In this TSMR study, we estimated the causal link between serum iron status and the risk of lung cancer based on genetic summary data from two previously GWASs. According to the estimates of MR analyses, we revealed that genetic predisposition to lower levels of serum iron was causally associated with a higher risk of lung cancer, while no significant causal effect was observed in transferrin saturation, ferritin, and transferrin. The association was driven by rs855791, which had the largest impact on iron status among the IVs. These findings might provide novel insights into the association of serum iron status with lung tumorigenesis.
To figure out the genetic association between systemic iron status and lung cancer, we used only the three SNPs proxied for all four iron status markers at genome-wide significance. These SNPs have a concordant direction of effect on serum iron, transferrin saturation, ferritin, and transferrin, thus to be valid instruments. Several sensitivity analyses were performed to support the direct causal relationship between serum iron and lung cancer. However, the causal estimates for transferrin saturation, ferritin, and transferrin showed an insignificant trend on the risk of lung cancer. This inconsistence might be attributed to the selected genetic IVs and the different populations derived from GWAS summary data. Future studies based on more robust GWASs are warranted to address the inconsistence.
Iron is an essential trace element required for cellular activities. Both iron overload and iron deficiency are related to significant abnormalities in cellular function . Given that, experimental studies have demonstrated a dual role of iron in tumor growth and metastasis . Epidemiological studies have suggested an association between excess iron and increased cancer incidence and risk . However, there are still controversies for iron status in cancer initiation and progression. Particularly, epidemiological studies on the role of iron status in lung cancer are sparse and inconsistent. Moreover, a recent TSMR study reported the associations of iron status with overall cancer and 22 site-specific cancers, and provide no evidence in support of a causal association between iron status and lung cancer . To be noted, the summary data for lung cancer used in the study contained only 2,838 individuals from UK Biobank, which might have limited potency to obtain meaningful results. Herein, we took advantage of the summary data from ILCCO composed of 11,348 cases and 15,861 controls, and indicated the causal association of serum iron with lung cancer.
However, there are several limitations in our study. First, our results were based on GWAS summary data from European populations, which impeded the generalization of findings to other populations. Second, linear association of iron status biomarkers with lung cancer was obtained by MR analyses, but U-shaped relationship or threshold effect may be more fitting and proper in practice. Third, this study did not explore the causal effect of iron status on different histologic subtypes of lung cancer including adenocarcinoma, squamous carcinoma, and non-small cell lung cancer.
In summary, our work suggested the causal association of reduced serum iron with an increased risk of lung cancer, while the levels of transferrin saturation, ferritin, and transferrin were not significantly associated with lung cancer. Future studies are required to explore the exact mechanism and relationship of iron status with lung cancer, which may provide a clinical value for prevention and treatment strategy.