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The C718T Polymorphism in the 3″-Untranslated Hypertension Research (2012) 35, 507–512 & 2012 The Japanese Society of Hypertension All rights reserved 0916-9636/12 www.nature.com/hr ORIGINAL ARTICLE The C718T polymorphism in the 3¢-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension Alexey V Polonikov1, Ekaterina K Vialykh2, Mikhail I Churnosov3, Thomas Illig4, Maxim B Freidin5, Oksana V Vasil¢eva1, Olga Yu Bushueva1, Valentina N Ryzhaeva1, Irina V Bulgakova1 and Maria A Solodilova1 In the present study we have investigated the association of three single nucleotide polymorphisms in glutathione peroxidase (GPx) genes GPX1 rs1050450 (P198L), GPX3 rs2070593 (G930A) and GPX4 rs713041 (T718C) with the risk of cerebral stroke (CS) in patients with essential hypertension (EH). A total of 667 unrelated EH patients of Russian origin, including 306 hypertensives (the EH–CS group) who suffered from CS and 361 people (the EH–CS group) who did not have cerebrovascular accidents, were enrolled in the study. The variant allele 718C of the GPX4 gene was found to be significantly associated with an increased risk of CS in hypertensive patients (odds ratio (OR) 1.53, 95% confidence interval (CI) 1.23–1.90, Padj¼0.0003). The prevalence of the 718TC and 718CC genotypes of the GPX4 gene was higher in the EH–CS group than the EH-alone group (OR¼2.12, 95%CI 1.42–3.16, Padj¼0.0018). The association of the variant GPX4 genotypes with the increased risk of CS in hypertensives remained statistically significant after adjusting for confounding variables such as sex, body mass index (BMI), blood pressure and antihypertensive medication use (OR¼2.18, 95%CI 1.46–3.27, P¼0.0015). Multiple logistic regression analysis did not reveal any interaction between various combinations of GPX1, GPX3 and GPX4 genotypes regarding the risk of CS in patients with EH. The study demonstrated for the first time that the C718T polymorphism in the 3¢-untranslated region of the GPX4 gene could be considered as a genetic marker of susceptibility to CS in patients with EH. Hypertension Research (2012) 35, 507–512; doi:10.1038/hr.2011.213; published online 8 December 2011 Keywords: cerebral stroke; essential hypertension; genetic susceptibility to disease; glutathione peroxidase genes; single nucleotide polymorphism INTRODUCTION identify new therapeutic targets and prophylactic strategies to afford According to JNC 7 (the Seventh Report of the Joint National neuroprotection promptly. Committee on Prevention, Detection, Evaluation, and Treatment of Growing evidences indicate that the increased production of High Blood Pressure), the relationship between blood pressure reactive oxygen species and oxidative stress, a condition occurring and cerebral-stroke risk is strong, continuous, graded, consistent, when this balance is disrupted by excessive production of reactive independent, predictive and etiologically significant.1 Essential oxygen species and/or by inadequate antioxidant defenses, in the brain hypertension (EH) remains the most important well-documented, are among the causative mechanisms of cerebral tissue damage in both modifiable risk factor for stroke, and the treatment of hypertension is ischemic and hemorrhagic strokes.3–5 It is noteworthy that increased among the most effective strategies for preventing both ischemic and vascular oxidative stress is thought to be involved in the pathogenesis hemorrhagic stroke.2 Although EH is frequently complicated by of both EH6 and CS.7,8 cerebral stroke (CS), there are many patients who did not suffer the One of the antioxidant enzymes protecting against oxidative stress cerebrovascular disease suggesting genetic susceptibility to stroke in is glutathione peroxidase (GPx), which reduces hydrogen peroxide some, but not in all hypertensive individuals. The increase of our (H2O2) and organic hydroperoxides to H2O and the corresponding understanding of the role of genetic factors in determining the alcohols using reduced glutathione as an essential co-substrate. In the susceptibility to stroke development may provide an insight into genes coding for these enzymes, several single nucleotide polymorph- the mechanisms of cerebrovascular complications, and help to isms have been described. As oxidative stress can be involved in the 1Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation; 2Medical Genetic Consultation, Kursk Regional Clinical Hospital, Kursk, Russian Federation; 3Department of Medical-Biological Disciplines, Belgorod State University, Belgorod, Russian Federation; 4Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany and 5Research Institute for Medical Genetics, Siberian Branch of Russian Academy of Medical