GSTM1 Research Articles

Association of glutathione S-transferase M1 and T1 polymorphisms on the susceptibility of diabetic retinopathy in the Bangladeshi population.

This study investigated the role of glutathione-S-transferase gene (GSTM1 and GSTT1) polymorphisms in the predisposition of type 2 diabetes mellitus (T2DM) with or without diabetic retinopathy (DR). Thecase-control study included188 subjects: 50 T2DMwith DR, 63T2DM without DR, and 75 healthy individuals' presenting no clinical signs or evidence of diabetes mellitus. Zinc and magnesium levels were measured using a flame atomic absorption spectrophotometer, and the lipid profile was evaluated using standard methods. The gene polymorphism of GSTs was performed by the multiplex-PCR method. Compared to the control, DR and T2DM had considerably greater total cholesterol, LDL-C, and decreased HDL-C levels. Magnesium levels were significantly lower in DR and T2DM than in control. Total cholesterol, LDL, TG, and magnesium levels didn't differ significantly between DR and T2DM groups. In DR, the GSTT1-null genotype was more prevalent than in T2DM subjects and controls (26.0%, 12.7%, and 10.7%, respectively). GSTT1-null genotype was considerably more common in DR than in controls and associated with 2.94-folds enhancing the chance of developing DR (OR = 2.94; 95% CI = 1.12-7.75;p = 0.02). However, the recurrence of GSTM1-null genotype was not clearly distinguishable among these three populations (28.0%, 38.1% and 29.3%, respectively) and not particularly prone to the risk of DR compared to T2DM subjects and controls (OR = 0.63; 95% CI = 0.28-1.41; p = 0.26; OR = 0.94; 95% CI = 0.42-2.07; p = 0.87, respectively). Taken together, these findings suggest the potential role of GSTT1 deletion mutation as a risk factor for the vulnerability of DR among T2DM patients in the Bangladeshi population.

Glutathione S-transferase genetic polymorphisms and fluoride-induced reproductive toxicity in men with idiopathic infertility.

Male infertility caused by idiopathic oligoasthenospermia (OAT) is known as idiopathic male infertility. Glutathione S-transferase (GST) and fluoride may play important roles in idiopathic male infertility, but their effects are still unknown. Our study examined the relationship between GST polymorphisms and fluoride-induced toxicity in idiopathic male infertility and determined the underlying mechanism. Sperm, blood, and urine samples were collected from 560 males. Fluoride levels were measured by a highly selective electrode method, and GST genotypes were identified using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). Semen parameters, DNA fragmentation index (DFI), mitochondrial membrane potential (MMP), and oxidative stress (OS) biomarkers were statistically assessed at the P < 0.05 level. Compared with healthy fertile group, semen parameters, fluoride levels, OS biomarkers, sex hormone levels, and MMP and DFI levels were lower in the idiopathic male infertility group. For glutathione S-transferase M1 (GSTM1[-]) and glutathione S-transferase T1 (GSTT1[-]) or glutathione S-transferase P1 (GSTP1) mutant genotypes, levels of semen fluoride, OS, MMP, and DFI were considerably higher, and the mean levels of sperm parameters and testosterone were statistically significant in GSTM1(+), GSTT1(+), and GSTP1 wild-type genotypes. Both semen and blood fluoride levels were associated with oxidative stress in idiopathic male infertility patients. Elevated fluoride in semen with the genotypes listed above was linked to reproductive quality in idiopathic male infertility patients. In conclusion, GST polymorphisms and fluorine may have an indicative relationship between reproductive quality and sex hormone levels, and OS participates in the development of idiopathic male infertility.

Null genotypes of Glutathione S-transferase M1 and T1 and risk of oral cancer: A meta-analysis.

