Exploring the Causal Relationship Between Frailty and Chronic Obstructive Pulmonary Disease: Insights From Bidirectional Mendelian Randomization and Mediation Analysis

Zewen Cheng,1 Jian Wu,1 Chun Xu,2 Xiaokun Yan1 1Department of Thoracic Surgery, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, Jiangsu, 215000, People’s Republic of China; 2Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, People’s Republic of ChinaCorrespondence: Xiaokun Yan, Department of Thoracic Surgery, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, Jiangsu, 215000, People’s Republic of China, Email [email protected]: Observational studies have underscored a robust association between frailty and chronic obstructive pulmonary disease (COPD), yet the causality remains equivocal.Methods: This study employed bidirectional two-sample Mendelian randomization (MR) analysis. Univariable MR investigated the causal relationship between frailty and COPD. Genetic correlation was assessed using linkage disequilibrium score (LDSC) regression. Multivariable MR and mediation analysis explored the influence of various confounders and their mediating effects. The primary analytic approach was inverse variance weighted (IVW).Results: LDSC analysis revealed moderate genetic correlations between frailty and Global Biobank Meta-Analysis Initiative (GBMI) COPD (rg = 0.643, P = 6.66× 10− 62) as well as FinnGen COPD (rg = 0.457, P = 8.20× 10− 28). IVW analysis demonstrated that frailty was associated with increased risk of COPD in both the GBMI cohort (95% CI, 1.475 to 2.158; P = 2.40× 10− 9) and the FinnGen database (1.411 to 2.434; 9.02× 10− 6). Concurrently, COPD was identified as a susceptibility factor for frailty (P < 0.05). These consistent findings persisted after adjustment for potential confounders in MVMR. Additionally, mediation analysis revealed that walking pace mediated 19.11% and 15.40% of the impact of frailty on COPD risk, and 17.58% and 23.26% of the effect of COPD on frailty risk in the GBMI and FinnGen cohorts, respectively.Conclusion: This study has strengthened the current evidence affirming a reciprocal causal relationship between frailty and COPD, highlighting walking pace as a pivotal mediator.Keywords: frailty, COPD, Mendelian randomization, mediation analysis, causality