03 and DQB1*0401 showed positive associations, while negative associations were found with DRB1*0803, DQA1*0103 and DQB1*0601. The risk for RA was found to be closely associated with particular amino acid sequences of DR-beta chain, including glycine residue at the 86th position in addition to those between 70 and 74, which are known to confer binding specificity and affinity to antigenic peptides. The observation that the frequency of HLA-A11 was increased in the DRB1*0405-positive patients suggested the interaction of these two alleles in the susceptibility to RA. On the other hand, the frequency of DPB1*0201 was increased in the DRB1*0405-negative patients and the frequency of HLA-A2 was increased in the DPB1*0201-positive patients, especially in the younger onset group. These findings suggested that the combination of HLA-A2 and DPB1*0201 may confer the susceptibility in the DRB1*0405-negative patients. Our results suggested the possibility that the susceptibility to RA is controlled by the interaction of HLA-A and DRB1 genes or by that of HLA-A and DPB1 genes in different patient subgroups.