Bidirectional Mendelian randomization identifies differential causal associations between inflammatory cytokines and lung cancer subtypes

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) being its two primary subtypes. While inflammation plays a crucial role in cancer development, its specific functions in different lung cancer subtypes remain unclear. METHODS: This study employed a bidirectional two-sample Mendelian randomization (MR) approach, utilizing Genome-Wide Association Studies (GWAS) data for NSCLC (5,315 cases) and SCLC (717 cases) from the FinnGen biobank, along with 314,193 controls and GWAS data for 91 circulating inflammatory factors. We investigated the causal relationships between inflammatory factors and lung cancer risk. Instrumental variables were selected based on p-value < 1 × 10− 5 and F-statistic > 10, with linkage disequilibrium (LD) clumping (R2 0.05). Reverse analyses did not reveal significant effects of lung cancer on these inflammatory factor levels (all p-values > 0.05). CONCLUSION: This study elucidated potential causal relationships between specific inflammatory factors and the risk of NSCLC and SCLC, highlighting the complex roles of different inflammatory factors in the pathogenesis of these two lung cancer subtypes. These findings provide novel insights for molecular subtyping and personalized treatment strategies in lung cancer.