Glutathione S-transferase Mu 1 Null Genotype Research Articles

Genotoxicity in humans exposed to arsenic, lithium, and boron in drinking water in the Bolivian Andes-A cross sectional study.

Elevated concentrations of arsenic, lithium and boron in drinking water have already been reported in Bolivia. Arsenic is known to cause genotoxicity but that caused by lithium and boron is less well known. The aim of the present cross-sectional study was to evaluate potential genotoxic effects of exposure to arsenic, while considering exposure to lithium and boron and genetic susceptibility. Women (n = 230) were recruited in villages located around Lake Poopó. Exposure to arsenic was determined as the sum of concentrations of arsenic metabolites inorganic arsenic, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in urine. Exposure to lithium and boron was determined based on their concentrations in urine. Genetic susceptibility was determined by GSTM1 (glutathione S-transferase-mu-1) and GSTT1 (glutathione S-transferase-theta-1) null genotypes and AS3MT (Arsenite Methyltransferase) rs3740393. Genotoxicity was measured in peripheral blood leukocytes using the comet assay. The geometric means of arsenic, lithium, and boron concentrations were 68, 897, and 3972 μg/L, respectively. GSTM1 and GSTT1 null carriers had more DNA strand breaks than gene carriers (p = .008, p = .005). We found no correlation between urinary arsenic and DNA strand breaks (rS = .03, p = .64), and only a weak non-significant positive association in the adjusted multivariate analysis (β = .09 [-.03; .22], p = .14). Surprisingly, increasing concentrations of lithium in urine were negatively correlated with DNA strand breaks (rS = -.24, p = .0006), and the association persisted in multivariate analysis after adjusting for arsenic (β = -.22 [-.36; -.08], p = .003). We found no association between boron and DNA strand breaks. The apparent protective effect of lithium merits further investigation.

A Review of the GSTM1 Null Genotype Modifies the Association between Air Pollutant Exposure and Health Problems.

Air pollution is one of the significant environmental risks known as the cause of premature deaths. It has deleterious effects on human health, including deteriorating respiratory, cardiovascular, nervous, and endocrine functions. Exposure to air pollution stimulates reactive oxygen species (ROS) production in the body, which can further cause oxidative stress. Antioxidant enzymes, such as glutathione S-transferase mu 1 (GSTM1), are essential to prevent oxidative stress development by neutralizing excess oxidants. When the antioxidant enzyme function is lacking, ROS can accumulate and, thus, cause oxidative stress. Genetic variation studies from different countries show that GSTM1 null genotype dominates the GSTM1 genotype in the population. However, the impact of the GSTM1 null genotype in modifying the association between air pollution and health problem is not yet clear. This study will elaborate on GSTM1's null genotype role in modifying the relationship between air pollution and health problems.

Worldwide Systematic Review of GSTM1 and GSTT1 Null Genotypes by Continent, Ethnicity, and Therapeutic Area.

Glutathione S-transferase Mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) enzymes are glutathione-S-transferases with broad significance for susceptibility or resistance to multifactorial human diseases, as well as detoxification of environmental chemicals and drugs. Moreover, some individuals may have a complete deletion of GSTM1 and GSTT1 genes, which can contribute to patient-to-patient variability in drug safety and efficacy. GSTM1 and GSTT1 gene deletion frequencies can vary according to ethnicity and continental origin of the studied population with implications for achieving the goal of precision/personalized medicine in clinical practice. We report here a worldwide systematic review of the null genotypes in these two clinically important genes by continents, ethnicities, and therapeutic areas (TAs). Searches were performed in the PubMed database covering the period from 1992 to 2020. Out of the 1925 articles included, most studies analyzed European individuals, corroborating the literature failure for not adequately considering the non-European ethnicities. The frequency of GSTM1 and GSTT1 null genotypes was higher in patients than in healthy volunteers. Conversely, in East Asians, higher frequencies of the null genotypes were observed in healthy volunteers than patients. Oncology was the most intensively studied TA (57% of the articles) in relation to GSTM1 and GSTT1. In all, these results demonstrate that there is an important gap in the literature in terms of failure to consider a broader range of populations, as well as diseases wherein GSTM1 and GSTT1 variations have clinical and biological implications. To achieve precision/personalized medicine on a global/worldwide scale, with equity and inclusiveness, this knowledge/research gap ought to be remedied in studies of GSTM1 and GSTT1 null genotypes. To the best of our knowledge, this is the largest systematic review conducted to date addressing the GSTM1 and GSTT1 null genotypes worldwide. The analyses from the 1925 articles highlighted the current knowledge gaps in different TAs, ethnicities, and populations. Filling these gaps is of importance, given the role these genes play in relation to the metabolism of substances to which we have frequent contact with, the associations observed between their deletion and diseases such as cancer, in addition to the interethnic differences observed for the deletion frequencies of these genes.

