Functional effects of a common single-nucleotide polymorphism (GPX4c718t) in the glutathione peroxidase 4 gene: interaction with sex

Catherine Meplan, Lynne K. Crosley, Fergus Nicol, Graham W. Horgan, John C. Mathers, John R. Arthur, John E. Hesketh

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Background: Selenium is essential for health in humans. Selenium is present as selenocysteine in selenoproteins such as the glutathione peroxidases (GPx). Selenocysteine incorporation requires specific structures in the 3'untranslated region (3'UTR) of selenoprotein mRNAs.
Objective: This study investigated the functional significance of the single-nucleotide polymorphism (SNP) GPx4c718t within the 3'UTR of the GPx4 gene.
Design: A selenium supplementation trial was carried out with prospectively genotyped individuals of both homozygote genotypes for this SNP. Blood samples were analyzed at baseline, after a 6-wk supplementation with 100 mu g Se as sodium selenite/d, and during a 6-wk washout period. RNA-protein binding studies were carried out in vitro.
Results: Both lymphocyte GPx I protein concentrations and plasma GPx3 activity increased significantly after selenium supplementation in CC but not IT participants. After selenium withdrawal, there was a significant fall in both lymphocyte GPx4 protein concentrations and GPx4 activity in TT but not in CC participants; this effect was modulated by sex. RNA-protein binding assays showed that both T and C variants of transcripts corresponding to the GPx4 3'UTR formed complexes in vitro and that the C variant bound more strongly than did either the T variant or the GPx1 3'UTR.
Conclusions: The GPX4c718t SNP both alters protein binding to the 3'UTR in vitro and influences the concentration of lymphocyte GPx4 and other selenoproteins in vivo. The latter is consistent with competition for selenium in selenoprotein synthesis, and, at low selenium intake, the SNP thus may influence susceptibility to disease.

Original languageEnglish
Pages (from-to)1019-1027
Number of pages9
JournalThe American Journal of Clinical Nutrition
Volume87
Issue number4
Publication statusPublished - Apr 2008

Keywords

  • hydroperoxide glutathione-peroxidase
  • selenocysteine incorporation
  • 3'-untranslated region
  • selenium deficiency
  • decoding apparatus
  • cancer prevention
  • binding protein
  • expression
  • RNA
  • selenoproteins

Cite this

Meplan, C., Crosley, L. K., Nicol, F., Horgan, G. W., Mathers, J. C., Arthur, J. R., & Hesketh, J. E. (2008). Functional effects of a common single-nucleotide polymorphism (GPX4c718t) in the glutathione peroxidase 4 gene: interaction with sex. The American Journal of Clinical Nutrition, 87(4), 1019-1027.

Functional effects of a common single-nucleotide polymorphism (GPX4c718t) in the glutathione peroxidase 4 gene : interaction with sex. / Meplan, Catherine; Crosley, Lynne K.; Nicol, Fergus; Horgan, Graham W.; Mathers, John C.; Arthur, John R.; Hesketh, John E.

In: The American Journal of Clinical Nutrition, Vol. 87, No. 4, 04.2008, p. 1019-1027.

Research output: Contribution to journalArticle

Meplan, C, Crosley, LK, Nicol, F, Horgan, GW, Mathers, JC, Arthur, JR & Hesketh, JE 2008, 'Functional effects of a common single-nucleotide polymorphism (GPX4c718t) in the glutathione peroxidase 4 gene: interaction with sex' The American Journal of Clinical Nutrition, vol. 87, no. 4, pp. 1019-1027.
Meplan, Catherine ; Crosley, Lynne K. ; Nicol, Fergus ; Horgan, Graham W. ; Mathers, John C. ; Arthur, John R. ; Hesketh, John E. / Functional effects of a common single-nucleotide polymorphism (GPX4c718t) in the glutathione peroxidase 4 gene : interaction with sex. In: The American Journal of Clinical Nutrition. 2008 ; Vol. 87, No. 4. pp. 1019-1027.
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abstract = "Background: Selenium is essential for health in humans. Selenium is present as selenocysteine in selenoproteins such as the glutathione peroxidases (GPx). Selenocysteine incorporation requires specific structures in the 3'untranslated region (3'UTR) of selenoprotein mRNAs. Objective: This study investigated the functional significance of the single-nucleotide polymorphism (SNP) GPx4c718t within the 3'UTR of the GPx4 gene. Design: A selenium supplementation trial was carried out with prospectively genotyped individuals of both homozygote genotypes for this SNP. Blood samples were analyzed at baseline, after a 6-wk supplementation with 100 mu g Se as sodium selenite/d, and during a 6-wk washout period. RNA-protein binding studies were carried out in vitro. Results: Both lymphocyte GPx I protein concentrations and plasma GPx3 activity increased significantly after selenium supplementation in CC but not IT participants. After selenium withdrawal, there was a significant fall in both lymphocyte GPx4 protein concentrations and GPx4 activity in TT but not in CC participants; this effect was modulated by sex. RNA-protein binding assays showed that both T and C variants of transcripts corresponding to the GPx4 3'UTR formed complexes in vitro and that the C variant bound more strongly than did either the T variant or the GPx1 3'UTR. Conclusions: The GPX4c718t SNP both alters protein binding to the 3'UTR in vitro and influences the concentration of lymphocyte GPx4 and other selenoproteins in vivo. The latter is consistent with competition for selenium in selenoprotein synthesis, and, at low selenium intake, the SNP thus may influence susceptibility to disease.",
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AU - Meplan, Catherine

