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

Overview

Journal Life (Basel)

Specialty Biology

Date 2022 Apr 23

PMID 35455093

Authors

Alexey Polonikov

Iuliia Bocharova

Iuliia Azarova

Elena Klyosova

Marina Bykanova

Olga Bushueva

Anna Polonikova

Mikhail Churnosov

Maria Solodilova

Affiliations

Soon will be listed here.

Abstract

The purpose of this pilot study was to explore whether polymorphisms in genes encoding the catalytic (GCLC) and modifier (GCLM) subunits of glutamate-cysteine ligase, a rate-limiting enzyme in glutathione synthesis, play a role in the development of ischemic stroke (IS) and the extent of brain damage. A total of 1288 unrelated Russians, including 600 IS patients and 688 age- and sex-matched healthy subjects, were enrolled for the study. Nine common single nucleotide polymorphisms (SNPs) of the GCLC and GCLM genes were genotyped using the MassArray-4 system. SNP rs2301022 of GCLM was strongly associated with a decreased risk of ischemic stroke regardless of sex and age (OR = 0.39, 95%CI 0.24−0.62, p < 0.0001). Two common haplotypes of GCLM possessed protective effects against ischemic stroke risk (p < 0.01), but exclusively in nonsmoker patients. Infarct size was increased by polymorphisms rs636933 and rs761142 of GCLC. The mbmdr method enabled identifying epistatic interactions of GCLC and GCLM gene polymorphisms with known IS susceptibility genes that, along with environmental risk factors, jointly contribute to the disease risk and brain infarct size. Understanding the impact of genes and environmental factors on glutathione metabolism will allow the development of effective strategies for the treatment of ischemic stroke and disease prevention.

Citing Articles

Chaperones vs. oxidative stress in the pathobiology of ischemic stroke.

Soldatov V, Venediktov A, Belykh A, Piavchenko G, Naimzada M, Ogneva N Front Mol Neurosci. 2024; 17:1513084.

PMID: 39723236 PMC: 11668803. DOI: 10.3389/fnmol.2024.1513084.

In vitro safety evaluation of dopamine D3R antagonist, R-VK4-116, as a potential medication for the treatment of opioid use disorder.

Nandre R, Newman A, Terse P PLoS One. 2024; 19(12):e0315569.

PMID: 39680602 PMC: 11649115. DOI: 10.1371/journal.pone.0315569.

(Hero20) Gene Polymorphism: Contribution to Ischemic Stroke Risk and Interactions with Other Heat-Resistant Obscure Chaperones.

Shilenok I, Kobzeva K, Soldatov V, Deykin A, Bushueva O Biomedicines. 2024; 12(11).

PMID: 39595169 PMC: 11592265. DOI: 10.3390/biomedicines12112603.

Dementia after Ischemic Stroke, from Molecular Biomarkers to Therapeutic Options.

Dammavalam V, Rupert D, Lanio M, Jin Z, Nadkarni N, Tsirka S Int J Mol Sci. 2024; 25(14).

PMID: 39063013 PMC: 11276729. DOI: 10.3390/ijms25147772.

Genetic and Transcriptomic Background of Oxidative Stress and Antioxidative Therapies in Late Complications of Type 2 Diabetes Mellitus: A Systematic Review.

Tonin G, Dolzan V, Klen J Antioxidants (Basel). 2024; 13(3).

PMID: 38539811 PMC: 10967328. DOI: 10.3390/antiox13030277.

References

Montaner J, Ramiro L, Simats A, Tiedt S, Makris K, Jickling G . Multilevel omics for the discovery of biomarkers and therapeutic targets for stroke. Nat Rev Neurol. 2020; 16(5):247-264. DOI: 10.1038/s41582-020-0350-6. View

Bushueva O, Barysheva E, Markov A, Belykh A, Koroleva I, Churkin E . DNA Hypomethylation of the MPO Gene in Peripheral Blood Leukocytes Is Associated with Cerebral Stroke in the Acute Phase. J Mol Neurosci. 2021; 71(9):1914-1932. DOI: 10.1007/s12031-021-01840-8. View

Wang R, Wang Y, Wang J, Yang K . Association of glutathione S-transferase T1 and M1 gene polymorphisms with ischemic stroke risk in the Chinese Han population. Neural Regen Res. 2015; 7(18):1420-7. PMC: 4308794. DOI: 10.3969/j.issn.1673-5374.2012.18.009. View