Glutathione S-transferase M1 (GSTM1) and Glutathione S-transferase T1 (GSTT1) null genotypes have been considered risk factors for many cancers. Numerous studies have been conducted to evaluate the association of null genotype of GSTM1 and GSTT1 with increased susceptibility to oral cancers, and these have produced inconsistent and inconclusive results. In the present study, the possible association of oral cancer(OC) with GSTM1 and GSTT1 null genotypes was explored by a meta analysis. A meta-analysis was conducted on published original studies retrieved from the literature using a bibliographic search from two electronic databases: MEDLINE (National library of medicine, USA) and EMBASE. The pooled odds ratio and presence of publication bias in those studies were evaluated. A total of 49 studies concerning oral cancer (OC) were identified for GSTM1 null genotype. Similarly, 36 studies were identified for GSTT1 null genotype. The pooled OR was 1.551(95% confidence interval [CI]: 1.355-1.774) for the GSTM1 null genotype, while for GSTT1 null genotype, the pooled OR was 1.377 (95% CI: 1.155-1.642). No evidence of publication bias was detected among the included studies. The results suggest that the Glutathione S-transferase M1 and Glutathione S-transferase T1 null genotypes significantly enhances the risk of developing oral cancer by a substantial percentage.

Investigating the Role of Glutathione S- Transferase Genes, Histopathological and Molecular Subtypes, Gene-Gene Interaction and Its Susceptibility to Breast Carcinoma in Ethnic North- Indian Population.

Breast Cancer (BC) is a genetically and clinically heterogeneous disease including complex interactions between gene-gene and gene-environment components. This study aimed, to explore whether the Glutathione S- transferase (GSTs) gene polymorphism has role in BC susceptibility. We further evaluated the frequency of four subtypes of BC based on molecular classification followed by microscopic histological analysis to study the grades of invasive ductal carcinoma (IDC). Polymorphism in GST genes in North-Indian BC patients was assessed by multiplex-PCR and PCR-RFLP methods. 105 BC patients and 145 healthy controls were enrolled for this study. Data was analyzed by calculating the odds ratio (OR) and 95% CI from logistic regression analyses. Our findings revealed that GSTM1 null genotype (OR = 2.231; 95% CI = 1.332-3.737; p-value= 0.002) is significantly associated to BC risk in ethnic North- Indian population. However, the risk for BC susceptibility in North-Indians does not appear to be associated with GSTT1 null genotype. The GSTP1 (Val/Val) genotype (OR=1.545; CI=0.663-3.605; p-value= 0.314) was also found to be susceptible for BC risk. Combination of three high risk GST genotypes association exhibiting gene-gene interaction further confirmed the increased risk to BC in this region. The results of present study indicated that polymorphism in GSTM1 and rs1695 of GSTP1 genes may influence BC development among North-Indian women. Thus, the screening of GSTM1 and GSTP1 gene should be recommended for the earlier investigation for BC as a precautionary measure.

Congenital aflatoxicosis, mal-detoxification genomics & ontogeny trigger immune-mediated Kotb disease biliary atresia variant: SANRA compliant review.

Biliary atresia (BA) is the most common indication for pediatric liver transplantation. We describe The BA variant: Kotb disease. Liver tissue in the Kotb disease BA is massively damaged by congenital aflatoxicosis resulting in inflammation, adhesions, fibrosis, bile duct proliferation, scarring, cholestasis, focal syncytial giant cell transformation, and typical immune response involving infiltration by CD4+, CD8+, CD68+, CD14+, neutrophil infiltration, neutrophil elastase spill, heavy loads of aflatoxin B1, accelerated cirrhosis, disruption of p53 and GSTPi, and have null glutathione S transferase M1 (GSTM1). All their mothers are heterozygous for GSTM1. This inability to detoxify aflatoxicosis results in progressive inflammatory adhesions and obliterative cholangiopathy early in life. The typical disruption of both p53 and GSTPi causes loss of fidelity of hepatic regeneration. Hence, regeneration in Kotb disease BA typically promotes accelerated cirrhosis. The immune response in Kotb disease BA is for damage control and initiation of regeneration, yet, this friendly fire incurs massive structural collateral damage. The Kotb disease BA is about actual ongoing hepatic entrapment of aflatoxins with lack of ability of safe disposal due to child detoxification-genomics disarray.The Kotb disease BA is a product of the interaction of persistent congenital aflatoxicosis, genetic lack of GSTM1 detoxification, ontogenically impaired activity of other hepatic detoxification, massive neutrophil-elastase, immune-induced damage, and disturbed regeneration. Ante-natal and neonatal screening for aflatoxicosis, avoiding cord milking, and stringent control of aflatoxicosis content of human, poultry and live-stock feeds might prove effective for prevention, prompt diagnosis and management based on our recent understanding of its patho-genomics.

