Effects of smoking and shared epitope on the production of anti-citrullinated peptide antibody in a Japanese adult population

Arthritis Care Res (Hoboken). 2014 Dec;66(12):1818-27. doi: 10.1002/acr.22385.


Objective: Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) are markers to rheumatoid arthritis (RA). Smoking and shared epitope (SE) in HLA-DRB1 are associated with the production of these autoantibodies in RA. Detailed distribution and characterization of ACPA and RF in the general population have remained unclear. We aimed to evaluate positivity of ACPA and RF in a general Japanese population and to detect correlates, including genetic components.

Methods: ACPA and RF were quantified in 9,804 Japanese volunteers ages 30-75 years. Logistic regression analyses were performed to evaluate the effects of candidates of correlates on the autoantibody positivity. A genome-wide association study (GWAS) was performed using 394,239 single nucleotide polymorphisms for 3,170 participants, and HLA-DRB1 alleles were imputed based on the GWAS data.

Results: A total of 1.7% and 6.4% of subjects were positive for ACPA and RF, respectively, and the 2 markers showed a significant correlation (P = 2.0 × 10(-23) ). Old age was associated with ACPA positivity (P = 0.00062). Sex, smoking, SE, and other candidates of correlates did not have significant effects. Interaction between smoking and SE positivity was not apparent, but smoking showed a significant association with high levels of ACPA (P = 0.0019).

Conclusion: ACPA and RF could be detected in 1.7% and 6.4% of the Japanese adult population without RA, respectively. ACPA and RF were suggested to share mechanisms even in healthy populations. Old age was associated with increasing ACPA positivity. While positivity of ACPA and RF was not associated with SE and smoking, an association between high ACPA and smoking was observed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Asian People
  • Autoantibodies / genetics*
  • Autoantibodies / immunology
  • Epitopes
  • Female
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Japan
  • Male
  • Middle Aged
  • Peptides, Cyclic / immunology*
  • Polymorphism, Single Nucleotide
  • Smoking / epidemiology*


  • Autoantibodies
  • Epitopes
  • Peptides, Cyclic
  • cyclic citrullinated peptide