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Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins
  1. Aase Haj Hensvold1,
  2. Patrik K E Magnusson2,
  3. Vijay Joshua1,
  4. Monika Hansson1,
  5. Lena Israelsson1,
  6. Ricardo Ferreira3,
  7. Per-Johan Jakobsson1,
  8. Rikard Holmdahl4,
  9. Lennart Hammarström3,
  10. Vivianne Malmström1,
  11. Johan Askling1,5,
  12. Lars Klareskog1,
  13. Anca Irinel Catrina1
  1. 1Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
  2. 2Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  3. 3Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
  4. 4Medical Inflammation Research, Department of Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  5. 5Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  1. Correspondence to Dr Anca I Catrina, Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm 171 76, Sweden; anca.catrina{at}ki.se

Abstract

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.

  • Ant-CCP
  • Smoking
  • Rheumatoid Arthritis
  • Autoantibodies

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