An updated analysis on the association of GSTM1 polymorphism and smoking exposure with the increased risk of coronary heart disease.

ObjectiveTo undertake a meta-analysis to investigate if there is an association between the glutathione S-transferase mu 1 (GSTM1) gene polymorphism, coronary artery disease (CAD) susceptibility and smoking.MethodsElectronic databases, including PubMed®, Web of Science and Embase®, were searched for relevant case–control studies. Data were extracted and the odds ratio (OR) was calculated and appropriate statistical methods were used for the meta-analysis.ResultsThe analysis included eight studies with a total of 1880 cases with CAD and 1758 control subjects. The results of this meta-analysis demonstrated that there is no association between the GSTM1 null and CAD (OR 1.24, 95% confidence interval [CI] 1.00, 1.55). An increased risk of CAD was observed in the smoking population with the GSTM1 null genotype (OR 1.48, 95% CI 1.02, 2.15). Subgroup analyses of geographical region, genotyping method and publication language category demonstrated potential relationships among gene polymorphism, smoking and CAD.ConclusionsBased on the current literature, the GSTM1 null genotype was associated to CAD in the smoking population. The interaction between smoking and GSTM1 polymorphism may contribute to the susceptibility of CAD.

GSTM1 and GSTT1 Null Genotype Polymorphisms and Susceptibility to Arsenic Poisoning: a Meta-analysis.

The value of the glutathione S-transferase (GST) null genotype in patients with arsenic poisoning has been recognized, but the conclusions of previous studies remain inconsistent. The objective of this study was to evaluate the relationship between GST mu 1 (GSTM1) and GST theta 1 (GSTT1) null genotype polymorphisms and susceptibility to arsenic poisoning. PubMed, Medline, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, and WeiPu databases were systematically searched for publications up to March 31, 2020. The quality of the studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to estimate the relationship between GSTM1 and GSTT1 null genotype polymorphisms and arsenic poisoning. The meta-analysis was conducted using STATA 14.0 software. Nine articles with 3324 subjects were included in the meta-analysis. A significantly negative correlation was observed between the GSTM1 null genotype and susceptibility to arsenic poisoning (OR = 0.731; 95% CI: 0.536-0.999; P = 0.049; I2 = 70.5%). There was no significant correlation between the GSTT1 null genotype (OR = 1.009; 95% CI: 0.856-1.189; P = 0.915, I2 = 36.8%) and GSTM1-GSTT1 double null genotype (OR = 1.105; 95% CI: 0.670-1.822; P = 0.695; I2 = 64.7%) and the risk of arsenic poisoning. Egger's and Begg's tests indicated no publishing bias. Compared with controls, individuals with the GSTM1 null genotype were less susceptible to arsenic poisoning. The GSTT1 single null genotype and GSTM1-GSTT1 dual-null genotype were not associated with the risk of arsenic poisoning. The GSTM1 single null genotype may have potential as a genotoxic biomarker to identify individuals who are not prone to arsenic poisoning, and as a reference for guiding the prevention of arsenic poisoning.

Polymorphisms and endometriosis: a systematic review and meta-analyses.

