Gene-environmental interaction between smoking and shared epitope on the development of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: A meta-analysis

Objective: The aim of this study was to determine the gene-environment interactions of smoking and shared epitope (SE) both separately and combined on anti-cyclic citrullinated peptide (CCP) antibodies in patients with rheumatoid arthritis (RA). Methods: The literature was searched using the MEDLINE, EMBASE and Cochrane databases. A meta-analysis on the associations between tobacco exposure (TE) and/or SE and the development of anti-CCP antibodies in patients with RA was performed. Results: Eight comparison studies with 5317 RA patients were considered in this meta-analysis. The odds ratio (OR) for positive anti-CCP antibodies in TE+/SE- patients with RA was increased compared with TE-/SE- patients (OR = 1.373, 95% CI = 1.111-1.698, P = 0.003). The ORs for positive anti-CCP antibodies in TE-/SE+ patients and TE+/SE+ patients with RA were also increased compared with TE-/SE- patients (OR = 2.678, 95% CI = 2.031-3.532, P < 1.0 × 1^0-9 in TE-/SE+; OR = 4.233, 95% CI = 2.458-7.291, P = 1.9 × 10^-8 in TE+/SE+). Stratification by ethnicity indicated the same pattern as that shown in the overall group. The OR for positive anti-CCP antibodies in TE+/SE+ patients with RA was much higher than in TE-/SE- patients in Europeans and Asians (OR = 3.879, 95% CI = 2.203-6.830, P = 2.6 × 10^-7; OR = 10.504, 95% CI = 3.182-34.67, P = 1.1 × 10^-4). Conclusions: This meta-analysis suggests a gene-environmental interaction between smoking and SE for the development of anti-CCP antibodies.