Risk of Cardiovascular Complications Among Type 2 Diabetes Mellitus Patients with GSTP1 Genetic Polymorphism: A Nested Case-Control Study and Docking Studies.

The genetic alteration in the antioxidant gene Glutathione-S-Transferases Pi 1 (GSTP1) namely GSTP1*IIe105Val (rs1695) and GSTP1*Ala114Val (rs1138272) changes the individual susceptibility to cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) by altering the substrate binding and catalytic activity. This study aims to investigate the association of GSTP1 rs1695 and rs1138272 polymorphism with CVD development in T2DM patients. Genotyping was performed with 400 study participants-group I: control; group II: T2DM; group III: CVD; and group IV: T2DM/CVD [n = 100 each] by PCR-RFLP. The rs1695 and rs1138272 polymorphism were docked against NPACT and NUBBE database and virtually screened using glide. The study reported that rs1695 polymorphism was associated with T2DM risk under dominant and allelic genetic models [OR = 1.97(1.08-3.59) p = 0.02 and OR = 1.79(1.20-2.66) p = 0.003, respectively]. The val/val genotype, dominant, recessive model, and T allelic genetic model were associated with increased CVD risk [OR = 4.15(1.97-8.73) p = < 0.01; OR = 3.16(1.65-6.04) p = < 0.01; OR = 3.47(1.91-6.31) p = < 0.01; and OR = 2.94(1.95-4.43) p = < 0.01, respectively]. In contrast, rs1695 polymorphism was not associated with CVD development among patients with T2DM. In rs1138272, the wild genotype was only detected and neither heterozygous nor val/val genotype was observed. The docking analysis revealed that the Ile105Val mutation plays a significant role in altering the GSTP1 capacity compared to the Ala115Val mutation. This suggests that the Ile105Val mutation has a greater impact on the protein's structure, function, or susceptibility to diseases compared to the Ala115Val mutation. In summary, genetic alteration in GSTP1 rs1695 potentially contributes to an increased risk of T2DM and CVD.

Progonostic effect of GSTM1/GSTT1 polymorphism in determining cardiovascular diseases risk among type 2 diabetes patients in South Indian population.

BACKGROUND: Cardiovascular disease (CVD) is a significant complication of type 2 diabetes mellitus (T2DM), with oxidative stress playing a significant role. Glutathione S-transferase (GST) polymorphisms - GSTM1, GSTT1 - have been linked to CVD and T2DM. The role of GSTM1 and GSTT1 in CVD development among T2DM patients in the South Indian population is investigated in this study. MATERIALS AND METHODS: The volunteers were grouped as Group 1: control, Group 2: T2DM, Group 3: CVD, and Group 4: T2DM with CVD (n = 100 each). Blood glucose, lipid profile, plasma GST, MDA, and total antioxidants were measured. GSTM1 and GSTT1 were genotyped using PCR. RESULTS: GSTT1 plays a significant role in the development of T2DM and CVD [OR 2.96(1.64-5.33), < 0.001 and 3.05(1.67-5.58), < 0.001] while GSTM1 null genotype was not associated with disease development. Individuals with dual null GSTM1/GSTT1 genotype had the highest risk of developing CVD [3.70(1.50-9.11), 0.004]. Group 2 and 3 individuals showed higher lipid peroxidation and lower total antioxidant levels. Pathway analysis further indicated that GSTT1 significantly affects GST plasma levels. CONCLUSION: GSTT1 null genotype may be considered a contributing factor that increases the susceptibility and risk of CVD and T2DM in the South Indian population.

Contribution of Glutathione-S-Transferases Polymorphism and Risk of Coronary Artery Diseases: A Meta-Analysis.

BACKGROUND: Oxidative stress is one of the risk components in the development of coronary artery diseases (CAD). Genetic polymorphism in major antioxidant genes like Glutathione- S-Transferases (GST) has been associated with increased CAD susceptibility and severity. OBJECTIVE: To get a precise evaluation and to update the association, a meta-analysis on GST (GSTM1, GSTT1, and GSTP1) polymorphism with CAD was performed. Moreover, the combined effect of GSTM1/GSTT1 null genotypes on CAD risk has not yet been studied, but it has the highest risk of developing diseases. MATERIALS AND METHODS: PubMed, Embase, and Web of Science were systematically searched for eligible studies. Case-control studies in the English language and with genotypic frequency were selected in order to provide data and calculate the odds ratio (OR). OR with 95% CI was calculated, and a random effect model was used. NOS scale was used to assess the quality of the included studies. RESULTS: Meta-analysis indicated that the GSTM1 null genotype and GSTP1 (Ile105Val) polymorphism is significantly associated with CAD risk with a pooled OR-1.38, p=0.01 for GSTM1 and OR-1.19, p=0.04 for GSTP1. The dual null genotype of GSTM1-GSTT1 has the highest risk for CAD development (OR-1.59, p=0.003), and there is no significant association between GSTT1 null genotype with CAD. In the subgroup analysis, GSTM1 showed an increased risk for Asians (OR- 1.68, p=<0.01) and smokers (OR-1.98, p=<0.01). Publication bias was not observed. CONCLUSION: The findings suggest that the GSTM1 and GSTP1 polymorphism can be a predictive factor for CAD risk, and a larger sample size is required further to confirm the association.

Susceptibility of Glutathione-S-Transferase Polymorphism to CVD Develo- pment in Type 2 Diabetes Mellitus - A Review.

Metabolic disorder affects normal homeostasis and can lead to the development of diseases. Diabetes mellitus is the most common metabolic disorder, and a cluster of metabolic conditions can lead to cardiovascular disease (CVD) development. Diabetes mellitus and CVD are closely related, with oxidative stress, playing a major role in the pathophysiology. Glutathione-S-Transferases (GST) potentially play an important role by reducing oxidative stress and is found to be the underlying pathophysiology in the development of diabetes, cardiovascular diseases (CVD), etc Background: In this review, the role of GST genetic variant in the development of diabetes mellitus, CVD and diabetic vascular complications has been focused. Objectives: Based on the literature, it is evident that the GST can act as an important biochemical tool providing significant evidence regarding oxidative stress predominant in the development of diseases. Analysis of GST gene status, particularly detection of GSTM1 and GSTT1 null mutations and GSTP1 polymorphism, have clinical importance. Results: The analysis of GST polymorphism may help identify the people at risk and provide proper medical management. Genotyping of GST gene would be a helpful biomarker for early diagnosis of CVD development in DM and also in CVD cases. More studies focusing on the association of GST polymorphism with CVD development in diabetic patients will help us determine the pathophysiology better.