Endometriosis is an estrogen-dependent gynecological disorder that affects at least 10% of women of reproductive age. It may lead to infertility and non-specific symptoms such as chronic pelvic pain. Endometriosis screening and diagnosis are difficult and time-consuming. Late diagnosis (with a delay ranging from 3.3 to 10.7years) is a major problem and may contribute to disease progression and a worse response to treatment once initiated. Efficient screening tests might reduce this diagnostic delay. As endometriosis is presumed to be a complex disease with several genetic and non-genetic pathogenic factors, many researchers have sought to identify polymorphisms that predispose to this condition. We performed a systematic review and meta-analysis of the most regularly reported polymorphisms in order to identify those that might predispose to endometriosis and might thus be of value in screening. The MEDLINE database was searched for English-language publications on DNA polymorphisms in endometriosis, with no date restriction. The PubTator text mining tool was used to extract gene names from the selected publications' abstracts. We only selected polymorphisms reported by at least three studies, having applied strict inclusion and exclusion criteria to their control populations. No stratification based on ethnicity was performed. All steps were carried out according to PRISMA guidelines. The initial selection of 395 publications cited 242 different genes. Sixty-two genes (corresponding to 265 different polymorphisms) were cited at least in three publications. After the application of our other selection criteria (an original case-control study of endometriosis, a reported association between endometriosis and at least one polymorphism, data on women of reproductive age and a diagnosis of endometriosis in the cases established by surgery and/or MRI and confirmed by histology), 28 polymorphisms were eligible for meta-analysis. Only five of the 28 polymorphisms were found to be significantly associated with endometriosis: interferon gamma (IFNG) (CA) repeat, glutathione S-transferase mu 1 (GSTM1) null genotype, glutathione S-transferase pi 1 (GSTP1) rs1695 and wingless-type MMTV integration site family member 4 (WNT4) rs16826658 and rs2235529. Six others showed a significant trend towards an association: progesterone receptor (PGR) PROGINS, interCellular adhesion molecule 1 (ICAM1) rs1799969, aryl-hydrocarbon receptor repressor (AHRR) rs2292596, cytochrome family 17 subfamily A polypeptide 1 (CYP17A1) rs743572, CYP2C19 rs4244285 and peroxisome proliferator-activated receptor gamma (PPARG) rs1801282), and 12 showed a significant trend towards the lack of an association: tumor necrosis factor (TNF) rs1799964, interleukin 6 (IL6) rs1800796, transforming growth factor beta 1 (TGFB1) rs1800469, estrogen receptor 1 (ESR1) rs2234693, PGR rs10895068, FSH receptor (FSHR) rs6166, ICAM1 rs5498, CYP1A1 rs4646903, CYP19A1 rs10046, tumor protein 53 (TP53) rs1042522, X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) rs25487 and serpin peptidase inhibitor clade E member 1 (SERPINE1) rs1799889; however, for the 18 polymorphisms identified in the latter two groups, further studies of the potential association with the endometriosis risk are needed. The remaining five of the 28 polymorphisms were not associated with endometriosis: glutathione S-transferase theta 1 (GSTT1) null genotype, vascular endothelial growth factor alpha (VEGFA) rs699947, rs833061, rs2010963 and rs3025039. By carefully taking account of how the control populations were defined, we identified polymorphisms that might be candidates for use in endometriosis screening and polymorphisms not associated with endometriosis. This might constitute the first step towards identifying polymorphism combinations that predispose to endometriosis (IFNG (CA) repeat, GSTM1 null genotype, GSTP1 rs1695, WNT4 rs16826658 and WNT4 rs2235529) in a large cohort of patients with well-defined inclusion criteria. In turn, these results might improve the diagnosis of endometriosis in primary care. Lastly, our present findings may enable a better understanding of endometriosis and improve the management of patients with this disease.

Association between polymorphisms in the CYP1A1, CYP2E1 and GSTM1 genes, and smoking, alcohol and upper digestive tract carcinomas in a high-incidence area of northern China.

