Evidence that a polymorphism within the 3′UTR of glutathione peroxidase 4 is functional and is associated with susceptibility to colorectal cancer
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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.
KeywordsColorectal cancer GPx4 Reporter gene Selenium SNP 3′Untranslated region
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.
- 9.Clark LC, Hixson LJ, Combs GF, Reid ME, Turnbull BW, Sampliner RE (1993) Plasma selenium concentration predicts the prevalence of colorectal adenomatous polyps. Cancer Epidemiol Biomark Prev 2:41–46Google Scholar
- 10.Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover RA, Graham GF, Gross EG, Krongrad A, Lesher JL Jr, Park HK, Sanders BB Jr, Smith CL, Taylor JR (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. J Am Med Assoc 276:1957–1963CrossRefGoogle Scholar
- 18.Forsberg L, de Faire U, Morgenstern R (1998) To identify genetic polymorphisms in the “Expressed Sequence Tag” (EST) database. Technical tips on-line http://www.elsevier.com_/locate_/tto, T01440
- 22.Hu YJ, Korotkov KV, Mehta R, Hatfield DL, Rotimi CN, Luke A, Prewitt TE, Cooper RS, Stock W, Vokes EE, Dolan ME, Gladyshev VN, Diamond AM (2001) Distribution and functional consequences of nucleotide polymorphisms in the 3′-untranslated region of the human Sep15 gene. Cancer Res 61:2307–2310PubMedGoogle Scholar
- 28.Jacobson-Brown P, Neuman MG (2004) Colorectal polyposis and immune-based therapies. Canad J Gastroenterol 18:239–249Google Scholar
- 33.Qatatsheh A, Seal CJ, Jowett SL, Welfare MR, Hesketh JE (2005) Patients with ulcerative colitis show an altered frequency distribution of a single nucleotide polymorphism in the gene encoding the phospholipid hydroperoxide glutathione peroxidase. Proceedings of the Nutrition Society 64, OCA, 20A (Abstract)Google Scholar
- 37.Schnurr K, Belkner J, Ursini F, Schewe T, Kuhn H (1996) The selenoenzyme phospholipid hydroperoxide glutathione peroxidase controls the activity of the 15-lipoxygenase with complex substrates and preserves the specificity of the oxygenation products. J Biol Chem 271:4653–4658PubMedCrossRefGoogle Scholar