Causal association of rheumatoid arthritis with obstructive lung disease: Evidence from Mendelian randomization study

Observational studies have found an association between rheumatoid arthritis (RA) and risk of obstructive lung disease (ORDs). However, whether RA plays a role in ORDs development remains unclear.This study aimed to explore the causal association of RA with ORDs.Both univariable and multivariable Mendelian randomization (MR) analyses were employed. Summary statistics for RA were obtained from the genome-wide association study (GWAS) meta-analysis, and the GWAS data source of ORDs, including the chronic obstructive pulmonary disease (COPD) and asthma, was accessed from the FinnGen Biobank. Causal Analysis Using Summary Effect Estimates (CAUSE) method was used to improve statistical power. multivariable and two-step mediation MR was applied to calculate the independent and mediated effects.The causal estimates by univariable and CAUSE results indicated genetic predisposition to RA had an effect on the increased risk of asthma/COPD (A/C) (ORCAUSE = 1.03; 95% CI: 1.02-1.04), COPD/asthma related infections (ACI) (ORCAUSE = 1.02; 95% CI: 1.01-1.03) and COPD/asthma related pneumonia or pneumonia derived septicemia (ACP) (ORCAUSE = 1.02; 95% CI: 1.01-1.03). Genetic predisposition to RA was significantly associated with early onset COPD (ORCAUSE = 1.02; 95% CI: 1.01-1.03) and asthma (ORCAUSE = 1.02; 95% CI: 1.01-1.03) risk and suggestively associated with non-allergic asthma (nAA) risk. After adjustment for confounders, independent causal effects remained for the associations of RA with risk of A/C, ACI, and ACP, as well as COPD, early-onset COPD, and asthma [total, nAA and allergic asthma (AA)] risk. Mediation analyses revealed no potential mediator.This study indicates a causal effect of increased genetic predisposition to RA on an increased risk of ORDs, including COPD and asthma, especially early-onset COPD and nAA, and on asthma/COPD related infections, pneumonia or pneumonia derived septicemia.