Metabolic gene variants, smoking, and alcohol consumption are important upper digestive tract cancer (UDTC) risk factors. However, the gene-gene and gene-environment interactions remain unclear. A case-control study in a high incidence area for upper digestive tract cancer was conducted in China. DNA was extracted from buffy coat samples for PCR or PCR-restriction fragment length polymorphism. Smoking and alcohol drinking status was determined by questionnaires. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the associations. After adjusting for confounding factors, smoking increased esophageal cancer (EC), gastric cardia cancer (GCC) and gastric antral carcinoma (GAC) risk by 3.594, 4.658, and 3.999-fold, respectively. Alcohol consumption increased EC, GCC and GAC risk by 1.953, 2.442 and 1.765-fold, respectively. The cytochrome P4501A1 (CYP1A1) rs4646903 T>C polymorphism increased GCC risk, the cytochrome P4502E1 (CYP2E1) rs2031920 C>T polymorphism increased EC risk, while the GSTM1 null genotype decreased EC risk. An association existed between the following: CYP1A1 rs4646903 and smoking in EC, GCC and GAC; CYP1A1 rs4646903 and alcohol consumption in EC and GCC; CYP2E1 rs2031920 and smoking in EC, GCC and GAC and CYP2E1 rs2031920 and alcohol consumption in EC and GCC. No association was observed between CYP1A1 and CYP2E1. The glutathione S-transferase mu 1 (GSTM1) null genotype decreased EC risk (OR=0.510). Smoking/drinking are upper digestive tract cancer risk factors. The CYP1A1 rs4646903 and CYP2E1 rs2031920 polymorphisms were risk factors of GCC or EC, and the GSTM1 null genotype may serve a protective role against EC. The results of the present study indicated that gene-environment interactions increase the risk of UDTC.

A novel association between GSTM1 null variant and anthracycline-induced cardiac dysfunction (ACD) in childhood cancer survivors (CCS): A COG ALTE03N1 report.

10030 Background: ACD is a leading cause of mortality in CCS. Previous studies have identified genomic variants that moderate the ACD risk. An agnostic evaluation of differential gene expression between those with and without ACD has not been explored, and could provide insights into the mechanism of cardiotoxicity. Methods: Gene expression profiles in leukocyte RNA from anthracycline-exposed non-Hispanic white (NHW) CCS (20 with ACD [cases]; 20 without ACD [controls]) used Illumina HumanHT-12 v4.0 Expression Beadchips. Gene expression profiles in h uman iPSC-derived cardiomyocytes (hiPSC-CMs – Day 30) from 6 childhood cancer patients (3 each with and without CD) treated with 1μM doxorubicin or vehicle for 24 h, used RNA-seq. Genotyping in leukocyte DNA from anthracycline-exposed NHW CCS (65 cases; 76 controls) to determine if the differentially-expressed genes mapped to genetic variants that modified ACD risk, used conditional logistic regression analysis adjusted for sex, age at cancer diagnosis, chest radiation and anthracycline dose. Patient characteristics are in Table. Results: Gene-expression in survivors:Glutathione S transferase mu 1 ( GSTM1) was differentially-expressed; RT q-PCR showed significant downregulation of GSTM1 in cases (0.67±0.57 vs. 1.33±1.33, p=0.049). hiPSC-CMs gene expression: GSTM1 was downregulated in patients with ACD (logFC = -1.4). Genotyping: Using PCR for GSTM1 null, we observed a significant association between CD risk and GSTM1 null genotype (OR=3.0; 95%CI, 1.4-6.2, p=0.003). Conclusions: We report an association between GSTM1 null genotype and ACD, previously unreported likely because GWAS studies did not examined gene deletions. GSTM1 is involved in detoxification of anthracyclines. This finding could facilitate identification of childhood cancer survivors at increased risk of ACD. [Table: see text]

Prognosis of hormone-dependent breast cancer seems to be influenced by KEAP1, NRF2 and GSTM1 genetic polymorphisms.

Influence of Glutathione S-transferase Mu1 (GSTM1) has long been studied in breast cancer and GSTM1 null genotype was correlated with breast cancer risk. Nuclear factor-erythroid 2-related factor-2 (NRF2) is a transcription factor that forms a complex with Kelch-like ECH-associated protein-1 (KEAP1). Recent studies have demonstrated that expression of these proteins is deregulated in several malignancies. Thus, in the present study we aim to distinguish GSTM1 heterozygous from wild type genotype in breast cancer patients and evaluate the presence and clinical significance of NRF2 and KEAP1 polymorphisms, alone or in association, with breast cancer prognosis, in cases confirmed to have GSTM1-present genotype. Study population consisted in 52 patients with breast cancer. Genomic DNA was extracted, GSTM1 was genotyped through multiplex PCR and gene dose was evaluated through real-time PCR. All cases were sequenced, through Sanger sequencing, for specific regions of NRF2 and KEAP1. Genotyping and clinicopathological data were correlated and statistical analysis was performed. GSTM1 wild type was identified in 1 case and 26 cases were identified as heterozygous, these data were correlated with Human Epidermal growth factor Receptor 2 (HER2) status (p value = 0.017). We also verified that most cancers diagnosed at younger ages had the presence of KEAP1 and/or NRF2 polymorphisms. The association of GSTM1 heterozygous genotype with rs1048290 and rs35652124 seems to be associated with HER2+ (p < 0.05). Our results suggest that GSTM1 * 1/0 genotype and the cumulative presence of at least one allele mutated in KEAP1 and/or NRF2 polymorphisms might be associated with worse prognosis for breast cancer patients.