Genetic factors of toxic effects development in pollution liquidators of the former factory with mercury electrolysis technology

Introduction. According to genetic factors, it is possible to determine the degree of manifestation of the toxic effects of mercury. The latter justifies the assessment of the genetic status of the exposed contingent in order to identify hypersensitive individuals in whom adverse health effects can be realized when exposed to relatively low levels of the toxicant. The study aims to research the distribution of genotypes of some polymorphic variants of genes of the xenobiotic biotransformation system, heat shock proteins and tumor necrosis factor in the contingent involved in liquidation measures, as well as to identify individuals with a high prognostic risk of toxic effects due to exposure to mercury. Materials and methods. We conducted genotyping of 231 people (men only): 193 employees of the Ministry of Emergency Situations (MES) of Russia in the Irkutsk Region and 38 employees of the Federal Environmental Operator (FEO) involved in the elimination of mercury pollution at the industrial site of the mercury electrolysis plant and adjacent facilities on the territory of a former chemical plant in Eastern Siberia. The researchers used real-time PCR and PCR-RFLP methods to study polymorphic variants of the genes CYP1A1 (rs1048943), GSTP1 (rs1695 and rs1138272), TNF-α (rs1800629) and HSPA1B (rs1061581). Results. For the polymorphism of the GSTP1 gene (rs1695), we have identified an increase in the frequency of AG genotypes (p=0.043) and a decrease in the frequency of GG genotypes (p=0.048) in employees of the MES compared to those from the FEO group. The researchers didn’t detect carriers of the TT genotype for the polymorphic locus GSTP1 (rs1138272) in both examined groups. There was the carriage of the rare GG-CYP1A1 homozygote only in one MES employee. We found that 33 MES employees and 3 examined from the FEO group who are carriers of the GG-HSPA1B (+1267A/G) genotype have a high predictive risk of developing toxic effects due to mercury exposure. The experts discussed the data obtained with the results of genotyping of former mercury electrolysis shop workers who were chronically exposed to metallic mercury vapor. The experts have reviewed the data obtained from the results of genotyping of former employees of the mercury electrolysis shop who were chronically exposed to metallic mercury vapor Limitations. The limitations, first of all, should include the number of examined individuals in the FEO group, as well as the lack of data on deletion polymorphisms of the GSTT1 and GSTM1 genes, potentially having a significant role in the toxicokinetics of mercury. Conclusion. The study has revealed 36 carriers of the GG genotype of the polymorphic locus +1267A/G of the HSPA1B gene associated with a high prognostic risk of toxic effects associated with exposure to mercury among the employees of the Ministry of Emergency Situations (MES) and the FEO involved in liquidation work. Taking into account the forthcoming volume and duration of work related to the demercurization of the territory of the former factory with mercury electrolysis technology and the surrounding area it is advisable to take into account the results obtained when monitoring the health status of the liquidators. Ethics. We have received voluntary informed consent, approved by the Committee on Biomedical Ethics (Protocol No. 6 of 10.03.2020), from each employee being examined.

Application of an antibody microarray for serum protein profiling of coronary artery stenosis

Protein expression profiling in the serum is used to identify novel biomarkers and investigate the signaling pathways in various diseases. The aim of the present study was to evaluate serum biomarkers associated with coronary artery stenosis resulting from atherosclerosis.The study included 4 groups of subjects: group A and B with and without coronary lesions, respectively, were selected from a previously reported cohort study on coronary atherosclerosis, control group C comprised of asymptomatic subjects and group D was used for independent validation of the microarray data by ELISA. Labeled serum proteins were profiled by an Explorer antibody array, which included 656 specific antibodies in two replicates (FullMoon Biosystems, USA). Cadherin-P, interleukin-5, glutathione S-transferase Mu, and neuronal nitric oxide synthase were sex-independently increased in Group A compared with those in group B. The microarray data on cadherin-P were externally validated in an independent group D using ELISA. Fibroblast growth factor-1, FGF-2, collagen II, granulocyte-macrophage colony-stimulating factor, IL-1 alpha, angiopoietin-2, granulocyte colony-stimulating factor, lymphocyte cell-specific protein tyrosine kinase, and IkappaB kinase b were increase in men in group A compared with group B. Cyclin-dependent kinase 1, DNA fragmentation factor subunit alpha DFF45/ICAD, adenovirus type 2 E1A, calponin, ADP-ribosylation factor-6, muscle-specific actin, thyroid hormone receptor alpha, and alpha-methylacyl-CoA racemase were specifically increased in women in Group A compared with group B. Alterations in the levels of specific proteins may point to the signaling pathways contributing to coronary atherosclerosis, and these proteins will be useful biomarkers for the progression of cardiovascular diseases.

