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.


METHODS
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.
Dorak
M Tevfik
MT
Northern Institute for Cancer Research, Newcastle University, Newcastle, UK. dorakmt@dorak.info
Mackay
Rachel K
RK
Relton
Caroline L
CL
Worwood
Mark
M
Parker
Louise
L
Hall
Andrew G
AG
D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D001724:Birth Weight / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004739:England / Q000453:epidemiology; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D020022:Genetic Predisposition to Disease; D006432:Hemochromatosis / Q000453:epidemiology / Q000235:genetics*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007223:Infant; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007501:Iron / Q000097:blood / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology* / Q000235:genetics; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000235:genetics*; D011990:Receptors, Transferrin / Q000235:genetics*; D012306:Risk; D012737:Sex Factors
D015703:Antigens, CD; D023181:Antimicrobial Cationic Peptides; C068126:CD71 antigen; C578702:HAMP protein, human; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D007501:Iron