School of Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
Arthritis Res Ther. 2020 Mar 6;22(1):44. doi: 10.1186/s13075-020-2134-1.
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.
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.
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 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.
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.
尽管观察性流行病学研究发现吸烟与类风湿关节炎（RA）风险呈正相关，但评估这种关系的因果关系仍然难以捉摸，因为传统的观察性研究容易受到混杂和反向因果关系等偏差的影响。在这里，我们应用孟德尔随机化（MR）方法来检验吸烟与 RA 风险之间潜在的因果关系。
从全基因组关联研究（GWAS）的荟萃分析中获得 RA 的汇总统计数据，包括 14361 例 RA 病例和 43923 例欧洲血统对照。吸烟起始和终生吸烟的工具变量（IV）和遗传关联估计值分别来自包括 1232091 个人的 GWAS 荟萃分析和包括 462690 个人的欧洲血统的 GWAS。使用逆方差加权（IVW）方法和加权中位数方法进行 MR 分析。使用 MR-Pleiotropy RESidual Sum and Outlier（MR-PRESSO）检验和 MR-Egger 回归评估潜在的混杂。进一步进行敏感性分析以测试关联的稳健性。
我们发现，与从不吸烟者相比，吸烟起始的遗传易感性与 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 使用 IVW 方法）。同样，遗传预测的终生吸烟与 RA 风险增加相关（OR=1.55，95%CI=1.13-2.14，P=0.007）。使用替代 MR 方法和不同 IV 集的敏感性分析产生了类似的结果，表明我们的发现具有稳健性。
这些结果为吸烟与 RA 风险增加之间存在因果关系提供了支持。需要进一步的研究来解释吸烟在 RA 发展中的潜在机制。
