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

Annette H M van der Helm-van Mil1, Kirsten N Verpoort, Saskia le Cessie

  • 1Leiden University Medical Center, Leiden, The Netherlands.

Arthritis and Rheumatism
|February 1, 2007
PubMed

Insights

Different HLA-DRB1 shared epitope (SE) subtypes influence rheumatoid arthritis (RA) risk and anti-CCP antibody development. Tobacco exposure (TE) exacerbates RA progression in SE-positive, anti-CCP-positive patients by increasing antibody levels.

Area of Science:

  • Immunogenetics
  • Rheumatology
  • Environmental Epidemiology

Background:

  • The HLA-DRB1 shared epitope (SE) alleles are established risk factors for rheumatoid arthritis (RA).
  • SE alleles are more strongly associated with anti-cyclic citrullinated peptide (anti-CCP) antibodies than with RA development itself.
  • Interaction between SE alleles and tobacco exposure (TE) is implicated in anti-CCP positive RA predisposition.

Purpose of the Study:

  • To investigate differential contributions of HLA-DRB1 SE subtypes to anti-CCP antibody presence.
  • To determine if SE subtypes interact with TE in the development of anti-CCP antibodies.
  • To assess the impact of TE, SE alleles, and anti-CCP antibodies on the progression from undifferentiated arthritis (UA) to RA.

Main Methods:

  • Retrospective analysis of 977 early arthritis patients from the Leiden Early Arthritis Clinic.
  • Assessment of HLA-DRB1 SE subtypes, tobacco exposure (TE), and anti-CCP antibody status.
  • Evaluation of the association with anti-CCP antibody levels and progression from UA to RA.

Main Results:

  • Specific SE alleles (HLA-DRB1*0401, *0404, *0405, *0408) showed the highest risk for anti-CCP antibodies (OR 5.0).
  • TE-SE allele interaction was strongest for HLA-DRB1*0101/*0102 and HLA-DRB1*1001 SE alleles.
  • In SE+, anti-CCP+ patients, TE correlated with higher anti-CCP antibody levels and UA to RA progression; however, only anti-CCP antibodies independently predicted RA development.

Conclusions:

  • HLA-DRB1 SE subtypes exhibit distinct interactions with smoking and influence anti-CCP antibody predisposition.
  • Tobacco exposure contributes to RA development in SE+, anti-CCP+ individuals by modulating anti-CCP antibody levels.
  • The level of anti-CCP antibodies is a key independent predictor of RA development in this cohort.
Abstract

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