Genetic-Based Tools for Investigating Causal Associations between Immune Cells, Blood Metabolites, and Lung Cancer Risk: A Two-Sample Mendelian Randomization Study

Background Previous observational studies have suggested a potential link between immune cell and blood metabolite levels and lung cancer risk, but the causality remains unclear. We aimed to investigate this relationship using a two-sample Mendelian randomization (MR) study and to explore the potential mediation by blood metabolites. Methods Genome-wide association study (GWAS) exposure data were extracted from immune cell levels in 3757 Europeans and blood metabolite levels in 8192 Europeans and ultimately analyzed in integration with the GWAS dataset of European lung cancer cases containing 492,803 samples. The inverse variance weighting (IVW) method was mainly applied for MR analysis, and MR-Egger regression with MR residuals was used to assess the potential level pleiotropy. Heterogeneity was detected using Cochran's Q test. Reverse MR analyses were also performed to assess reverse causality. Results MR analysis conclusively identified 5 immune cell and 20 metabolite profiles as strongly causally associated with lung cancer risk (p < 0.01). In addition, reverse MR analysis and mediated Mendelian analysis revealed that one type of immune cell may mitigate the risk of developing lung cancer by influencing a specific blood metabolite-related metric: CD39 + secreting Tregs (OR: 0.958, 95% CI: 0.931–0.985, p = 0.002) and sphingomyelin (d18:2/14:0, d18:1/14:1) levels (OR: 1.176, 95% CI: 1.041–1.329, p = 0.009). Conclusions Our study confirmed a causal relationship between immune cells and lung cancer risk, which may be mediated by blood metabolites. These findings provide a basis for future investigations into targeted prevention strategies.