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

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 3Јuntranslated region (3ЈUTR) of selenoprotein mRNAs. Objective: This study investigated the functional significance of the single-nucleotide polymorphism (SNP) GPx4c718t within the 3ЈUTR 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 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 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 3ЈUTR formed complexes in vitro and that the C variant bound more strongly than did either the T variant or the GPx1 3ЈUTR. Conclusions: The GPX4c718t SNP both alters protein binding to the 3ЈUTR 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.

Effects of Selenium Status and Polymorphisms in Selenoprotein Genes on Prostate Cancer Risk in a Prospective Study of European Men

“…In Europe, a relatively low Se status comparable with that in the bottom tertile of the NPC study is common (9), suggesting that Se supplementation could elicit some prostate cancer protection in European men. In addition, recent data not only indicate that genetic variations in selenoprotein genes account for interindividual differences in response to Se supplementation (10,11) but also that they may influence cancer risk (12,13). Such observations may help to reconcile the complex observations from both the NPC and SELECT studies and also identify subgroups of the population at increased or decreased risk of prostate cancer depending on their Se status and capacity to respond to Se intake.…”

Polymorphisms in the selenoprotein S and 15-kDa selenoprotein genes are associated with altered susceptibility to colorectal cancer

“…For example, rs1050450 causes a Pro-Leu amino acid change in glutathione peroxidise 1 and affects protein function [12], rs713041 causes a T-C substitution in a region of the glutathione peroxidise 4 (GPX4) gene corresponding to the 3 0 UTR of the mRNA and alters the protein binding to the 3 0 UTR and reporter gene activity [3,21], rs5859 and rs5845 in the 3 0 UTR of the 15-kDa selenoprotein affect reporter gene activity [13] and rs7579 and rs3877899 in the SEPP1 gene affect biomarkers of selenoprotein status in vivo [20]. Variants in the promoter of SELS are functional in that they modulate SelS expression and plasma levels of inflammatory cytokines [10].…”

The C718T polymorphism in the 3′-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension

“…Gautrey with coworkers 23 have shown that the C718T variant of the GPX4 gene alters the pattern of selenoprotein synthesis under low selenium intake. Méplan with coworkers 15 have observed that carriers of the genotype 718CC maintain GPX4 concentrations better than carriers of genotype 718TT do when selenium intake falls after withdrawal of the selenium supplement. Interestingly, the authors have also showed that the polymorphism influences the expression of other selenoproteins such as GPX1 and GPX3.…”

“…15 The gene for glutathione peroxidase-4 is expressed in most tissues, including the brain (Gene Expression Atlas, available at http://www.ebi.ac.uk/gxa/gene/ ENSG00000167468). Although the GPX4 gene is highly polymorphic, a limited number of studies [16][17][18][19] have been done to investigate genetic variations within the GPX4 gene that could potentially alter the function of the enzyme.…”

“…24,25 It has been proposed that variations in the 3¢-untranslated region of the GPX4 gene can influence the position of GPX4 in the hierarchy of demands on the components of the selenoprotein-synthesis apparatus, with consequent effects on the synthesis of other selenoproteins. 15 Thus, a competition for selenium incorporation would be responsible for the decrease of the biosynthesis or activity of GPxs 1 and 3 leading to accumulation of H 2 O 2 that has been suggested to exert neurotoxic effects promoting oxidative stress and inflammation, which are critical factors of brain damage induced by cerebral ischemia. 26,27 Furthermore, it is known that GPxs are involved in the regulation of platelet activity, endothelial function, platelet-dependent thrombosis and propensity for vascular thrombosis, and a deficiency of this enzyme has been associated with platelet-dependent thrombosis and arterial ischemic stroke.…”