Anti-citrullinated peptide antibody (ACPA) is a highly specific serological marker for rheumatoid arthritis (RA).1,–,3 Different HLA-DRB1 alleles have been shown to be associated with the susceptibility to ACPA-positive RA.4 5 Former studies demonstrated that HLA-DRB alleles carrying a shared epitope (SE),6 consisting of a conserved amino acid motif at positions 70–74 of the HLA-DRβ chain, were strongly associated with ACPA-positive RA and with higher ACPA levels in European and Japanese populations.7,–,9 On the other hand, HLA-DRB1*09:01 was recently found to be negatively associated with ACPA levels in the Japanese.9 These observations imply that combinations of HLA-DRB1 alleles differentially influence ACPA levels in ACPA-positive RA.

To address this question, we conducted a genetic association study employing 2457 ACPA-positive Japanese RA patients. ACPA was quantified by MESACUP CCP ELISA kit (MBL Co Ltd, Nagoya, Japan) with a cut-off level of 4.5 U/ml. The patients were then divided into three groups …