Abstract
BACKGROUND: Although observational epidemiological studies have found that smoking is positively associated with risk of rheumatoid arthritis (RA), assessing the causality of this relationship has remained elusive because conventional observational studies are susceptible to bias such as confounding and reverse causation. Here, we applied the Mendelian randomization (MR) approach to examine the potential causal relationship between smoking and risk of RA. METHODS: Summary statistics data for RA were obtained from a meta-analysis of genome-wide association studies (GWAS), including 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables (IV) and the genetic association estimates for smoking initiation and lifetime smoking were obtained from a GWAS meta-analysis including 1,232,091 individuals and a GWAS of 462,690 individuals of European ancestry, respectively. MR analyses were performed using the inverse-variance weighted (IVW) method and supplemented with the weighted-median method. Potential pleiotropy was assessed using the MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test and MR-Egger regression. Sensitivity analyses were further performed to test the robustness of the association. RESULTS: We found that compared with never smokers, genetic predisposition to smoking initiation was positively associated with risk of RA (odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.15-1.52, P = 9.17 × 10(-5) using the IVW method). Similarly, genetically predicted lifetime smoking was associated with an increased risk of RA (OR = 1.55, 95% CI = 1.13-2.14, P = 0.007). Sensitivity analyses using alternative MR methods and different sets of IVs produced similar results, suggesting the robustness of our findings. CONCLUSIONS: These results provide support for a causal association between smoking and increased risk of RA. Further studies are warranted to explain the underlying mechanisms of smoking in the development of RA.