Association of glutathione S‐transferase theta 1 and glutathione S‐transferase mu 1 gene polymorphism with the risk of pre‐eclampsia during pregnancy in Bangladesh

In this study, we analyzed the risk of developing pre-eclampsia with respect to glutathione S-transferase theta 1 (GSTT1) and glutathione S-transferase mu 1 (GSTM1) genotypes. We also tried to find relationship between genotypes and biochemical parameter change in pre-eclampsia patients. In total, 104 pre-eclampsia patients and 200 healthy controls were recruited for the study. Peripheral venous blood was drawn from study subjects and DNA was extracted from whole blood and multiplex polymerase chain reaction method was used to identify genotypes of GSTT1 and GSTM1 gene. All biochemical parameters were measured using colorimetric method. Serum glutamic pyruvic transaminase level was significantly higher (P < 0.01) and hemoglobin level was significantly lower (P < 0.001) in pre-eclampsia patients compared to control subjects. Significant association was found in GSTM1 null genotype with pre-eclampsia (P < 0.001) with an odds ratio (OR) analysis showing more than four-fold increased risk (OR = 4.75; 95% CI = 2.17-10.39; P <0.001). But for GSTT1 gene, null genotype was not associated with increased risk of developing pre-eclampsia (P > 0.05). In case of GSTT1 and GSTM1, the patients having both null genotypes for GSTT1 and GSTM1 showed significant (P < 0.001) higher risk of developing pre-eclampsia (OR = 7.64; 95% CI = 2.38-24.60; P < 0.001). GSTM1 null genotype increases the risk of pre-eclampsia. Combined GSTT1 and GSTM1 null genotype, the risk was even higher.

POLYMORPHIC DELETIONS OF GLUTATHIONE S-TRANSFERASES M1, T1 AND BLADDER CANCER RISK IN ALGERIAN POPULATION

Objective: Glutathione S-transferase mu 1 (GSTM1) and GST theta 1 (GSTT1) genes are two xenobiotic metabolizing genes in Phase II of the detoxification process. The polymorphisms of GSTM1, GSTT1 genes, and smoking are involved in many cancers such as bladder cancer. Our aim was to assess the role of smoking status and GSTM1 and GSTT1 null genotypes in bladder cancer development in Algerian population.Methods: The current case–control study included 175 bladder cancer patients and 188 controls matched for age, gender, and ethnic origin. The GSTM1 and GSTT1 genotypes were determined by multiplex polymerase chain reaction using blood genomic DNA. Possible associations of stage and grade with the obtained genotypes were also tested.Results: A significant associations were observed between bladder cancer risk and tobacco smoke (p value: p=1.21E-08), GSTM1 null genotype (p=0.018), GSTT1 null genotype (p=0.009), and GSTM1/GSTT1-double null genotype (p=0.001). The combined effect of smoking and testing deletions increased the risk of bladder cancer and the most important risk was observed among smokers carrying GSTM1/GSTT1-double null genotype (p=1.09E-05). No significant association was shown between stage and grade of bladder cancer and the testing genotypes.Conclusion: This study indicated that smoking, GSTM1 null, GSTT1 null, and GSTM1/GSTT1-double null genotypes individually represent a risk factor for bladder cancer in Algerian population. The interaction smoking gene increased the risk considerably. In fact, it is suggested that patients with cigarette smoking habit and combined GSTM1 and T1 genes deletion might be at increased risk of bladder cancer.

Glutathione S-transferase mu-1, glutathione S-transferase theta-1 null genotypes, and oral cancer risk: A meta-analysis in the Chinese population.

