Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins

Ann Rheum Dis. 2015 Feb;74(2):375-80. doi: 10.1136/annrheumdis-2013-203947. Epub 2013 Nov 25.


Objective: To investigate the role of genetic and environmental factors in the development of anticitrullinated protein antibodies (ACPA) and ACPA-positive rheumatoid arthritis (RA) in a twin cohort.

Methods: A total of 12 590 twins were analysed for the presence of ACPAs (CCP2 ELISA), HLA-DRB1 shared epitope (SE) gene alleles, and exposure to smoking. Twins with established RA were identified in national public care registers. Antibody reactivities against citrullinated and native forms of α-enolase, vimentin, fibrinogen and type II collagen peptides were tested by ELISA in anti-CCP2-positive subjects and their cotwins. Structural equation models and ORs for the development of ACPA and ACPA-positive RA were computed for smokers and SE carriers.

Results: A total of 2.8% (350/12 590) of the twins were ACPA positive, and 1.0% (124/12 590) had ACPA-positive RA. Most of the variability in the ACPA status was accounted for by non-shared environmental or stochastic factors (78%, 95% CI 55% to 100%) rather than shared environmental and genetic factors. Analysis of specific risk factors revealed an association between smoking and SE and the presence of ACPAs. Twins with ACPA-positive RA were more frequently SE positive than twins with ACPAs without RA. Reactivities against multiple citrullinated peptides were present in most twins with ACPA-positive RA but in fewer twins with ACPAs without RA.

Conclusions: Environment, lifestyle and stochastic factors may be more important than genetics in determining which individuals develop ACPAs. Genetic factors (particularly SE) may have a relatively larger role in determining which ACPA-positive individuals will ultimately develop arthritis.

Keywords: Ant-CCP; Autoantibodies; Rheumatoid Arthritis; Smoking.

Publication types

  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies / genetics*
  • Autoantibodies / immunology*
  • Citrulline / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / immunology
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • HLA-DRB1 Chains / genetics*
  • Humans
  • Male
  • Middle Aged
  • Smoking / immunology
  • Socioeconomic Factors


  • Autoantibodies
  • Epitopes
  • HLA-DRB1 Chains
  • Citrulline