Hereditary hemochromatosis gene (HFE) variants are associated with birth weight and childhood leukemia risk.

Background: Our original studies reported an association between the iron-metabolism gene HFE and risk of childhood acute lymphoblastic leukemia (ALL), and a birth weight association in ALL. Through its effect on cell proliferation, iron is involved in both fetal development and cancer. We hypothesize that HFE links higher infant birth weight with leukemia risk and that maternal HFE genotype modifies this association.

Procedure: Nine hundred ninety-five infants and their mothers from the North Cumbria Community Genetics Project, and 163 incident childhood ALL cases from the Newcastle Haematology Biobank were genotyped for HFE, HAMP, TFRC variants and 21 genomic control loci. Cord blood iron levels were measured in 217 control infants.

Results: Three HFE variants showed correlations with birth weight with a gene-dosage relationship in males (gender effect). The association was stronger in homozygotes for TFRC S142G and when the mother was positive for any HFE variant (maternal effect). The genotypes expected to increase fetal iron levels correlated with birth weight in males and their association with ALL was stronger in females who, we postulate, could not offset iron excess by increasing their weight.

Conclusions: Certain materno-fetal genotype combinations that increase fetal iron exposure showed associations with higher birth weight in males and somewhat higher ALL risk in females. Gender-specific use of iron during fetal growth may lead to this dichotomy in birth weight change. Only the materno-fetal genotype combinations that increase iron levels most extremely correlated with birth weight and ALL risk in males.