Protection against anti-citrullinated protein antibody-positive rheumatoid arthritis is predominantly associated with HLA-DRB1*1301: a meta-analysis of HLA-DRB1 associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in four European populations.

OBJECTIVE: The protective effect of HLA-DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA-DRB1 alleles are associated with protection in anti-citrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA. METHODS: Data for >2,800 patients and >3,000 control subjects for whom information on HLA-DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA-DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association. RESULTS: In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB1*13 alleles (OR 0.54 [95% CI 0.38-0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97 [95% CI 0.75-1.25]), indicating that DRB1*13, rather than the DERAA or D70 sequence as such, is associated with protection. Among the DRB1*13 alleles, only DRB1*1301 was associated with protection (OR 0.24 [95% CI 0.09-0.59]). Protection appeared to follow a north-to-south gradient, with the strongest association in northern European countries. In ACPA-negative RA, there were no robust associations with HLA-DRB1 alleles. CONCLUSION: Our data do not support any of the classifications of protective alleles and indicate that protection against ACPA-positive RA is predominantly associated with HLA-DRB1*1301.