Opposing effects of HLA-DRB1*13 alleles on the risk of developing anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis

Arthritis Rheum. 2009 Apr;60(4):924-30. doi: 10.1002/art.24410.


Objective: The effect of non-shared epitope HLA-DRB1 alleles on rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate the effects of several HLA-DRB1 alleles, independent of the shared epitope, on the risk of developing anti-citrullinated protein antibody (ACPA)-positive or ACPA-negative RA in a large case-control study.

Methods: HLA typing for the DRB1 gene was performed in 1,352 patients with RA and 922 controls from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated.

Results: DRB1*13 was found to protect against ACPA-positive RA when stratifying for the shared epitope and using a dominant genetic model (RR 0.41 [95% CI 0.26-0.64]). Furthermore, DRB1*13 neutralized the effect of the shared epitope in ACPA-positive RA (RR 3.91 [95% CI 3.04-5.02] in patients who had the shared epitope but not DRB1*13, and RR 1.22 [95% CI 0.81-1.83] in patients with both the shared epitope and DRB1*13, as compared with patients negative for both the shared epitope and DRB1*13). However, we did not replicate the previous published risk of ACPA-negative RA conferred by DRB1*03 when a dominant genetic model was used (RR 1.29 [95% CI 0.91-1.82]). Similarly, no significant effect of DRB1*03 on RR for ACPA-negative RA was seen using the recessive genetic model (RR 1.18 [95% CI 0.6-2.4]). In contrast, the combination of DRB1*03 and DRB1*13 was significantly associated with increased risk of developing ACPA-negative RA (RR 2.07 [95% CI 1.17-3.67]).

Conclusion: Our findings indicate that the DRB1*13 allele plays a dual role in the development of RA, by protecting against ACPA-positive RA but, in combination with DRB1*03, increasing the risk of ACPA-negative RA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Arthritis, Rheumatoid* / epidemiology
  • Arthritis, Rheumatoid* / genetics
  • Arthritis, Rheumatoid* / immunology
  • Autoantibodies / genetics*
  • Autoantibodies / immunology
  • Case-Control Studies
  • Epitopes / genetics
  • Epitopes / immunology
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • HLA-DR Antigens / genetics*
  • HLA-DR Antigens / immunology
  • HLA-DRB1 Chains
  • Humans
  • Male
  • Middle Aged
  • Peptides, Cyclic / immunology*
  • Risk Factors


  • Autoantibodies
  • Epitopes
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HLA-DRB1*13 antigen
  • Peptides, Cyclic
  • cyclic citrullinated peptide