Several studies have evaluated the correlation between glutathione S-transferase mu-1 (GSTM1), GST theta-1 (GSTT1) polymorphisms and oral cancer in Chinese people. However, the results are inconsistent. To assess the effects of GSTM1, GSTT1 null genotypes on the risk for development of oral cancer in the Chinese population, a meta-analysis was performed. Studies were identified using PubMed and Chinese databases through February 2016. The associations were assessed with pooled odds ratios (ORs) and 95% confidence intervals (CIs). This meta-analysis included six studies with 1306 oral cancer cases and 1484 controls. In the overall analysis, no significant association between GSTM1, GSTT1 polymorphisms and oral cancer was found in the Chinese population. In the subgroup analyses by geographic areas and source of controls, significant risk was found between GSTM1 null genotype and oral cancer in Mainland China (OR = 2.715, 95% CI = 2.17-3.38), but not in Taiwan China. Our meta-analysis suggested that GSTM1 null genotype might be associated with an increased risk of developing oral cancer in individuals from Mainland China.

Effect of Glutathione S-transferase mu 1 (GSTM1) gene polymorphism on chronic myeloid leukemia risk and Imatinib treatment response

Glutathione S-transferases (GSTs) gene polymorphisms were demonstrated to be associated with inter-individual variability of Imatinib mesylate (IM) response for chronic myeloid leukemia (CML) patients in a few studies; however, the results have been inconclusive. The aim of this study was to assess the role of such GSTs gene polymorphisms (GSTT1 and GSTM1) in relation to IM treatment outcome in 96 Syrian CML in chronic phase (CP) patients. Screening of GSTM1 and GSTT1 genotypes (null or present of these genes) was determined by multiplex polymerase chain reaction. Our results revealed that a GSTM1 null genotype frequency was significantly higher in CML patients than control (reference group) (OR=2.12, 95% CI: 1.24–3.7; p=0.007) while the GSTT1 null had no significant effect on CML development (OR=1.54, 95% CI: 0.83–2.9; p=0.19). Dual GSTM1 and GSTT1 null were associated with the risk of CML development (OR=3.6, 95% CI: 1.37–9.3; p=0.01). The GSTM1 null significantly increased the risk of minimal cytogenetic response (p=0.001). The similar trend was observed in patients with GSTT1 present/GSTM1 null genotypes (p=0.009). The highest number of patients with minimal cytogenetic response was in the group treated with 400mg of IM, while 600 and 800mg of IM significantly decreased this frequency. Our results highlight the significance of GSTM1 null alone, or in combination with the GSTT1 gene null, significantly increased the likelihood of IM failure in the CML patients studied. Especially patients with minimal cytogenetic response and GSTM1 null suffered from IM treatment failure in case of low dosage IM.

Genetic Basis of Diabetic Nephropathy

It is well known that all patients with Type 2 Diabetes Mellitus (T2DM) do not develop chronic kidney disease (CKD). Several metabolic, hemodynamic and intracellular mechanisms have been proposed to play role in the pathogenesis of Diabetic Nephropathy (DN). Clustering of patients with DN in certain ethnic groups and families suggests the role of genetic factors. We have studied various facets about genetic determinants which may influence the development of kidney disease in patients with T2DM. We have found that Angiotensin Converting Enzyme (ACE) DD genotype conferred the maximum risk, whereas ACE II genotype seemed to confer protective role against development of diabetic and nondiabetic CKD. Further, we found that oxidative stress (OS) plays a significant role in the development of DN and that Glutathione S-transferase theta-1and/or Glutathione S-transferase Mu-1 null genotypes are associated with higher OS in patients with DN. In addition, we also found that increased levels of inflammatory mediators, i.e. Tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP) and Urinary Monocyte Chemoattractant Protein-1 (uMCP-1) play a significant role in contributing to OS. We have shown that genetic polymorphism of NF-kB gene and TNF-α gene plays a role in determining serum level of various inflammatory markers and oxidant stress parameters. We found significant association of -429T/C and Gly82Ser Receptors for Advanced Glycation End-products (RAGE) polymorphisms with the development of macrovascular and microvascular complications, respectively in T2DM subjects. Further, we have observed that AGE-mediated exacerbation of RAGE expression may play a role in pathogenesis of various vascular complications in T2DM. To conclude, polymorphisms of various genes involved in renin-angiotensin aldosterone system (RAAS), inflammatory, oxidant stress, cytoprotective and nitrous oxide pathways and enhanced RAGE mRNA expression may adversely influence final common pathway through oxidant stress mechanisms, and influence the levels of various cytokines and intracellular signaling mechanisms, thereby influencing the susceptibility of patients with diabetes mellitus for development of kidney disease and vascular complications.

