From chronic obstructive pulmonary disease (COPD) to lung cancer: a Mendelian randomization study revealing mediation...

Chronic obstructive pulmonary disease (COPD) and lung cancer are pathologically intertwined, with chronic inflammation fostering carcinogenic transformation through dynamic interactions in the tumor microenvironment.

This investigation utilized a comprehensive two-sample Mendelian randomization (MR) approach on public genetic datasets to mitigate confounding and determine causality between COPD and lung cancer. We integrated 1400 plasma metabolite characteristics (N = 8299), 731 immune cell attributes (N = 3757), and 4907 plasma protein characteristics (N = 35,559), employing two-sample MR to deduce causal correlations with lung cancer. Sensitivity assessments were executed to fortify the robustness of MR outcomes. Finally, Mendelian mediation analysis was administered to delineate the pathways mediated by plasma immune cells, metabolites, and proteins in the COPD-to-lung cancer continuum. Additionally, we validated our findings using external datasets from the NHANES and TCGA databases to further confirm the reliability of the results.

MR analysis confirmed COPD as a causal risk factor for lung cancer (IVW P-value = 1.38 × 10^-5, OR = 1.63(1.31-2.02). We recognized 96 plasma metabolites (comprising 77 distinct metabolites and 19 ratios), 30 immune cell categories, and 58 plasma proteins as having putative causal associations with lung cancer. Mediation analysis revealed 9 mediator interactions, implicating 3 immune cell types, 1 metabolite, and 5 proteins, Sensitivity analyses verified homogeneity and negated pleiotropic effects.

Our genetic inquiry endorses a causal link from COPD to lung cancer, mediated through plasma-based immunological, metabolic, and proteomic mechanisms. These biomarkers afford groundbreaking insights into the etiology of lung cancer, facilitating its prophylaxis, diagnosis, and therapeutic interventions.