Interaction between smoking, the shared epitope, and anti–cyclic citrullinated peptide: A mixed picture in three large North American rheumatoid arthritis cohorts

Objective Recently, Swedish members of the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) provided evidence that smoking may trigger RA‐specific immune reactions to citrullinated protein in carriers of HLA–DR shared epitope alleles. In an effort to confirm this interaction between smoking and shared epitope alleles, we performed a case‐only analysis of 3 North American RA cohorts. Methods A total of 2,476 white patients with RA were studied, 1,105 from the North American Rheumatoid Arthritis Consortium (NARAC) family collection, 753 from the National Inception Cohort of Rheumatoid Arthritis Patients (Inception Cohort), and 618 from the Study of New Onset Rheumatoid Arthritis (SONORA). All patients were HLA–DRB1 typed, and tested for anti–cyclic citrullinated peptide (anti‐CCP) and rheumatoid factor. Information about smoking history was obtained by questionnaire. Results A significant association was found between smoking and the presence of anti‐CCP in the NARAC and the Inception Cohort, but not in the SONORA. The shared epitope alleles consistently correlated with anti‐CCP in all 3 populations. Using multiple logistic regression analyses, shared epitope alleles were still the most significant risk factor for anti‐CCP positivity. Weak evidence of gene–environment interaction between smoking and shared epitope alleles for anti‐CCP formation was found only in the NARAC. Conclusion Unlike the EIRA data, we could not confirm a major gene–environment interaction for anti‐CCP formation between shared epitope alleles and smoking in 3 North American RA cohorts. Our data indicate a need for further studies to address the full range of environmental factors other than smoking that may be associated with citrullination and RA.