Effects of 4-n-nonylphenol in liver of male and female viviparous fish (Poecilia vivipara)

4-n-Nonylphenol (NP) is one of the most toxic alkylphenols found in the environment. To evaluate the transcriptional effects of NP in the viviparous fish Poecilia vivipara, a hepatic transcriptome and qPCR analysis of genes were carried out. Guppies separated by sex were injected with two doses of NP (15 μg/g and 150 μg/g) or peanut oil (control). After 24 h, analysis of transcriptional level of Aryl Hydrocarbon Receptor (AhR), Estrogen Nuclear Receptor Alpha (ESR1), Pregnane X Receptor (PXR), Cytochromes P450 (CYP1A, CYP2K1 and CYP3A30), Glutathione S-transferase A3 and Mu 3 (GSTa3 and GSTMu3), SRY-Box Transcription Factor 9 (SOX9), Vitellogenin-1 (VIT), ATP Binding Cassette Subfamily C Member 1 (ABCC1), Multidrug Resistance-Associated Protein 2 (MRP2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1) was evaluated. 205,046 transcripts were assembled and protein prediction resulted in 203,147 predicted peptides. In females, no significant changes were detected in the transcription of some phase I biotransformation and ABC transporter genes. AhR, PXR, GSTa3 and SOX9 genes where higher in the lower dose group (15 μg/g) compared to control. In male fish, no changes were observed in the transcript levels of the nuclear receptors, in endocrine disruption and phase I biotransformation genes. GSTa3 showed lower transcription in fish treated with both doses. ABCC1 was higher in guppies treated with the lower dose while MRP2 showed less transcripts. This short-term and low-dose exposure to NP caused changes that could serve as early indicators of deleterious processes. These results indicate P. vivipara as a good sentinel in biomonitoring programs.

Frequency of polymorphic loci of GSTM1 and GSTT1 modifier genes in the genotype of children with pyelonephritis and congenital urinary malformations

IntroductionThe growing number, prevalence, numerous complications, and deaths in patients with congenital anomalies of the kidney and urinary tract (CAKUT) indicate the high relevance of the declared topic. Currently, clinical medicine is actively engaged in research on the cellular and molecular mechanisms that cause the appearance of these diseases.AimThe aim of the work is to study genetic markers of CAKUT and the tendency to a more severe course of pyelonephritis in young children.Material and methodsUsing the multiplex polymerase chain reaction method, 50 children with pyelonephritis were examined for the presence of deletion alleles of the glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) genes.Results and discussionAs a result, 35 children were diagnosed with certain CAKUT. A statistically significant associative relationship between the development of pyelonephritis in a child and the presence of a null allele GSTM1 0/0 in its genotype and a high probability of CAKUT with quantitative and positional anomalies and impaired formation and differentiation of renal tissue in carriers of null alleles GSTT1 0/0, GSTM1 0/0 in their combination was revealed.ConclusionsThe fact that different forms of abnormalities are detected in members of the same family suggests that certain genetic mutations can potentially lead to CAKUT syndrome, but the final phenotype of the renal system depends either on the genetic background or on environmental factors.

Copper metabolism patterns and tumor microenvironment characterization in colon adenocarcinoma.

