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

Polonikov, Alexey; Bocharova, Iuliia; Azarova, Iuliia; Klyosova, Elena; Bykanova, Marina; Бушуева, О. Ю.; Polonikova, Anna; Churnosov, Mikhail; Solodilova, Maria

doi:10.3390/life12040602

Cited by 13 publications

(10 citation statements)

References 122 publications

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“…The previous studies have already revealed genetic markers associated with the development of IS [6,7,8], as well as related phenotypes/risk factors, such as hypertension [9,10,11], atherosclerosis [12,13], and thrombosis [14]. However, despite the large number of studies conducted in the world, the molecular mechanisms of IS development remain poorly understood.…”

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confidence: 99%

C9orf16 (BBLN) gene, encoding a member of Hero proteins, is a novel marker in ischemic stroke risk

Kobzeva¹,

Shilenok²,

Белых³

et al. 2022

RR. in B.

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Background: Ischemic stroke (IS) is the leading cause of death and disability worldwide. Chaperone proteins protect brain cells from the ischemic damage by restoring the structures of damaged proteins. Chaperone C9orf16 (also known as BBLN) belongs to the class of heat-resistant obscure (HERO) proteins, characterized by the ability to stabilize various proteins, suppress neurotoxicity and reduce proteotoxic stress. In this regard, it may play a potentially significant role in the risk of development and clinical manifestations of IS. The aim of the study: To investigate an association between a single nucleotide polymorphism rs2900262 in the gene encoding C9orf16 and predisposition to IS. Materials and methods: A total of 897 patients with IS and 1140 healthy controls were recruited for the study. Genotyping was done using a probe-based genotyping assay. Multiple logistic regression analysis was performed to evaluate the associations of the rs2900262 genotypes with the risk of IS and ischemic events. Dominant, recessive and additive models of associations of genotypes were analyzed. Adjustment for sex, age, and smoking was done throughout. Benjamini-Hogberg false-discovery rate was used to correct for multiple comparisons. Results: The rs2900262*T allele was found to be associated with the increased risk of IS exclusively in females (dominant model: OR=1.74, 95% CI=1.07-2.82, PFDR=0.042; additive model: OR=1.69, 95% CI=1.06-2.71, PFDR=0.042). Additional analysis showed that the rs2900262*T is associated with the increased risk of IS in smokers only (dominant model: OR=1.92, 95% CI=1.09-3.37, PFDR=0.042; additive model: OR=1.79, 95%CI=1.04-3.08, PFDR=0.042). Also, we demonstrated that C/T-T/T genotype carriers exhibit an earlier manifestation of IS (59.53±1.12 years) compared to the C/C genotype carriers (61.63±0.4 years); mean difference=-1.98; 95% CI=-3.61 – -0.36; PFDR=0.026. Conclusion: This study is the first in the world to demonstrate the possible contribution of the rs2900262 C9orf16 gene polymorphism to the risk of ischemic stroke.

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confidence: 99%

C9orf16 (BBLN) gene, encoding a member of Hero proteins, is a novel marker in ischemic stroke risk

Kobzeva¹,

Shilenok²,

Белых³

et al. 2022

RR. in B.

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“…GSH is synthesized in two steps that are catalyzed, successively, by two polymorphic enzymes: γ-glutamylcysteine synthetase (glutamate-cysteine ligase, GCL) and GSH synthetase. GCL is the rate-limiting enzyme in glutathione biosynthesis and genetic polymorphisms in its catalytic (GCLC) and modifying (GCLM) subunits were associated with increased susceptibility to oxidative stress and with increased MI risk in the general population and T2D patients [ 96 ]. Although no associations with either GCLC or GCLM polymorphisms as stand-alone risk factors for T2DM complications were observed within Slovenian T2DM patients [ 40 ], in Japanese patients, GCLM C-588T polymorphism was included in the composite 5 polymorphic gene score associated with increased risk for CHD [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

