Investigating the genetic causal link between iron regulation and lung cancer risk: A 2-sample Mendelian randomization analysis

Lung cancer (LC) is among the most prevalent cancers and is the leading cause of cancer-related mortality. Smoking behavior is the primary etiological factor for LC; however, the potential causal relationship with other risk factors, such as iron status, remains unclear. Currently, there is a significant lack of research investigating the potential causal link between iron homeostasis and LC development. This study employs a 2-sample Mendelian randomization approach to explore the causal relationship between these 2 entities. Data on small cell LC (SCLC) and non-small cell LC (NSCLC) were obtained from the FinnGen R11 database, while data on iron homeostasis, encompassing 4 indicators (ferritin, serum iron, total iron binding capacity, and transferrin saturation) were sourced from the Decode Genetic Sequence Bank. The inverse variance weighted analysis demonstrated a causal genetic association between ferritin levels (β = 0.351; 95% confidence interval = 1.006-2.046; P = .045) and SCLC. The application of Cochran Q test, Rucker Q test, MR Egger intercept, and MR-PRESSO global tests did not reveal any evidence of heterogeneity or pleiotropy (P > .05). In conclusion, from a genetic perspective, elevated ferritin levels are positively correlated with an increased risk of SCLC. Furthermore, no genetic causality was observed between the other 3 indicators of iron homeostasis and either SCLC or NSCLC, nor between ferritin and NSCLC.