A large-scale association study identified multiple HLA-DRB1 alleles associated with ACPA-negative rheumatoid arthritis in Japanese subjects

Background HLA-DRB1 is associated with rheumatoid arthritis (RA). However, it has recently been suggested that HLA-DRB1 is only associated with patients with RA who have anticitrullinated peptide/protein antibodies (ACPA), which are specific to RA. Objective To elucidate whether specific HLA-DR alleles are associated with ACPA-negative RA development. Methods HLA-DRB1 typing was carried out in 368 Japanese ACPA-negative patients with RA and 1508 healthy volunteers as the first set, followed by HLA-DRB1 typing of 501 cases and 500 controls as the second set. The HLA-DRB1 allele frequency and diplotype frequency were compared in each group, and the results of the two studies were combined to detect HLA-DRB1 alleles or diplotypes associated with ACPA-negative RA. Results HLA-DRB1*12:01 was identified as a novel susceptibility allele for ACPA-negative RA (p = 0.000088, OR= 1.72, 95% CI 1.31 to 2.26). HLA-DRB1*04:05 and *14:03 showed moderate associations with ACPA-negative RA (p = 0.0063, OR= 1.26, 95% CI 1.07 to 1.49 and p = 0.0043, OR= 1.81, 95% CI 1.20 to 2.73, respectively). The shared epitope was weakly associated with ACPA-negative RA, but no dosage effect was detected (p = 0.016, OR= 1.17, 95% CI 1.03 to 1.34). A combination of HLA-DRB1*12: 01 and DRB1*09:01 showed a strong association with susceptibility to ACPA-negative RA (p = 0.00013, OR= 3.62, 95% CI 1.79 to 7.30). Homozygosity for HLA-DR8 was significantly associated with ACPA-negative RA (p = 0.0070, OR= 2.16, 95% CI 1.22 to 3.82). It was also found that HLA-DRB1*15:02 and *13:02 were protective against ACPA-negative RA (p = 0.00010, OR= 0.68, 95% CI 0.56 to 0.83 and p = 0.00059, OR= 0.66, 95% CI 0.52 to 0.84, respectively). Conclusions In this large-scale association study multiple alleles and diplotypes were found to be associated with susceptibility to, or protection against, ACPA-negative RA.