The HLA-DRB1 shared epitope alleles differ in the interaction with smoking and predisposition to antibodies to cyclic citrullinated peptide

Arthritis Rheum. 2007 Feb;56(2):425-32. doi: 10.1002/art.22373.


Objective: The HLA shared epitope (SE) alleles are primarily a risk factor for the presence of antibodies to cyclic citrullinated peptide (anti-CCP antibodies) rather than for the development of rheumatoid arthritis (RA). The SE alleles interact with the environmental risk factor tobacco exposure (TE) for predisposition to anti-CCP+ RA. The objectives of this study were to determine 1) whether different SE subtypes contribute differently to the presence of anti-CCP antibodies, 2) whether different SE subtypes all interact with TE for the development of anti-CCP antibodies, and 3) the effect of TE in relation to the SE alleles and anti-CCP antibodies on the risk of progression from undifferentiated arthritis (UA) to RA.

Methods: We assessed the effect of SE subtypes and TE on the presence and level of anti-CCP antibodies and on the risk of progression from UA to RA in 977 patients with early arthritis who were included in the Leiden Early Arthritis Clinic.

Results: The HLA-DRB1*0401, *0404, *0405, or *0408 SE alleles conferred the highest risk of developing anti-CCP antibodies (odds ratio [OR] 5.0, compared with an OR of 2.0 for the HLA-DRB1*0101 or *0102 SE alleles and an OR of 1.7 for the HLA-DRB1*1001 SE allele). Conversely, the TE-SE allele interaction was the strongest for the HLA-DRB1*0101 or *0102 SE alleles and the HLA-DRB1*1001 SE allele. TE in SE+, anti-CCP+ patients correlated with higher levels of anti-CCP antibodies and with progression from UA to RA. In logistic regression analysis, only the presence and level of anti-CCP antibodies were associated independently with RA development.

Conclusion: The HLA-DRB1 SE subtypes differ in their interaction with smoking and in their predisposition to anti-CCP antibodies. TE contributes to the development of RA in SE+, anti-CCP+ patients, which is explained by its effect on the level of anti-CCP antibodies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Antibodies / immunology*
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / physiopathology
  • Cohort Studies
  • Disease Progression
  • Epitopes / genetics
  • Epitopes / immunology
  • Female
  • Genetic Predisposition to Disease*
  • HLA-DR Antigens / genetics*
  • HLA-DR Antigens / immunology
  • HLA-DRB1 Chains
  • Humans
  • Male
  • Middle Aged
  • Peptides, Cyclic / immunology*
  • Peptides, Cyclic / physiology
  • Protein Binding
  • Risk Factors
  • Smoking / genetics*
  • Smoking / immunology
  • Tobacco / adverse effects


  • Antibodies
  • Epitopes
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HLA-DRB1*04:01 antigen
  • Peptides, Cyclic
  • cyclic citrullinated peptide