Causal Relationship Between Metabolic Traits and Risk of NSCLC: A Two-Sample Mendelian Randomization Analysis

Although the impact of circulating metabolites on the immune microenvironment of lung cancer has been recognized, the causal relationship between these metabolites and non-small cell lung cancer (NSCLC) remains unclear. We investigated whether 233 metabolic traits have a causal effect on NSCLC using data from population-based genome-wide association studies (GWAS). We employed the inverse variance weighted (IVW) method with random effects as the primary analytical tool. After performing two-sample Mendelian randomization (MR) analysis of 233 metabolic traits on NSCLC risk, we selected the significant ones for further sensitivity analyses. Applying a false discovery rate (FDR) correction (P_FDR < 0.05), we identified a causal relationship between two metabolic traits and NSCLC: the ratio of Omega-3 fatty acids to total fatty acids (Omega_3_pct) (OR: 1.18, 95% CI: 1.08-1.29, P_FDR=0.036) and the ratio of 22:6 docosahexaenoic acid to total fatty acids (DHA_pct) (OR: 1.26, 95% CI: 1.11-1.42, P_FDR=0.036). Sensitivity analyses yielded consistent results. We innovatively utilized GWAS data for multiple metabolic traits to conduct a two-sample Mendelian randomization analysis of the association between 233 metabolic traits and NSCLC. The findings suggest that higher proportions of Omega-3 fatty acids and 22:6 docosahexaenoic acid in total fatty acids may causally increase the risk of NSCLC, providing novel insights into the role of circulating metabolites in lung cancer development.