Functional effects of a common single nucleotide polymorphism (GPX4c718t) in the glutathione peroxidise 4 gene and interaction with gender

Abstract
Selenium (Se) is essential for health in humans. Low Se status is associated with increased risk of colorectal cancer and Se supplementation decreases cancer mortality. Se is present as the amino acid selenocysteine in selenoproteins, such as the glutathione peroxidises (GPx). Se incorporation requires specific RNA structures in the 3 ' untranslated region (3 &prime UTR) of selenoprotein mRNAs. The aim of the present work was to investigate the functional significance of the single nucleotide polymorphism (SNP) GPx4c718t within the 3 ' UTR of the GPx4 gene. A supplementation trial was carried out with prospectively genotyped individuals of both homozygote genotypes for this SNP. Blood samples were analysed at baseline and after supplementation with 100μg sodium selenite / day for 6 weeks and then during a 6 week wash-out period. Following withdrawal of Se there was a fall in both lymphocyte GPx4 protein levels and GPx4 activity in TT individuals but not those with CC genotype. This effect was modulated by gender, with female CC having higher GPx4 concentration. There was a significant increase in both lymphocyte GPx1 protein levels and plasma GPx3 activity after Se supplementation in CC individuals but not TT. RNA-protein binding assays showed that both T and C variants of the transcripts corresponding to the GPx4 3 ' UTR formed complexes in vitro and that the C bound more strongly than either the T variant or the GPx1 3 ' UTR. The present data indicate that the GPx4c718t SNP alters protein binding to the 3 ' UTR which in turn affects synthesis of not only GPx4 but a range of selenoproteins.
Year
2008
Category
Refereed journal
Output Tags
SG 2006-2011 WP 4.3 Vascular Health