Genetic predisposition to smoking is associated with risk of rheumatoid arthritis: a Mendelian randomization study

Yu Qian,David J H Wu,Yingying Mao,Lingzhi Zhang,Chengping Wen,Zhijun Xie

doi:10.1186/s13075-020-2134-1

Abstract

BackgroundAlthough 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.MethodsSummary 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.ResultsWe 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.ConclusionsThese 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.

Highlights

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
Genetically predicted smoking initiation was positively associated with an increased risk of RA (odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.15–1.52, P = 9.17 × 10− 5) using the inverse-variance weighted (IVW) method (Fig. 2)
Though three possible outlier Single nucleotide polymorphism (SNP) were identified using the Mendelian randomization (MR)-PRESSO test, the effect estimate of the association between genetically predicted smoking initiation and risk of RA did not change markedly after outlier correction (OR = 1.32, 95% Confidence interval (CI) = 1.16–1.50, P = 2.62 × 10− 5)

Summary

Introduction

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. Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes cartilage and bone damage, functional loss, and associated comorbidity. It affects about 1% of the population and is more prevalent in women than in Historically, observational epidemiological studies have investigated smoking as an important modifiable risk factor for RA. Conventional observational studies generally rely on self-reported information and are susceptible to potential confounding and reverse causation.

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Conclusion