GSTM1 gene polymorphism and the risk of colorectal cancer in a Saudi Arabian population.

The enzyme glutathione S-transferase Mu 1 (GSTM1) is encoded by the GSTM1 gene. Polymorphisms in GSTM1 affect the detoxifying function of the enzyme variants. This forms the basis of the debate about the impact of the GSTM1 null/present genotype on colorectal carcinoma risk. We tested the potential influence of GSTM1 polymorphisms on the development of colorectal cancer. DNA extracted from 83 samples taken from patients that were previously diagnosed as having colorectal carcinoma and from 35 control subjects who did not have colorectal carcinoma were amplified. GSTM1 genotypes were determined by DNA sequencing. The current study revealed that the majority (69/83, 83%) of colorectal cancer cases harbored the null genotype (GSTM1*0/*0), and the remaining 14 (17%) cases harbored either the GSTM1wt/wt or the GSTM1wt/*0 genotype. In contrast, among the control cases, 23 (65%) had the null genotype (GSTM1*0/*0) and 12 (35%) had either the GSTM1wt/wt or the GSTM1wt/*0 genotype. The current report emphasizes the impact of the GSTM1 null genotype on the increased risk of colorectal carcinoma in Saudi Arabia.

Relevance of GSTM1, GSTT1 and GSTP1 Gene Polymorphism to Breast Cancer Susceptibility in Mizoram Population, Northeast India.

The enzymes encoded by glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genes are involved in the metabolism of wide range of carcinogens that are ubiquitous in the environment. Homozygous deletions of the GSTM1 and GSTT1 genes are commonly found and result in lack of enzyme activity. This study was undertaken to evaluate the association between GSTM1, GSTT1 and GSTP1 gene polymorphism and breast cancer risk in Mizoram population. Odd ratio (OR) and 95% confidence interval (CI) from conditional logistic regression model were used to estimate the association between genetic polymorphism and breast cancer risk. The GSTM1 and GSTT1 null genotypes were associated with an increased risk of breast cancer [OR = 10.80 (95% CI 1.16-100.43)]. The risk of breast cancer associated with the GSTT1 null genotype was observed to be low among postmenopausal women. When considered together, GSTM1 and GSTT1 genotypes were found to be associated with an increased risk of breast cancer. The relationship between GSTM1 and GSTT1 gene deletions and breast cancer risk was substantially altered by consumption of Smoked Meat/Vegetable. In the present study, GSTP1Ile105Val (rs1695) polymorphism was related to breast cancer susceptibility or phenotype. Our data provides evidence for substantially increased risk of breast cancer associated with GSTM1 and/or GSTT1 homozygous gene deletions in Mizoram population.

Genetic polymorphisms of glutathione S-transferase Mu 1, glutathione S-transferase theta 1, and glutathione S-transferase P1 in oral squamous cell carcinoma: A case-control study in Iranian population

Background: Gene variability related to activation and detoxification of procarcinogens affects the susceptibility to oral squamous cell carcinoma (OSCC). The results of numerous studies investigating the interrelationship between polymorphisms of glutathione S- transferase enzymes are not conclusive and there are little data regarding this topic on Iranian population. Aims and Objectives: This study aimed to investigate the genetic polymorphisms in glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), and glutathione S-transferase P1 (GSTP1) and the association with the risk of OSCC in Iranian population. Materials and Methods: The genetic polymorphisms of GSTM1, GSTT1, and GSTP1 genes were investigated in 35 Iranian patients with the OSCC and 60 age-sex matched controls. GSTP1 genotyping was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism method and GSTM1 and GSTT1 genotyping was amplified with PCR using specific primers. Odds ratios (ORs) and their 95% confidence intervals (CIs) were obtained using SPSS 17 and the risk of OSCC in relation to GSTM1, GSTT1, and GSTP1 polymorphism was defined. Results: The prevalence of GSTM1 and GSTT1 null genotypes in OSCC group were significantly higher than the control group.(OR = 2.6, 95% CI = 1.04-6.5; P = 0.01 for GSTM1) (OR = 11, 95% CI = 9-31; P = 0.001 for GSTT1). The GSTP1 valine polymorphism was not significantly different between the study groups (P = 0.145). Conclusions: GSTM1 and GSTT1 null genotypes may increase the risk for OSCC development in Iranian patients.

