Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes

Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI = 0.83-2.35), which increased to 2.96 (95% CI = 1.29-6.80) in the presence of a particular TFRC genotype for rs3817672 (Pinteraction = 0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR = 2.54, 95% CI = 1.05-6.12; Pinteraction with ethnicity = 0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR = 1.52-2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR = 2.0 per incremental change, 95% CI = 1.29-3.12; P = 0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.