Assessing causality between frailty and lung cancer: A bi-directional Mendelian randomization analysis

<bold>Background:</bold> Lung cancer is globally prevalent, often linked with frailty. This study, utilizing Mendelian randomization with UK Biobank frailty and TRICL lung cancer GWAS summary data, reveals causative relationships. <bold>Methods:</bold> Bi-directional Mendelian randomization, employing IVW, MR-Egger, and weighted median methods, was conducted. Sensitivity tests included Cochran’s Q, MR-Egger intercept, leave-one-out, and MR-PRESSO. <bold>Results:</bold> Genetically predicted higher Fried frailty score (FFS) robustly causally relates to small cell lung cancer (SCLC) (P=0.003, OR=8.832). No causal effects were found for overall lung carcinoma and lung adenocarcinomas. IVW identified a significant association between genetically predicted FFS and lung squamous cell carcinoma (P=0.024). However, directions varied compared to MR-Egger (IVW: OR=2.45; MR-Egger: OR=0.065). Reverse MR suggests overall lung cancer increases frailty risk (IVW: P=0.025, OR=1.013). <bold>Conclusion:</bold> Genetically predicted higher FFS causally links to SCLC, while overall lung cancer is associated with increased frailty, highlighting the interplay between frailty and specific lung cancer subtypes. <fig><object-id>erj;64/suppl_68/PA4207/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>