Association between serum iron status and primary liver cancer risk: a Mendelian randomization analysis

Background: Serum iron status has been reported as associated with primary liver cancer (PLC) risk. However, whether iron status plays a role in the development of PLC remains inconclusive. Methods: Genetic summary statistics of the four biomarkers (serum iron, ferritin, transferrin saturation, and transferrin) of iron status and PLC were retrieved from two independent genome-wide association studies (GWAS) that had been performed in European populations. Two-sample univariate and multivariate Mendelian randomization (MR) analyses were conducted to determine the causal link between iron status and PLC risk. Results: No significant horizontal pleiotropy was detected for the four biomarkers according to the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test. No evidence of between-single nucleotide polymorphism (SNP) heterogeneity and directional pleiotropy was detected by the Cochran's Q test and MR-Egger regression for serum iron, ferritin, and transferrin. For transferrin saturation, although no heterogeneity was detected, the directional pleiotropy was significant (P value for intercept of MR-Egger regression =0.033). Univariate MR estimates based on inverse variance weighting (IVW) method suggested that there was no causal link between serum iron [odds ratio (OR) =0.71, 95% confidence interval (CI): 0.45 to 1.11], ferritin (OR =0.56, 95% CI: 0.16 to 2.04), and transferrin (OR =0.91, 95% CI: 0.72 to 1.15) and PLC risk. We found a significant causal relationship between transferrin saturation and PLC risk (OR =0.45, 95% CI: 0.22 to 0.90), although this link was non-significant in multivariate MR analysis. Conclusions: There might be no causal relationship between iron status and PLC risk. However, data from larger sample size and people with different ethnic background were needed to further validate our findings.