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

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.

• Authors: Aase Haj Hensvold, Patrik K E Magnusson, Vijay Joshua, Monika Hansson, Lena Israelsson, Ricardo Ferreira, Per-Johan Jakobsson, Rikard Holmdahl, Lennart Hammarström, Vivianne Malmström, Johan Askling, Lars Klareskog, Anca Irinel Catrina
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 74 Issue 2 Pg. 375-80 (Feb 2015) ISSN: 1468-2060 [Electronic] England
• PMID: 24276366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Twin Study)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Chemical References

• Autoantibodies
• Epitopes
• HLA-DRB1 Chains
• Citrulline

Topics

• Aged
• Aged, 80 and over
• Arthritis, Rheumatoid (genetics, immunology)
• Autoantibodies (genetics, 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