Copper participates in biological processes such as oxygen metabolism and iron uptake, and is a key factor in immune regulation. Based on the transcription data, mutation data and clinical data of colon adenocarcinoma (COAD) patients from The Cancer Genome Atlas (TCGA) database and Gene Expression Profiling Interactive Analysis (GEPIA2) database, the expression and mutation of copper metabolization-related genes in COAD patients and their correlation with tumor immune microenvironment were analyzed. Copper metabolization-related genes (CMRGs) were used to construct COAD subtypes and prognostic risk models for COAD patients. Furthermore, Kaplan-Meier (K-M) curve and receiver operating characteristic (ROC) curve were used to analyze the clinical value of COAD subtypes and genotyping models in distinguishing clinical characteristics of patients, and the immune infiltration of patients with different genotypes was analyzed. Finally, the clinical tissue samples from COAD patients were used to analyze the mRNA expression of genes in risk model between tumor and normal tissues by the method of Polymerase Chain Reaction (PCR). Of the 479 CMRGs, 68 genes were differentially expressed in normal and tumor tissues of COAD patients in TCGA and GEPIA2. Two subtypes with different clinical and immunological characteristics were identified by using 482 genes related to copper metabolism. Finally, a prognostic risk model consisting of five CMRGs was constructed, which could not only predict the prognosis of patients, but also correlated with COAD subtypes. In addition, some genes (glutathione S-transferase mu 1, cyclin D1and cytochrome P450 family 2 subfamily S member 1) in risk model was show significant difference between normal and tumor tissues. The COAD subtypes identified by CMRGs can help clinically distinguish patients with different prognosis and tumor progression, and the risk score can assist in clinical evaluation of patient prognosis, serving as a valuable biomarker for COAD immunotherapy.

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.

Pangenomic analysis of Chinese gastric cancer

Pangenomic study might improve the completeness of human reference genome (GRCh38) and promote precision medicine. Here, we use an automated pipeline of human pangenomic analysis to build gastric cancer pan-genome for 185 paired deep sequencing data (370 samples), and characterize the gene presence-absence variations (PAVs) at whole genome level. Genes ACOT1, GSTM1, SIGLEC14 and UGT2B17 are identified as highly absent genes in gastric cancer population. A set of genes from unaligned sequences with GRCh38 are predicted. We successfully locate one of predicted genes GC0643 on chromosome 9q34.2. Overexpression of GC0643 significantly inhibits cell growth, cell migration and invasion, cell cycle progression, and induces cell apoptosis in cancer cells. The tumor suppressor functions can be reversed by shGC0643 knockdown. The GC0643 is approved by NCBI database (GenBank: MW194843.1). Collectively, the robust pan-genome strategy provides a deeper understanding of the gene PAVs in the human cancer genome.

Association of Polymorphic Gene Variants of Xenobiotic Biotransformation Enzymes with Lung Tissue Destruction in Tuberculosis Patients

The objective: to investigate the association of polymorphic gene variants of xenobiotic biotransformation enzymes (NAT2, CYP2E1, ABCB1, GSTM1, GSTT1) and cytokines (IL1B, IL-4, IL-10, TNF) with lung tissue destruction in pulmonary tuberculosis patients.Subjects and Methods. An ethnically homogeneous population sample of unrelated individuals of Slavic nationalities (mainly Russians) living in Kursk Oblast suffering from new pulmonary tuberculosis was examined.Results. New pulmonary tuberculosis with no destructive changes in the lungs was associated with the EE genotype of the GSTM1 gene (p &lt; 0.0001) in 89.5%, while the DD genotype of the GSTM1 gene (p &lt; 0.0001) was associated with the presence of destructive changes in the lungs in 56.1% of cases; the dominant GG genotype of the TNF-α gene was associated with destructive changes in the lungs in 93.3% (p = 0.027), and the recessive GA genotype of the TNF-α gene was associated with no destructive changes in the lungs in 71.9% (p = 0.027).

Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. Combination of PGG and metformin nearly completely reversed weight gain, elevation of serum aminotransferases, and hepatic steatosis and steatohepatitis. In addition, the downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD.

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.

