Association between rheumatoid arthritis-interstitial lung disease and lung cancer: a two -sample Mendelian randomization study with East Asian genetic instruments.

OBJECTIVES: Epidemiological studies consistently report an increased risk of lung cancer among rheumatoid arthritis patients. Proposed risk factors include male sex, smoking, and rheumatoid arthritis-associated interstitial lung disease. However, whether a direct genetic causal link exists between rheumatoid arthritis-associated interstitial lung disease and lung cancer remains unexplored. We used Mendelian randomization with East Asian genetic instruments to evaluate this relationship. METHODS: We conducted a two-sample Mendelian randomization in which genetic instruments for rheumatoid arthritis-associated interstitial lung disease were derived from an East Asian GWAS (358 RA-ILD cases, 4 550 RA controls), and lung cancer associations were obtained from a cross-ancestry GWAS meta-analysis (20 378 cases, 18 696 controls). Causal effects were estimated using inverse-variance weighted, Mendelian randomization-Egger, and weighted median methods. RESULTS: Ten single nucleotide polymorphisms were identified as genetic instruments. Inverse-variance weighted analysis revealed no significant causal association between genetically predicted rheumatoid arthritis-associated interstitial lung disease and lung cancer (odds ratio = 1.00; 95% confidence interval: 0.99-1.01; p-value = 0.78). Sensitivity analyses showed no horizontal pleiotropy or heterogeneity. CONCLUSIONS: Our findings suggest that the severe lung complications of rheumatic arthritis do not inherently share a direct, genetically driven pathway with malignancy. The observed clinical risk may be explained by shared environmental factors, such as smoking, or chronic immune dysregulation, rather than inherent genetic pleiotropy, although further investigation is needed to clarify these mechanisms.