Glutathione S-Transferase (GSTT1 rs17856199) and Nitric Oxide Synthase (NOS2 rs2297518) Genotype Combination as Potential Oxidative Stress-Related Molecular Markers for Type 2 Diabetes Mellitus

Abstract

Background: Deregulation of the antioxidant enzymes was implicated in pathogenesis and complications of type 2 diabetes mellitus (T2DM). The data relate the genetic variants of these enzymes to T2DM are inconsistent among various populations. Purpose: We aimed to explore the association of 13 genetic variants of "superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and nitric oxide synthase (NOS)" with T2DM susceptibility and the available clinical laboratory data. Subjects and Methods: A total of 384 individuals were enrolled in this work. Different genotypes of the genes mentioned above were characterized using TaqMan OpenArray Genotyping assays on a Real-Time polymerase chain reaction system. Results: After age-and sex-adjustment, among the studied 13 variants, GSTT1 rs17856199 was associated with T2DM under homozygote (OR=3.42; 95% CI:1.04-11.2, p=0.031), and recessive (OR=3.57; 95% CI: 1.11-11.4, p=0.029) comparison models. The NOS2 rs2297518*A allele was more frequent among the T2DM cohort (58.1% vs 35.4%, p<0.001) and showed a dose-response effect; being heterozygote was associated with higher odds for developing DM (OR=4.06, 95% CI=2.13-7.73, p<0.001), whereas being AA homozygote had double the risk (OR=9.06, 95% CI=3.41-24.1, p<0.001). Combined NOS2 rs2297518*A and either GSTT1 rs17856199*A or *C genotype carriers were more likely to develop T2DM. Different associations with sex, BMI, hyperglycemia, and/or hyperlipidemia were evident. The principal component analysis revealed NOS2 rs2297518*G, old age, dyslipidemia, high systolic blood pressure, and elevated HbA1c were the main classifiers of T2DM patients. Conclusion:The oxidative stress-related molecular markers, GSTT1 rs17856199 and NOS2 rs2297518 variants were significantly associated with T2DM risk and phenotype in the study population.

Antioxidants-Related Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPX), Glutathione-S-Transferase (GST), and Nitric Oxide Synthase (NOS) Gene Variants Analysis in an Obese Population: A Preliminary Case-Control Study

“…This missense variant (S608L), which is mapped in the catalytic domain of the enzyme [88], was reported to increase NOS2 activity and impact many disease prevalence [89]. This observation agrees with other genetic association studies on type 2 diabetes mellitus cohort in our lab [90] and in Caucasians [91].…”

Individual and combined effects of the GSTM1, GSTT1, and GSTP1 polymorphisms on type 2 diabetes mellitus risk: A systematic review and meta-analysis

“…12 is excluded from the full text. As a result, 48 studies ( Fujita et al, 2000 ; Yang et al, 2004 ; Hayek et al, 2006 ; Wang et al, 2006 ; Hori et al, 2007 ; Yalin et al, 2007 ; Oniki et al, 2008 ; Nowier et al, 2009 ; Tiwari et al, 2009 ; Bid et al, 2010 ; Datta et al, 2010 ; Amer et al, 2011 ; Ramprasath et al, 2011 ; Tsai et al, 2011 ; Amer et al, 2012 ; Cilenšek et al, 2012 ; Gonul et al, 2012 ; Jana and Petrovic., 2012 ; Moasser et al, 2012 ; Dadbinpour et al, 2013 ; Grubisa et al, 2013 ; Mastana et al, 2013 ; Pinheiro et al, 2013 ; Vats et al, 2013 ; Abbasi et al, 2014 ; Al-Badran and Al-Mayah, 2014 ; Moasser et al, 2014 ; Purkait et al, 2014 ; Rao et al, 2014 ; Raza et al, 2014 ; Afrand et al, 2015 ; Rasheed et al, 2015 ; Stoian et al, 2015 ; Zaki et al, 2015 ; Etemad et al, 2016 ; Mergani et al, 2016 ; Mir et al, 2016 ; Rasheed et al, 2016 ; Ahmed and Al-Bachary, 2017 ; Azarova et al, 2018 ; de Lima et al, 2018 ; Abbas et al, 2019 ; Osman et al, 2019 ; Klusek et al, 2020 ; Pourkeramati et al, 2020 ; Gusti et al, 2021 ; Albeladi et al, 2022 ; Jamil et al, 2022 ) were included ( Figure 1 ). There were 28 articles (involving 4,878 cases and 4,621 controls, Table 1 ) on the GSTM1 present/null polymorphism, 28 articles (involving 4,710 cases and 4,471 controls, Table 2 ) on the GSTT1 present/null polymorphism, 24 studies on the GSTP1 IIe105Val polymorphism (including 4,297 cases and 4,244 controls, Table 3 ),17 studies inc...…”

GST gene family polymorphism and the risk of colorectal cancer in patients with type 2 diabetes

“…As GST are involved in the processing of reactive oxygen, lipid peroxidation products and some key metabolites of toxicants, the potential links between genetic polymorphisms of these enzymes and the pathogenesis of T2D and CRC seem reasonable. Functional polymorphisms of GST genes have been reported to be involved in the pathogenesis of T2D [16,17]. One of the risk factors for diabetes is oxidative stress which is known to be implicated in insulin resistance, β-cell dysfunction and impaired glucose tolerance.…”

“…Glutathione S-transferases among other functions act as scavengers for reactive oxygen species reducing the oxidative stress in cells. That is why the GST gene variants associated with a decline or lack of catalytic activity might increase the risk of T2D [17]. Moreover, it is known that GST gene polymorphisms are involved in the development of malignancies, such as gastric cancer [18], lung cancer [19] or colorectal cancer [7].…”