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Functional effects of a common single-nucleotide polymorphism (GPX4c718t) in the glutathione peroxidase 4 gene: interaction with sex^1,2,3

¹ From the Institute for Cell and Molecular Biosciences (CM and JEH), the Human Nutrition Research Centre (CM, JCM, and JEH), and the School of Clinical Medical Sciences (JCM), The Medical School, Newcastle University, Newcastle, United Kingdom; BioSS, Aberdeen, United Kingdom (GWH); and the Rowett Research Institute, Aberdeen, United Kingdom (LKC, FN, and JRA)

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 µg Se as sodium selenite/d, and during a 6-wk washout period. RNA-protein binding studies were carried out in vitro.

Results: Both lymphocyte GPx1 protein concentrations and plasma GPx3 activity increased significantly after selenium supplementation in CC but not TT 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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