Glutathione S-transferase M1 and glutathione S-transferase T1 genotype in chronic pancreatitis: a meta-analysis.

A meta-analysis to determine the association between chronic pancreatitis and glutathione-S transferase (GST) mu 1 (GSTM1) and theta 1 (GSTT1) deletions. Case-control studies concerning the relationship between chronic pancreatitis and GSTM1 or GSTT1 deletions were identified (up to October 2013). Meta-analyses of the association between GSTM1 and GSTT1 genotype and chronic pancreatitis or alcoholic chronic pancreatitis (ACP) were performed. Seven studies were included in the meta-analysis (650 patients/1382 controls for GSTM1 and 536 patients/1304 controls for GSTT1). There were no significant relationships between GSTM1/GSTT1 and chronic pancreatitis or GSTT1 and ACP. There was a significant association between GSTM1 null genotype and ACP (odds ratio 1.16, 95% confidence intervals 1.03, 1.30). The GSTM1 null genotype was significantly associated with ACP risk.

Lack of any association of GST genetic polymorphisms with susceptibility to ovarian cancer--a meta-analysis.

Epidemiology studies have reported conflicting results between glutathione S-transferase Mu-1 (GSTM1), glutathione S-transferase theta-1 (GSTT1) and glutathione S-transferase pi-1 (GSTP1) and ovarian cancer (OC) susceptibility. In this study, an updated meta-analysis was applied to determine whether the deletion of GSTM1, GSTT1 and GSTP1 has an influence on OC susceptibility. A published literature search was performed through PubMed, Embase, Cochrane Library, and Science Citation Index Expanded database for articles published in English. Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated using random or fixed effects models. Heterogeneity between studies was assessed using the Cochrane Q test and I2 statistics. Sub-group analysis was conducted to explore the sources of heterogeneity. Sensitivity analysis was employed to evaluate the respective influence of each study on the overall estimate. In total, 10 published studies were included in the final analysis. The combined analysis revealed that there was no significant association between GSTM1 null genotype and OC risk (OR=1.01, 95%CI: 0.91-1.12). Additionally, there was no significant association between GSTT1 genetic polymorphisms and OC risk (OR=0.98, 95% CI: 0.85-1.13). Similalry, no significant associations were found concerning the GSTP1 rs1695 locus and OC risk. Meanwhile, subgroup analysis did not show a significant increase in eligible studies with low heterogeneity. However, sensitivity analysis, publication bias and cumulative analysis demonstrated the reliability and stability of the current meta-analysis. These findings suggest that GSTs genetic polymorphisms may not contribute to OC susceptibility. Large epidemiological studies with the combination of GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphisms and more specific histological subtypes of OC are needed to prove our findings.

Glutathione S-transferase Mu-1 gene polymorphism in Egyptian patients with idiopathic male infertility.

The aim of this study was to examine whether an association exists between glutathione S-transferase Mu-1 (GSTM1) gene polymorphism and idiopathic male infertility. Sixty men with primary idiopathic infertility and 60 fertile men, serving as controls, were recruited for the study. The polymorphism was analysed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The frequency of GSTM1 null genotype was observed to be higher in infertile men 40% in comparison with 33.3% in the fertile men, but this difference was not statistically significant. There was statistically significant difference between cases and controls as regards GSTM1 genotype distribution ((MC) P=0.006*) in GSTM1-positive men. Patients with the GSTM1 null genotype had significantly lower sperm concentrations and total sperm count when compared with patients with GSTM1-positive genotype. In the control group, men with GSTM1 null genotype had significantly lower sperm concentrations but not total sperm count when compared with men with GSTM1-positive genotype. The results of this study suggest a possible negative effect of GSTM1 null genotype on the spermatogenic potential of the testis.