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

Background: 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. Objectives: In this review, the role of GST genetic variant in the development of diabetes mellitus, CVD and diabetic vascular complications has been focused. Results: 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. Conclusion: 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.

Polymorphisms in Genes Encoding Glutathione Transferase Pi and Glutathione Transferase Omega Influence Prostate Cancer Risk and Prognosis

Considering the pleiotropic roles of glutathione transferase (GST) omega class members in redox homeostasis, we hypothesized that polymorphisms in GSTO1 and GSTO2 might contribute to prostate cancer (PC) development and progression. Therefore, we performed a comprehensive analysis of GSTO1 and GSTO2 SNPs’ role in susceptibility to PC, as well as whether they might serve as prognostic biomarkers independently or in conjunction with other common GST polymorphisms (GSTM1, GSTT1, and GSTP1). Genotyping was performed in 237 PC cases and 236 age-matched controls by multiplex PCR for deletion of GST polymorphisms and quantitative PCR for SNPs. The results of this study, for the first time, demonstrated that homozygous carriers of both GSTO1*A/A and GSTO2*G/G variant genotypes are at increased risk of PC. This was further confirmed by haplotype analysis, which showed that H2 comprising both GSTO1*A and GSTO2*G variant alleles represented a high-risk combination. However, the prognostic relevance of polymorphisms in GST omega genes was not found in our cohort of PC patients. Analysis of the role of other investigated GST polymorphisms (GSTM1, GSTT1, and GSTP1) in terms of PC prognosis has shown shorter survival in carriers of GSTP1*T/T (rs1138272) genotype than in those carrying at least one referent allele. In addition, the presence of GSTP1*T/T genotype independently predicted a four-fold higher risk of overall mortality among PC patients. This study demonstrated a significant prognostic role of GST polymorphism in PC.

Comparative Hepatotoxicity of Aflatoxin B1 among Workers Exposed to Different Organic Dust with Emphasis on Polymorphism Role of Glutathione S-Transferase Gene

AIM: The study aimed to investigate effects of organic dust exposure from different sources on aflatoxin B1-albumin adducts (AFB1/Alb), and role of glutathione S-transferase (GST) gene polymorphism in hepatotoxicity of (AFB1) among exposed workers. MATERIAL AND METHODS: Liver enzymes, AFB1/Alb, and GST polymorphism were estimated in 132 wheat flour dust and 87 woods sawmill workers, and 156 controls.RESULTS: Results revealed that AFB1/Alb and liver enzymes were significantly elevated in exposed workers compared to controls, and were significantly higher in sawmill workers compared to flour workers. AFB1/Alb in flour and sawmill workers with GSTT1 and GSTM1&GSTT1 null genotypes were significantly higher than controls, and in sawmill workers with GSTM1&GSTT1 null than flour workers. Liver enzymes (ALT and AST) in sawmill workers were significantly higher than flour workers and controls in all GST polymorphism; except in GSTT1 polymorphism, where these enzymes were significantly higher in the two exposed groups than controls.CONCLUSIONS: In conclusion, organic dust exposure may cause elevation in AFB1/Alb and liver enzymes of exposed workers, and GST gene polymorphism plays an important role in susceptibility to hepatic parenchymal cell injury; except in workers with GSTT1&GSTM1 null genotype, gene susceptibility seemed to have little role and the main role was for environmental exposures.

Association between Inflammatory Marker, Environmental Lead Exposure, and Glutathione S-Transferase Gene

A number of studies suggested that lead is related to the induction of oxidative stress, and alteration of immune response. In addition, modifying these toxic effects varied partly by GST polymorphism. The objectives of this study were to assess the association between the lead-induced alteration in serum hs-CRP, with GSTM1, GSTT1, and GSTP1 Val105Ile genetic variations and the health consequence from environmental lead exposure. The 924 blood samples were analyzed for blood lead, CRP, and genotyping of three genes with real-time PCR. Means of blood lead and serum hs-CRP were 5.45 μg/dL and 2.07 mg/L. Both CRP and systolic blood pressure levels were significantly higher for individuals with blood lead in quartile 4 (6.48–24.63 μg/dL) compared with those in quartile 1 (1.23–3.47 μg/dL,P<0.01). In particular, in men with blood lead >6.47 μg/dL the adjusted odds ratio (OR) of CRP levels for individuals with GSTP1 variants allele, GSTM1 null, GSTT1 null, double-null GSTM1, and GSTT1 compared with wild-type allele was 1.46 (95% CI; 1.05–2.20), 1.32 (95% CI; 1.03–1.69), 1.65 (95% CI; 1.17–2.35), and 1.98 (95% CI; 1.47–2.55), respectively. Our findings suggested that lead exposure is associated with adverse changes in inflammatory marker and SBP. GST polymorphisms are among the genetic determinants related to lead-induced inflammatory response.