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

Tonin,

Dolžan,

Klen

2024

Antioxidants

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This systematic review extensively investigated the role of the genetic and transcriptomic factors in late complications of type 2 diabetes mellitus (T2DM) and the current approaches targeting oxidative-stress-related pathways with antioxidant therapies. To cover our broad research area, we have conducted two systematic searches, the first focusing on genetic and transcriptomic factors affecting oxidative stress and the second one focusing on the antioxidant therapies in late complications of T2DM. The final review included 33 genetic and transcriptomic studies and 23 interventional randomized clinical trials. The conducted systematic review highlights the important role of oxidative stress in the development of late complications in T2DM patients. However, the current level of evidence does not support the use of genetic and transcriptomic factors as predictive and prognostic biomarkers for the development of T2DM late complications. Further studies are needed to elucidate the potential of targeting oxidative-stress-related pathways for novel preventative and therapeutic approaches. Additionally, antioxidants both in dietary and supplement form have been shown to improve different metabolic and biochemical parameters in T2DM patients with developed late complications. In recent years, studies have improved in methodological quality despite still mainly focusing on microvascular late complications of T2DM. Furthermore, the observed interventional studies suggest non-homogeneity in the duration of observation. As many studies do not provide post-intervention follow-up testing, it is difficult to assess the long-term health benefits of antioxidant supplementation.

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“…Genetic polymorphisms of glutamate cysteine ligase that are correlated with a decrease in GCLC mRNA and protein expression, enzyme activity, and GSH content [ 47 , 48 , 49 , 50 , 51 ] represent attractive markers for studying the molecular mechanisms of psoriasis. Polymorphisms of the GCLC gene have been found to be associated with the risk of cardiometabolic diseases such as coronary artery disease [ 52 , 53 ], ischemic stroke [ 54 ], type 1 [ 55 , 56 ] and type 2 [ 51 ] diabetes mellitus, polycystic ovary syndrome [ 57 ], and nonalcoholic fatty liver disease [ 58 ], as well as other multifactorial disorders such as bronchial asthma [ 59 ], pulmonary tuberculosis [ 60 ], and colorectal cancer [ 61 ]. However, no studies have been designed so far to investigate the role of GCLC gene polymorphisms in psoriasis susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of the GCLC Gene Are Novel Genetic Markers for Susceptibility to Psoriasis Associated with Alcohol Abuse and Cigarette Smoking

Efanova,

Bushueva,

Saranyuk

et al. 2023

Life

Self Cite

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The aim of this pilot study was to investigate whether single nucleotide polymorphisms (SNP) in the gene encoding the catalytic subunit of glutamate cysteine ligase (GCLC) are associated with the risk and clinical features of psoriasis. A total of 944 unrelated individuals, including 474 patients with a diagnosis of psoriasis and 470 healthy controls, were recruited for the study. Six common SNPs in the GCLC gene were genotyped using the MassArray-4 system. Polymorphisms rs648595 (OR = 0.56, 95% CI 0.35–0.90; Pperm = 0.017) and rs2397147 (OR = 0.54, 95% CI 0.30–0.98; Pperm = 0.05) were associated with susceptibility to psoriasis in males. In the male group, diplotype rs2397147-C/C × rs17883901-G/G was associated with a decreased risk of psoriasis (FDR-adjusted p = 0.014), whereas diplotype rs6933870-G/G × rs17883901-G/G (FDR-adjusted p = 0.045) showed an association with an increased disease risk in females. The joint effects of SNPs with tobacco smoking (rs648595 and rs17883901) and alcohol abuse (rs648595 and rs542914) on psoriasis risk were observed (Pperm ≤ 0.05). We also found multiple sex-independent associations between GCLC gene polymorphisms and various clinical features such as earlier disease onset, the psoriatic triad, and specific localizations of skin lesions. The present study is the first to show that polymorphisms of the GCLC gene are significantly associated with the risk of psoriasis and related to its clinical features.

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

Cited by 13 publications

References 122 publications

C9orf16 (BBLN) gene, encoding a member of Hero proteins, is a novel marker in ischemic stroke risk

C9orf16 (BBLN) gene, encoding a member of Hero proteins, is a novel marker in ischemic stroke risk

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

Polymorphisms of the GCLC Gene Are Novel Genetic Markers for Susceptibility to Psoriasis Associated with Alcohol Abuse and Cigarette Smoking

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