Association analysis of Glutathione S-transferase omega-1 and omega-2 genetic polymorphisms and ischemic stroke risk in a Turkish population

Abstract

, 131 pages Stroke is defined as the acute neurological cerebrovascular disease based on interruptions to blood flow in the brain. These interruptions are caused by loss of blood supply due to vessel bursts or vessel blocked by clotting. Atherosclerosis, a main cause of stroke, is blockage of endothelium layer of arteries and losing the flexibility of tissue. The oxidative stress is known as a risk factor for atherosclerosis. The increased free radicals such as reactive oxygen species (ROS) and decreased antioxidant level cause the oxidative stress and this situation damages the tissue on brain and blood vessels. Oxidative stress is influenced by imbalance in production of phase II enzymes which are responsible for xenobiotic mechanism in terms of decreasing oxidative stress. Glutathione S-transferase omega 1 and omega 2 are members of phase II enzymes family which catalyze detoxification reactions. The polymorphisms, Ala140Asp (C→A) in GSTO1 gene and Asn142Asp (A→G) in GSTO2 gene may cause a decrease in enzyme activity and this situation promotes oxidative stress damage in blood vessels. The aim of this study is to investigate the possible association between GSTO1 vi Ala140Asp and GSTO2 Asn142Asp SNPs and ischemic stroke risk in Turkish population. The study population includes 239 patients and 130 controls and both polymorphisms were determined by PCR/RFLP method. Conventional risk factors for ischemic stroke such as hypertension, diabetes mellitus, obesity and smoking were found significantly higher in patients compared to controls (Odds Ratios; OR=3.35, OR=2.614, OR=4.191 and OR=2.662, respectively). Mutant allele 'A' frequencies for Ala140Asp polymorphism of GSTO1 gene were calculated as 0.358 for patients and 0.342 for controls. For the Asn142Asp SNP of GSTO2 gene, the mutant allele 'G' frequencies were found 0.370 for patients and 0.404 for controls. There was no statistically significant difference between patients and controls in terms of allele frequencies. Detailed analyses have shown that stroke risk can change depending on the genotypes of GSTO1 and GSTO2 genes within conventional risk factors. For Ala140Asp SNP, the risk of having stroke is significantly lower within hypertensive subgroup and obesity subgroup when the individual carrying the mutant allele (OR=2.24 for hypertensive and OR=2.75 for obesity subgroup). Besides, having mutant allele increased the stroke risk for diabetics and smokers (OR=3.873 for diabetics and OR=3.55 for smokers). As regard to Asn142Asp SNP, the mutant allele caused an increase in stroke risk for people with obesity while decrease in diabetics (OR=9.09 for obesity and OR=2.4 for diabetics). In addition, the wild type allele increased the stroke risk for smokers (OR=3.171). Logistic regression analysis revealed that hypertension, smoking, obesity and HDL were significant predictors of stroke. Hypertension, smoking and obesity increased the stroke risk (OR= 3.043, OR=3.258 and OR=2.593, respectively) while HDL had protective role (OR=0.270). In this study, the associati...

The Impact of Genetic Polymorphisms in Glutamate-Cysteine Ligase, a Key Enzyme of Glutathione Biosynthesis, on Ischemic Stroke Risk and Brain Infarct Size

“…In addition, these GCLC and GCLM gene polymorphisms showed statistically significant associations with an increased risk of myocardial infarction and endothelial dysfunction [53,54]. Much more often, the objects of genetic association studies in ischemic stroke were polymorphic variants of glutathione-S-transferase genes, which showed associations with disease risk [17,19,21]. Furthermore, in a previous study, we looked at the associations between polymorphisms in glutathione peroxidase genes such as GPX1 (rs1050450), GPX3 (rs2070593), and GPX4 (rs713041) and the risk of cerebral stroke in hypertensive patients, and we observed that SNP rs713041 of the GPX4 gene is associated with an increased risk of stroke [23].…”

“…A few studies have so far investigated the relationship between genes encoding glutathione-metabolizing enzymes and the risk of ischemic stroke and its outcomes. These genetic association studies have been focused on enzymes such as glutathione S-transferases [17][18][19][20][21] and glutathione peroxidases [22,23] that use glutathione as a substrate for the detoxification of foreign compounds and hydrogen peroxide, respectively [19][20][21]23]. No studies have so far been undertaken to investigate the contribution of polymorphic genes involved in glutathione biosynthesis to the development and severity of ischemic stroke, although a deficiency of glutathione in IS patients has been reported by several studies [24][25][26].…”

GST null polymorphisms may affect the risk of coronary artery disease: evidence from a meta-analysis

“…Considering that our updated analyses were derived from more eligible studies, our observations should be considered as a valuable confirmation for pre-existing literatures. Fifthly, GST null polymorphisms have also been found to be closely associated with the risk of diabetes, essential hypertension and other types of atherothrombotic disorders such as ischemic stroke or peripheral artery disease [16][17][18][19][20]. Considering that the above mentioned diseases are either considered to be conventional risk factors of CAD or usually manifest as co-morbid conditions of CAD, it would be interesting to perform some stratified analyses accordingly.…”

Insights into the Authentic Active Ingredients and Action Sites of Oral Exogenous Glutathione in the Treatment of Ischemic Brain Injury Based on Pharmacokinetic-Pharmacodynamic Studies

“…As an intracellular thiol tripeptide present in all mammalian tissues, GSH plays a crucial role in cellular protection against oxidant damage. Reduction of the GSH level in vivo may lead to the degeneration of dopaminergic neurons (Li et al, 1997;Cadenas, 2004;Bilgin et al, 2019). Song et al, 2015 reported that intravenous injection of exogenous GSH attenuated cerebral infarct volume after ischemic stroke by promoting the PI3K/Akt pathway.…”