Effects of genetic polymorphisms of GSTM1, GSTT1, and GSTP1 genes on blood metal levels in non-ferrous metal alloy smelter operators

Heavy metal ions are known to induce generation of a large number of reactive oxygen species (ROS). Glutathione S-transferases (GSTs) play an important role in adaptation and response to oxidative stress. GSTM1, GSTT1, and GSTP1 genes have numerous described polymorphisms, the most significant being GSTM1, GSTT1, and GSTP1 Ile105Val deletion ones. Our objective was to study the relationship between the genetic polymorphism of GSTM1, GSTT1, GSTP1 genes and blood levels of metals in smelter operators engaged in crude lead refining. We examined 55 male lead-refining furnace operators working at a non-ferrous metal alloy plant. Blood metal concentrations were measured by inductively coupled plasma mass spectrometry. GSTM1 and GSTT1 deletion polymorphisms were determined using real-time SYBR Green qPCR and that of GSTP1 Ile105Val – using a commercial SNP Screening Kit. Statistical data processing was carried out using the Mann – Whitney U-test. Blood levels of industry-specific metals were not statistically different between the workers with GSTT1 and GSTP1 genotypes. We established, however, that men with the null genotype of GSTM1 had significantly higher blood arsenic levels. Our findings indicate that a high blood arsenic level associated with occupational exposure may be attributed to the GSTM1 null genotype. This observation can be used to identify the most vulnerable groups of individuals at risk of overexposure to arsenic.

Abstract 128: Loss Of Gstm1 Augments Kidney Neutrophil Population In Angii-induced Hypertension

Background: Glutathione-S-transferase Mu1( Gstm1 ) gene, a member of Glutathione-S-transferases (GST) superfamily, encodes an enzyme that functions in the detoxification of electrophilic compounds. The common GSTM1 deletion variant in humans is associated with increased risks of chronic kidney disease (CKD) progression and incident end stage kidney failure. We reported that deletion of Gstm1 increases oxidative stress, kidney inflammation and injury in angiotensin II induced hypertension (Ang II-HTN) in mice. At 4 weeks of Ang II-HTN, neutrophils, CD4+T cells, and F4/80+ cells were significantly increased in Gstm1 knockout (KO) kidney. While a link between oxidative stress and immune activation in hypertension has been well documented, the molecular mechanism by which Gstm1 regulates immune cell activation in hypertension is unknown. Methods: To further characterize the inflammatory response in GSTM1 deficiency, Gstm1 KO and wild-type (WT) male mice at ~ 12 weeks of age were subjected to Angiotensin II at 1000 ng/kg per minute for 4 days via a mini osmotic pump. The kidney cells and bone marrow cells were isolated for flow cytometry analysis. Results: At baseline, there were no differences in inflammatory cell populations including neutrophils between WT and Gstm1 KO mice. At Day 4 of Ang II-HTN, Gstm1 KO kidneys exhibited about a 2.3 fold increase in neutrophil population (CD45 + Ly6G + CD11b + ), compared to WT control mice (10 WT and 8 Gstm1 KO mice, p=0.0075). Interestingly, CD45+ bone marrow cells isolated from both Gstm1 KO and WT mice have similar percentile of neutrophil populations ; however, neutrophils in Gstm1 KO bone marrow express relatively higher levels of CXCR2. Unlike at 4 weeks, there was no difference in other inflammatory cells at Day 4. Conclusion: Deletion of Gstm1 increases renal neutrophil population early in Ang II-HTN and CXCR2 expression in bone marrow neutrophils. Gstm1 may play a role in regulating neutrophil migration and recruitment. Further studies are needed to delineate whether GSTM1 deficiency drives kidney injury via early neutrophil migration, which could shed light on potential therapeutic target for CKD progression in those genetically susceptible.

Влияние генетического полиморфизма генов GSTM1, GSTT1 и GSTP1 на содержание металлов в крови у плавильщиков производства сплавов цветных металлов

