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.

中文翻译：

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吸烟的遗传易感性与类风湿关节炎的风险有关：孟德尔随机研究。

背景技术尽管观察性流行病学研究发现吸烟与类风湿性关节炎（RA）的风险呈正相关，但是评估这种关系的因果关系仍然很困难，因为常规的观察性研究容易受到诸如混杂和反向因果关系的偏见的影响。在这里，我们应用孟德尔随机（MR）方法来检查吸烟与RA风险之间的潜在因果关系。方法RA的汇总统计数据来自全基因组关联研究（GWAS）的荟萃分析，包括14361例RA病例和43923例欧洲血统对照。从GWAS荟萃分析获得的吸烟开始和终生吸烟的工具变量（IV）和遗传关联估计值包括1,232,091个人和GWAS为462，分别有690名欧洲血统的人。MR分析使用反方差加权（IVW）方法进行，并辅以加权中值方法。潜在多效性使用MR多效性残差和和（MR-PRESSO）测试和MR-Egger回归进行评估。进一步进行敏感性分析以测试关联的鲁棒性。结果我们发现，与从不吸烟的人相比，吸烟的遗传易感性与RA风险呈正相关（比值比（OR）= 1.32，95％置信区间（CI）= 1.15-1.52，P = 9.17×10-5） IVW方法）。同样，从遗传学角度预测终生吸烟与RA风险增加相关（OR = 1.55，95％CI = 1.13-2.14，P = 0.007）。使用替代的MR方法和不同的IV组进行的敏感性分析产生了相似的结果，表明了我们发现的稳健性。结论这些结果为吸烟与RA风险增加之间的因果关系提供了支持。有必要进行进一步的研究来解释吸烟在RA发生中的潜在机制。