Genetic association of Glutathione peroxidase-1 (GPx-1) and NAD(P)H:Quinone Oxidoreductase 1(NQO1) variants and their association of CAD in patients with type-2 diabetes

Abstract

Coronary artery disease (CAD) is a major health concern and the leading cause of death in individuals with type-2 diabetes mellitus (T2DM). Glutathione peroxidase-1 (GPx-1) and NAD(P)H: quinone oxidoreductase (NQO1) are known for its broad range of detoxification. The role of functional variants of these genes in the development of various disorders is proven. Hereby, we investigated the possible role of these variants in the development of CAD in T2DM patients of South Indian population. In this case-control study, a total of 539 patients (T2DM = 241; T2DM-CAD = 298) and 285 controls were included. The C198T GPx-1 and C609T NQO1 single-nucleotide polymorphisms were analyzed by PCR-RFLP. Further, these genotypes were correlated with blood lipid profile. Regression analysis showed that GPx1-C/T genotype is associated with a 1.35-fold increase (95% CI = 1.000-1.824; P = 0.048) and GPx1-T/T genotype is associated with a 1.76-fold increase (95% CI = 1.011 to 3.066; P = 0.046) to the T2DM development. Increased odds ratio showed that NQO1-T/T genotype had a higher occurrence of CAD in diabetic patients with CAD (95% CI = 1.003-2.674, P = 0.049) than T2DM patients without CAD. The level of triglycerides alone showed significant increase for GPx-1-C/T and -T/T genotypes in Tukey's Post hoc analysis (177.1 ± 19.2 vs. 184 ± 23.5; P = 0.039 and 177.1 ± 19.2 vs. 190 ± 22.4; P = 0.006) among the patients with T2DM-CAD. Our work concludes that GPx-1 variants might contribute to the development of diabetes and both GPx-1 and NQO1 variants confirm the association of CAD in people with T2DM of South Indian population.

Overexpression of CYB5R3 and NQO1, two NAD+‐producing enzymes, mimics aspects of caloric restriction

“…In addition to its well‐known antioxidant properties [reviewed in (Ross & Siegel, 2017)], NQO1 exerts significant metabolic functions by conferring protection against obesity, hypertension, arterial restenosis, renal injury, and neurodegenerative disorders (Chhetri, King & Gueven, 2017; Hwang et al., 2009; Kim et al., 2011; Son et al., 2015). The C609T (Pro187Ser) null polymorphism of the NQO1 gene is associated with increased risk of complications related to metabolic syndrome, Alzheimer's disease, and an overall increased risk of cancer in humans (Chhetri et al., 2017; Lajin & Alachkar, 2013; Martinez‐Hernandez et al., 2015; Ramprasath et al., 2012). Genetic ablation of NQO1 in rodent models also increases sensitivity to skin carcinogenesis (Iskander et al., 2005) and causes severe dysregulation of lipid and glucose metabolism (Gaikwad, Long, Stringer & Jaiswal, 2001).…”

Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

“…Despite low GPX1 and SOD1 activities in islets (only 2% and 29% of that in liver, respectively) (39), we have found that knockout of GPX1 (GPX1 knockout [GKO]) and SOD1 (SOD1 knockout [SKO]) alone or in combination (double knockout of GPX1 and SOD1 [dKO]) caused substantial impairment of GSIS (68). Consistently, a Gpx1 gene variant (C198T) lowering the enzyme activity was identified in the South Indian population, which resulted in increased incidences of type 2 diabetes (C/T, 1.4-fold and T/T, 1.8-fold) (54). Intriguingly, the overt phenotypes of GSIS impairments in the GKO and SKO mice were similar (68), although GPX1 catalyzes H 2 O 2 breakdown whereas SOD1 catalyzes H 2 O 2 formation.…”

Sulfur Mustard Exposure and Cardiovascular Effects: A Review

“…Shohrati et al demonstrated that SM injured patients with higher severity of injuries had lower levels of glutathione than those with mild injuries (44). In addition, it was shown that glutathione peroxidase can be associated with CAD (45).…”

“…In addition, the mentioned molecules and mediators play a remarkable role in cardiovascular disorders, such as endothelial injuries secondary to reactive oxygen species and toxins (9,45,53). Although the inflammatory process is carried out in airway leaking, even small amounts of these mediators within the systemic circulation can affect other organs.…”

“…Although the inflammatory process is carried out in airway leaking, even small amounts of these mediators within the systemic circulation can affect other organs. For example, when vast amounts of the body's supply of coenzyme NAD(P)H, which plays an important role in the cellular energy crisis, are consumed to repair damaged DNA by SM due to over-activation of the PARP system, injuries of other tissues that have routinely occurred may remain without effective repair in addition to the defect in mitochondrial cells, resulting in energy crisis (45). Moreover, the defect in mitochondrial oxygen metabolism in SM exposure can explain the impairment in the cardiopulmonary exercise test while O 2 saturation is normal (54).…”