Sciences, Tomsk, Russian Federation Correspondence: Professor AV Polonikov, Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Karl Marx Street, 3, 305041 Kursk, Russian Federation. E-mail: [email protected] Received 4 September 2011; revised 16 October 2011; accepted 25 October 2011; published online 8 December 2011 The GPX4 gene and stroke-complicated hypertension AV Polonikov et al 508 etiology of hypertension and cerebrovascular disease, polymorphic rs2070593 was digested with 7 U of PspCI restriction enzyme (Sibenzyme, genes encoding for GPxs can be putative candidates for the genetic Novosibirsk, Russia) producing two fragments of 183 and 180 bp (these bands susceptibility to CS. Several genetic studies have been done so far to overlap each other at electrophoresis) in case of the G allele and leaving the A search for the association between polymorphisms of glutathione allele uncut (one fragment of 363 bp) on 2%-agarose gel. peroxidase 1 (GPX1)and3(GPX3) genes and the risk of CS.9–12 The C718T polymorphism (rs713041) of the GPX4 gene was amplified within a 226-bp genomic fragment with forward primer: 5¢-TTTCTAGCTCCAC These association studies were designed for use of normotensive AAGTGTGTG-3¢ and reverse primer: 5¢-AGATCCAGCAGGCTAATTTGTC-3¢. subjects as a control population and did not assess the stroke risk The thermal cycling comprised an initial denaturation step at 95 1Cfor4min, in the hypertensive population. In the present study, we have followed by 35 cycles at 95 1Cfor30s,591C for 30 s and 72 1C for 30 s, with the investigated, for the first time, the prevalence of three single nucleotide final extension at 72 1C for 7 min. The PCR product was subjected to restriction polymorphisms in GPx genes (GPX1 rs1050450, GPX3 rs2070593 digestion with 10 U of the BssT1I enzyme (Sibenzyme) at 60 1C for 4 h followed and GPX4 rs713041), and the association between these genetic by 2.5%-agarose gel electrophoresis. For the 718C allele, BssT1I cleaves the 226- polymorphisms and CS risk in patients with EH. bp PCR fragment into a 145-bp and an 81-bp fragment, whereas three fragments were generated for the 718T allele: 97, 81 and 48 bp. METHODS The P198L polymorphism (rs1050450) of glutathione peroxidase-1 (GPX1) 14 Study population was genotyped as described by Hu and Diamond. PCR amplification was performed in a final volume of 25 ml of the reaction mixture containing 1.5 U of A total of 667 unrelated subjects with EH, including 306 hypertensives who Taq DNA polymerase (Sibenzyme), about 1 mg DNA of each patient’s DNA, suffered from CS (EH–CS group) and 361 hypertensives (EH group) who did 0.25 mM each primer, 250 mM of dNTPs, 2 mM of MgCl ,1Â PCR buffer of the not have cerebrovascular accidents, were enrolled in the study. Patients who 2 following composition: 67 mM Tris-HCl pH 8.8, 16.6 mM (NH ) SO suffered CS (281 hypertensives were with ischemic stroke, 25 hypertensives 4 2 4 and 0.01% Tween-20. Digested products were resolved through ethidium suffered from hemorrhagic stroke) were recruited at the Neurology Clinics of bromide-stained 2%-agarose gels and visualized under UV light on the Kursk Emergency Medicine Hospital between 2007 and 2010. Hypertensive GDS-8000 Computer Detection System (UVP Inc, Upland, CA, USA). A ‘no patients without a clinical history of cerebrovascular disease were enrolled from template’ control (water) was used in each restriction fragment length the Cardiology Clinics of both Kursk Regional Clinical Hospital and Kursk polymorphism assay. The genotyping results were scored by two independent Emergency Medicine Hospital during two study periods; the first was between investigators who did not know whether a sample was from the EH–CS or the 2003 and 2006 as described in our recent paper,13 and the second was between EH group. In addition, about 10% of the samples from each study group were 2007 and 2010. All study participants were of Russian origin from Central randomly selected to perform direct sequencing of the PCR products of each Russia. All patients provided their informed consent before the study and the polymorphism. Sequencing was carried out by Sanger methodology on ABI protocol was approved by the Ethical Review Committee of Kursk State PRISM 310 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA) and Medical University. 100% concordance with restriction fragment length polymorphism assays was shown providing confidence in using the full dataset in subsequent analysis. Diagnosis Demographic data were obtained for each subject from medical records at the Statistical data analysis time of the enrollment and included current age, sex and family history of Categorical variables (sex, family
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