Causal relationships between plasma protein ratios and lung cancer risk: a Mendelian randomization study

Plasma proteins significantly influence the pathogenesis and progression of Lung cancer (LC). However, research examining the plasma protein-to-protein ratios (rQTL) in LC is limited. Mendelian randomization (MR) uses genetic variants as instrumental variables to infer causal relationships between exposures and outcomes, minimizing confounding and reverse causation. The rQTL approach captures biologically meaningful protein-protein interactions and pathway-level regulation that may be missed when studying individual proteins. We performed a two-sample MR analysis by using summary statistics to investigate the causal relationship between rQTLs and LC risk. Reverse MR analysis confirmed unidirectional causality. Additionally, Bayesian and Susie colocalization analyses were conducted to assess the strength of causal relationships, whereas linkage disequilibrium score regression (LDSC) genetic scores were used to examine the robustness of the genetic associations. The discovery cohort identified 20 significant rQTLs associated with LC risk after false discovery rate correction, with the strongest effects observed for: DNAJA2/SCAMP3 (OR = 0.66, 95% CI, 0.54–0.81), CNST/MAVS (OR = 1.40, 95% CI, 1.05–1.88), whereas the LDSC genetic score for DNAJA2/SCAMP3 and DSC2/SPINT1 exhibited statistical significance. Replication confirmed CNST/MAVS (OR = 1.002, 95% CI, 0.993–1.007) and four additional rQTLs (BSG/TNFRSF4, AXIN1/HEXIM1, BIN2/F11R, and CDC27/CEP85). Sensitivity analyses confirmed no evidence of pleiotropy and robust causal estimates. This study provides genetic evidence supporting causal roles for specific plasma protein ratios in LC susceptibility. These findings highlight the value of protein ratio-based biomarkers and suggest potential targets for further mechanistic and clinical investigation. The identified rQTLs may contribute to improved risk prediction and therapeutic strategies for LC.