Causal effects of plasma protein–protein ratios on lung cancer subtypes: A proteome-wide Mendelian randomization and mediation analysis

Lung cancer remains the leading cause of cancer-related mortality worldwide, with major subtypes including lung adenocarcinoma, lung squamous cell carcinoma (LUSC), and small cell lung cancer, yet the causal role of plasma protein-protein ratios in subtype-specific development remains poorly understood. We performed a bidirectional, two-sample Mendelian randomization (MR) analysis to assess the causal effects of plasma protein-protein ratios on lung cancer. Genetic instruments for protein-protein ratios were derived from a large-scale proteomic genome-wide association study, and lung cancer summary statistics were obtained from the FinnGen and Transdisciplinary Research in Cancer of the Lung and International Lung Cancer Consortium databases. Our study identified 17 plasma protein-protein ratios associated with lung cancer across both databases, including 5 for overall lung cancer (LC), 4 for lung adenocarcinoma, 5 for LUSC, and 4 for small cell lung cancer. Notably, a higher melanoma inhibitory activity (MIA)/DAN family BMP antagonist ratio was associated with increased risk for both LC and LUSC. When analyzing the constituent proteins of these ratios individually, only the causal association between MIA and LC remained significant. Subsequent 2-step MR analysis revealed that the MIA/DAN family BMP antagonist ratio mediated the effect of body mass index on LUSC development, with consistent mediation proportions across both databases (13.46%, 95% confidence interval: 3.14%-23.77% in FinnGen; 9.26%, 95% confidence interval: 0.05%-18.47% in Transdisciplinary Research in Cancer of the Lung and International Lung Cancer Consortium). Additional exploratory mediation pathways were identified for smoking initiation and body mass index; however, these findings should be interpreted with caution, given the assumptions underlying 2-step MR and the exploratory nature of the analysis. Multiple sensitivity analyses confirmed the robustness of these findings. This MR study offers novel proteomic insights into lung cancer pathogenesis and identifies candidate protein-protein ratios that warrant further functional investigation to assess their therapeutic potential.