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Genes & Nutrition

, Volume 2, Issue 2, pp 225–232 | Cite as

Evidence that a polymorphism within the 3′UTR of glutathione peroxidase 4 is functional and is associated with susceptibility to colorectal cancer

  • G. Bermano
  • V. Pagmantidis
  • N. Holloway
  • S. Kadri
  • N. A. G. Mowat
  • R. S. Shiel
  • J. R. Arthur
  • J. C. Mathers
  • A. K. Daly
  • J. Broom
  • J. E. HeskethEmail author
Research Paper

Abstract

Low selenium (Se) status has been associated with increased risk of colorectal cancer (CRC). Se is present as the amino acid selenocysteine in selenoproteins, such as the glutathione peroxidases. Se incorporation requires specific RNA structures in the 3′ untranslated region (3′UTR) of the selenoprotein mRNAs. A single nucleotide polymorphism (SNP) occurs at nucleotide 718 (within the 3′UTR) in the glutathione peroxidase 4 gene. In the present study, Caco-2 cells were transfected with constructs in which type 1 iodothyronine deiodinase coding region was linked to the GPx4 3′UTR with either C or T variant at position 718. Higher reporter activity was observed in cells expressing the C variant compared to those expressing the T variant, under either Se-adequate or Se-deficient conditions. In addition, a disease association study was carried out in cohorts of patients with either adenomatous polyps, colorectal adenocarcinomas and in healthy controls. A higher proportion of individuals with CC genotype at the GPx4 T/C 718 SNP was present in the cancer group, but not in the polyp group, compared with the control group (P < 0.05). The present data demonstrate the functionality of the GPx4 T/C 718 SNP and suggest that T genotype is associated with lower risk of CRC.

Keywords

Colorectal cancer GPx4 Reporter gene Selenium SNP 3′Untranslated region 

Notes

Acknowledgments

We thank the World Cancer Research Fund for financial support (grants 2000/10, 2002/41), clinical staff for assistance with sampling and the patients for consenting to take part in this study. We greatly acknowledge Brian Burtle, Rebecca Lamb, Leanne Boulding and Rachel Ledward for help with genotyping and Fergus Nicol for help with IDI activity assay. JRA’s lab is funded by The Scottish Executive Environment and Rural Affairs Department (SEERAD). Conflict of interest-None declared.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • G. Bermano
    • 1
  • V. Pagmantidis
    • 2
  • N. Holloway
    • 1
  • S. Kadri
    • 3
  • N. A. G. Mowat
    • 3
  • R. S. Shiel
    • 4
  • J. R. Arthur
    • 5
  • J. C. Mathers
    • 6
  • A. K. Daly
    • 8
  • J. Broom
    • 1
  • J. E. Hesketh
    • 7
    Email author
  1. 1.School of Life SciencesThe Robert Gordon UniversityAberdeenUK
  2. 2.Institute for Cell and Molecular BiosciencesNewcastle UniversityNewcastle upon TyneUK
  3. 3.Aberdeen Royal InfirmaryAberdeenUK
  4. 4.School of Agriculture and Rural DevelopmentNewcastle UniversityNewcastle upon TyneUK
  5. 5.Rowett Research InstituteAberdeenUK
  6. 6.School of Clinical Medical Sciences and Human Nutrition Research CentreNewcastle UniversityNewcastle upon TyneUK 
  7. 7.Institute for Cell and Molecular Biosciences and Human Nutrition Research CentreNewcastle UniversityNewcastle upon TyneUK 
  8. 8.School of Clinical and Laboratory SciencesNewcastle UniversityNewcastle upon TyneUK 

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