Heavy metal ions are known to induce generation of a large number of reactive oxygen species (ROS). Glutathione S-transferases (GSTs) play an important role in adaptation and response to oxidative stress. GSTM1, GSTT1, and GSTP1 genes have numerous described polymorphisms, the most significant being GSTM1, GSTT1, and GSTP1 Ile105Val deletion ones. Our objective was to study the relationship between the genetic polymorphism of GSTM1, GSTT1, GSTP1 genes and blood levels of metals in smelter operators engaged in crude lead refining. We examined 55 male lead-refining furnace operators working at a non-ferrous metal alloy plant. Blood metal concentrations were measured by inductively coupled plasma mass spectrometry. GSTM1 and GSTT1 deletion polymorphisms were determined using real-time SYBR Green qPCR and that of GSTP1 Ile105Val – using a commercial SNP Screening Kit. Statistical data processing was carried out using the Mann – Whitney U-test. Blood levels of industry-specific metals were not statistically different between the workers with GSTT1 and GSTP1 genotypes. We established, however, that men with the null genotype of GSTM1 had significantly higher blood arsenic levels. Our findings indicate that a high blood arsenic level associated with occupational exposure may be attributed to the GSTM1 null genotype. This observation can be used to identify the most vulnerable groups of individuals at risk of overexposure to arsenic.

PREDICTIVE MODELING OF N-ACETYL TRANSFERASE 2 SINGLE NUCLEOTIDE POLYMORPHISMS AND BREAST CANCER RISK USING IN-SILCO APPROACHES

N-acetyltransferase 2, also known as arylamine N-acetyltransferase, commonly known as NAT2. The objective of this study was to identify non-synonymous SNPs of NAT2 and their association with breast cancer using computational analysis. For this purpose, different online tools like SIFT, Polyphen, Polyphen-2, fuNTRp, SNAP2 (to identify pathogenic SNPs), SNP&amp;GO, PhD-SNP, PredictSNP, MAPP, SNAP, MetaSNP, PANTHER (disease associated SNPs), Mu-Pro, I-Mutant, and CONSURF (to check protein stability) were used. Post-translational modifications (PTMs) were detected by Musitedeep, Protein secondary structure by SOPMA, and protein to protein interaction by STRING. Nineteen SNPs having rsIDs (rs1435840670, rs747536177, rs753310036, rs1175197943, rs1805158,rs1019316375, rs201345576, rs1476310549, rs72466458, rs201080763, rs746734312, rs561124342, rs549917500, rs1383708687, rs4986996, rs559660817, rs1344597702, rs749948990, and rs148566670) showing mutations on Y6H, G11V, F37S, H43P, R64W, G65D, W67R, W67C, C68Y, N72S, G83S, G83A, H107Q, V112M, D122N, D122G, C223W, G230V, and L275M, respectively found to be completely deleterious. The PTMs found were Glycosylation at amino acid number 125; Ubiquitination at 256 and 282, Acetylation at 272; Hydroxylation at 281, and Phosphorylation at 287. The protein secondary structure consisted of Alpha helix (Hh) 80 is (27.59%), Extended strand (Ee) 65 is (22.41%), Beta turn (Tt) 21 is 7.24% and Random coil (Cc) 124 is (42.76%). Protein-protein interaction analysis revealed that it has strong interaction with Myeloperoxidase, Xanthine dehydrogenase, Liver carboxylesterase 1, Glutathione S-transferase Mu 1, and with cytochrome family. Based on these results, it is concluded that these SNPs found in NAT2 are involved in breast cancer. Further in vitro and in vivo analysis should be performed to conduct these interactions.

GSTM1 and GSTT1 Gene Polymorphisms with Gallbladder Carcinoma

In order to explore the relationship between GSTM1 and GSTT1 gene polymorphisms and gallbladder cancer, so as to find a better treatment and prevention of gallbladder cancer and improve the treatment effect. In this paper, 247 patients with gallbladder cancer were selected for the experiment, including 187 male patients and 60 female patients. The total number of patients was randomly divided into two groups, namely the case group and the control group. The patients in normal condition and after treatment of tumor tissue and adjacent non-tumor tissue gene detection, and then through the logistic regression model to analyze the data. After the experiment, we found that the frequency ratio of GSTM1 and GSTT1 in gallbladder cancer patients before treatment was 57.33% and 52.37%, which was very high, which was very disadvantageous in gene detection. However, after treatment, the frequency of deletion of the two genes was 45.73% and 51.02%, which was significantly reduced. The reduced gene ratio is very beneficial to the observation of gallbladder cancer. Therefore, the surgical treatment of gallbladder cancer before the first drug after gene testing, in the understanding of various principles, will have twice the result with half the effort.