AU - Crosley, Lynne K.

AU - Nicol, Fergus

AU - Horgan, Graham W.

AU - Mathers, John C.

AU - Arthur, John R.

AU - Hesketh, John E.

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N2 - Background: Selenium is essential for health in humans. Selenium is present as selenocysteine in selenoproteins such as the glutathione peroxidases (GPx). Selenocysteine incorporation requires specific structures in the 3'untranslated region (3'UTR) of selenoprotein mRNAs. Objective: This study investigated the functional significance of the single-nucleotide polymorphism (SNP) GPx4c718t within the 3'UTR of the GPx4 gene. Design: A selenium supplementation trial was carried out with prospectively genotyped individuals of both homozygote genotypes for this SNP. Blood samples were analyzed at baseline, after a 6-wk supplementation with 100 mu g Se as sodium selenite/d, and during a 6-wk washout period. RNA-protein binding studies were carried out in vitro. Results: Both lymphocyte GPx I protein concentrations and plasma GPx3 activity increased significantly after selenium supplementation in CC but not IT participants. After selenium withdrawal, there was a significant fall in both lymphocyte GPx4 protein concentrations and GPx4 activity in TT but not in CC participants; this effect was modulated by sex. RNA-protein binding assays showed that both T and C variants of transcripts corresponding to the GPx4 3'UTR formed complexes in vitro and that the C variant bound more strongly than did either the T variant or the GPx1 3'UTR. Conclusions: The GPX4c718t SNP both alters protein binding to the 3'UTR in vitro and influences the concentration of lymphocyte GPx4 and other selenoproteins in vivo. The latter is consistent with competition for selenium in selenoprotein synthesis, and, at low selenium intake, the SNP thus may influence susceptibility to disease.

AB - Background: Selenium is essential for health in humans. Selenium is present as selenocysteine in selenoproteins such as the glutathione peroxidases (GPx). Selenocysteine incorporation requires specific structures in the 3'untranslated region (3'UTR) of selenoprotein mRNAs. Objective: This study investigated the functional significance of the single-nucleotide polymorphism (SNP) GPx4c718t within the 3'UTR of the GPx4 gene. Design: A selenium supplementation trial was carried out with prospectively genotyped individuals of both homozygote genotypes for this SNP. Blood samples were analyzed at baseline, after a 6-wk supplementation with 100 mu g Se as sodium selenite/d, and during a 6-wk washout period. RNA-protein binding studies were carried out in vitro. Results: Both lymphocyte GPx I protein concentrations and plasma GPx3 activity increased significantly after selenium supplementation in CC but not IT participants. After selenium withdrawal, there was a significant fall in both lymphocyte GPx4 protein concentrations and GPx4 activity in TT but not in CC participants; this effect was modulated by sex. RNA-protein binding assays showed that both T and C variants of transcripts corresponding to the GPx4 3'UTR formed complexes in vitro and that the C variant bound more strongly than did either the T variant or the GPx1 3'UTR. Conclusions: The GPX4c718t SNP both alters protein binding to the 3'UTR in vitro and influences the concentration of lymphocyte GPx4 and other selenoproteins in vivo. The latter is consistent with competition for selenium in selenoprotein synthesis, and, at low selenium intake, the SNP thus may influence susceptibility to disease.

KW - hydroperoxide glutathione-peroxidase

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KW - 3'-untranslated region

KW - selenium deficiency

KW - decoding apparatus

KW - cancer prevention

KW - binding protein

KW - expression

KW - RNA

KW - selenoproteins

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JO - The American Journal of Clinical Nutrition

JF - The American Journal of Clinical Nutrition

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