Feigin V . Stroke epidemiology in the developing world. Lancet. 2005; 365(9478):2160-1. DOI: 10.1016/S0140-6736(05)66755-4. View

Man B, Baum L, Fu Y, Chan Y, Lam W, Hui C . Genetic polymorphisms of Chinese patients with ischemic stroke and concurrent stenoses of extracranial and intracranial vessels. J Clin Neurosci. 2010; 17(10):1244-7. DOI: 10.1016/j.jocn.2010.01.050. View

Prasad A, Andrews N, Padder F, Husain M, Quyyumi A . Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability. J Am Coll Cardiol. 1999; 34(2):507-14. DOI: 10.1016/s0735-1097(99)00216-8. View

Burdo J, Schubert D, Maher P . Glutathione production is regulated via distinct pathways in stressed and non-stressed cortical neurons. Brain Res. 2007; 1189:12-22. PMC: 2635888. DOI: 10.1016/j.brainres.2007.10.077. View

Ritchie M, Hahn L, Roodi N, BAILEY L, Dupont W, Parl F . Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet. 2001; 69(1):138-47. PMC: 1226028. DOI: 10.1086/321276. View

Lu M, Ye W, Adami H, Weiderpass E . Stroke incidence in women under 60 years of age related to alcohol intake and smoking habit. Cerebrovasc Dis. 2008; 25(6):517-25. DOI: 10.1159/000131669. View

10.

Cho S, Hazama M, Urata Y, Goto S, Horiuchi S, Sumikawa K . Protective role of glutathione synthesis in response to oxidized low density lipoprotein in human vascular endothelial cells. Free Radic Biol Med. 1999; 26(5-6):589-602. DOI: 10.1016/s0891-5849(98)00232-9. View

11.

Lapenna D, de Gioia S, Ciofani G, Mezzetti A, Ucchino S, Calafiore A . Glutathione-related antioxidant defenses in human atherosclerotic plaques. Circulation. 1998; 97(19):1930-4. DOI: 10.1161/01.cir.97.19.1930. View

12.

Espinosa-Diez C, Miguel V, Vallejo S, Sanchez F, Sandoval E, Blanco E . Role of glutathione biosynthesis in endothelial dysfunction and fibrosis. Redox Biol. 2017; 14:88-99. PMC: 5596265. DOI: 10.1016/j.redox.2017.08.019. View

13.

Aoyama K, Watabe M, Nakaki T . Regulation of neuronal glutathione synthesis. J Pharmacol Sci. 2008; 108(3):227-38. DOI: 10.1254/jphs.08r01cr. View

14.

Bazzini C, Rossetti V, Civello D, Sassone F, Vezzoli V, Persani L . Short- and long- term effects of cigarette smoke exposure on glutathione homeostasis in human bronchial epithelial cells. Cell Physiol Biochem. 2014; 32(7):129-45. DOI: 10.1159/000356633. View

15.

Polonikov A, Rymarova L, Klyosova E, Volkova A, Azarova I, Bushueva O . Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease. J Cell Biochem. 2019; 120(10):16467-16482. DOI: 10.1002/jcb.28815. View

16.

Allen C, Bayraktutan U . Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke. 2009; 4(6):461-70. DOI: 10.1111/j.1747-4949.2009.00387.x. View

17.

Zimmermann C, Winnefeld K, Streck S, Roskos M, Haberl R . Antioxidant status in acute stroke patients and patients at stroke risk. Eur Neurol. 2004; 51(3):157-61. DOI: 10.1159/000077662. View

18.

Matys V, Kel-Margoulis O, Fricke E, Liebich I, Land S, Barre-Dirrie A . TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 2005; 34(Database issue):D108-10. PMC: 1347505. DOI: 10.1093/nar/gkj143. View

19.

Hwang C, Sinskey A, Lodish H . Oxidized redox state of glutathione in the endoplasmic reticulum. Science. 1992; 257(5076):1496-502. DOI: 10.1126/science.1523409. View

20.

Koide S, Kugiyama K, Sugiyama S, Nakamura S, Fukushima H, Honda O . Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction. J Am Coll Cardiol. 2003; 41(4):539-45. DOI: 10.1016/s0735-1097(02)02866-8. View