Polymorphisms of the GSTT1 and GSTM1 genes in women of central Serbia: Absence of association with uterine myoma

Since glutathione S-transferase (GST) enzymes are involved in cellular protection, we aimed to determine the distribution of GSTT1 and GSTM1 null genotypes in women in central Serbia in order to assess the risk of development of uterine myoma. The study consisted of 34 clinically diagnosed uterine myoma patients and 35 healthy control women. Analyses of GST polymorphism were carried out by multiplex PCR. Our results showed no significant differences in the GSTT1 and GSTM1 null genotypes between the patients and controls. Using the GSTT1 positive/GSTM1 positive combination as reference, there was no statistically significant risk of uterine myoma with the combination of GSTT1 null and GSTM1 null genotypes. We conclude that polymorphism of both GSTT1 and GSTM1 genes, alone or in combination, did not present the main risk for uterine myoma in women from central Serbia.

Association of Genetic Polymorphisms of Glutatione-S-Transferase Genes and Overall Response/Clinical Features in Diffuse Large B-Cell Lymphoma Patients Treated with Rituximab.

Abstract 1939 Poster Board I-962 Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma. It is a heterogeneous disease. Approximately 40% of the patients respond well to chemotherapy based on rituximab-CHOP (R-CHOP). The prognosis for the other 60% is poor and only half of the patients survives 5 years after the onset of the disease. Glutathione-S-transferase (GST) genes, including GSTM1 (GST mu 1), GSTT1 (GST Tetha 1), and GSTP1 (GST pi 1), are a complex multigene family involved in metabolism and detoxification of chemical agents such as alkylators and steroids. They are involved with cell proliferation and cell survival. Since many of these drugs are regularly used to treat LDGCB we studied the GST gene polymorphisms regarding there involvement in prognosis and clinical features of this disease. Methods: 79 patients with DLBCL classified according to WHO criteria were studied for GSTM1 or GSTT1 null deletion polymorphism by multiplex PCR and GSTP1 1578A>G and 2295C>T alleles polymorphism by PCR-RFLP using B-globin gene as an internal control. Results: The median age of the 79 patients was 54 years (15 to 75); 47(59%) were male. Thirty-five (44.3%) patients were treated with R-CHOP21 and 44 (55.7%) with CHOP-like chemotherapy with no rituximab. Twenty-nine (37%) patients had stage III + IV and more than 2 factors described by the International Prognostic Index. Sixty-eight (86%) patients acquired complete remission (CR) (IC95%: 77-93%), 3(4%) acquired partial remission (PR) and 8(10%) were refractory (RD) to treatment. The overall response (OR) with R-CHOP was 35 (44%), 34 (43%) with CHOP with no Rituximab and 10 (13%) with other therapy (p=0.41). The GSTM null genotype was found in 44 (56%) patients with no correlation with treatment response. The GSTT1 null polymorphism was found in 62 (78%) patients, more often in those with bulky disease (61% versus 29%, p=0.02). Further associations between GSTT1 null polymorphism and disease features were not demonstrated. Regarding the GSTP1 1578 A>G allele, 26(42.0%) patients had AA, 35(44%) had AG and 11(14%) had GG polymorphism. Patients with GG polymorphism had extranodal involvement more often than those with the AA and AG polymorphism (50% vs. 6.7% vs. 5.7%, p<0.001). Unexpectedly, all of those 11 patients with GG polymorphism were male (p=0.01). Seventy-seven patients were studied for GSTP1 2293 C>T allele. The wild type CC was found in the majority of them 73(92%). The remaining patients had CT polymorphism and none of them had mutant TT polymorphism. Association between GSTP1 2293 C>T polymorphism and disease characteristics was not observed. Indeed, none of the studied polymorphisms was associated to treatment outcome with CHOP or R-CHOP. Conclusions: The knowledge concerning the impact of the genetic GST polymorphism in predicting outcome in DLBCL is scarce. In this trial we demonstrated that GSTT1 was the most common GST polymorphism found in patients with DLBCL, mainly in those with bulky disease. In the other hand, the genotype GSTP1 GG was more often associated to extranodal involvement in DLBCL. Concerning to outcomes, we did not found any association between overall response or survival rate and genetic polymorphism of the GST genes. Disclosures: No relevant conflicts of interest to declare.