The role of chronic obstructive pulmonary disease mediated by immune cells on lung adenocarcinoma: A two-step, two-sample Mendelian randomization study

Chronic obstructive pulmonary disease (COPD) commonly co-occurs with lung cancer, particularly lung adenocarcinoma (LUAD), suggesting a potential shared molecular mechanism and risk factors between the 2 conditions. This study aimed to explore the causal relationship between COPD and LUAD mediated by immune cells using a 2-step, 2-sample Mendelian randomization (MR) analysis. The random-effect inverse variance weighted method, which combines the Wald ratio of individual single-nucleotide polymorphisms, was employed as the primary approach for causal inference, with random-effects models utilized in the presence of heterogeneity. Mediation analysis was conducted to assess indirect effects in the pathway from COPD to LUAD. The MR analysis demonstrated that COPD increased the risk of LUAD (odds ratio = 1.180, 95% confidence interval [CI]: 1.004-1.387, P = .045). Furthermore, among 40 immune cell traits examined, 5 were associated with an elevated risk of LUAD, while 6 exhibited a detrimental effect. Importantly, the mediation MR analysis revealed that the indirect impact of COPD on LUAD was partially mediated by Activated & resting Treg cells (mediation effect: 0.010, 95% CI: 0.001-0.021; P = .047) and Activated & secreting Treg cells (mediation effect: 0.004, 95% CI: 0.001-0.008; P = .044). These findings suggest a positive association between COPD and LUAD, with a partial mediation effect through Activated & resting Treg cells and Activated & secreting Treg cells.