Research Article

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

  1. M. Tevfik Dorak MD, PhD1,*,
  2. Rachel K. Mackay BSc1,
  3. Caroline L. Relton PhD2,
  4. Mark Worwood PhD3,
  5. Louise Parker PhD4,
  6. Andrew G. Hall MBBS, PhD1

Article first published online: 26 AUG 2009

DOI: 10.1002/pbc.22236

Issue

Pediatric Blood & Cancer

Pediatric Blood & Cancer

Volume 53, Issue 7, pages 1242–1248, 15 December 2009

Additional Information

How to Cite

Dorak, M. T., Mackay, R. K., Relton, C. L., Worwood, M., Parker, L. and Hall, A. G. (2009), Hereditary hemochromatosis gene (HFE) variants are associated with birth weight and childhood leukemia risk. Pediatr. Blood Cancer, 53: 1242–1248. doi: 10.1002/pbc.22236

Author Information

  1. 1

    Northern Institute for Cancer Research, Newcastle University, Newcastle, UK

  2. 2

    Institute of Human Genetics, Newcastle University, Newcastle, UK

  3. 3

    Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK

  4. 4

    Community Health and Epidemiology, Department of Paediatrics, Dalhousie University IWK Health Centre, Halifax, Nova Scotia, Canada

*Head of Genomic Immunoepidemiology Laboratory, HUMIGEN LLC, The Institute for Genetic Immunology, 2439 Kuser Road, Hamilton, NJ 08690-3303.

  1. †

    The authors have no conflicts of interest to report.

Publication History

  1. Issue published online: 9 OCT 2009
  2. Article first published online: 26 AUG 2009
  3. Manuscript Accepted: 13 JUL 2009
  4. Manuscript Received: 28 APR 2009

Funded by

  • North of England Children's Cancer Research Fund
  • Foundation for Children with Leukaemia (London, U.K.)

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Keywords:

  • birth weight;
  • genetic predisposition to childhood leukemia;
  • genetic epidemiology;
  • HFE gene;
  • iron metabolism;
  • sex effect

Abstract

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. Pediatr Blood Cancer 2009; 53:1242–1248. © 2009 Wiley-Liss, Inc.

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