GSTM1 Null Genotype Research Articles

Influence of GSTM1, GSTT1, and GSTP1 genetic polymorphisms on disorders in transplant patients: a systematic review.

The glutathione-S-transferase (GST) enzymes are phase II isoenzymes responsible for protection against free radicals and xenobiotics. Since these proteins are described as polymorphic, polymorphisms in genes that encode them may alter enzymatic function and contribute to oxidative stress. In this context, such polymorphisms were already associated with several diseases and multiple therapeutic outcomes. A systematic review was performed to evaluate studies regarding the association between polymorphisms in three genes encoding enzymes of the GST family- GSTM1, GSTT1, and GSTP1- and disorders in transplant patients. A total of 125 articles on which inclusion and exclusion criteria were applied were identified at PubMed database. Thirty-two studies met the target criteria and were included in the review. The mechanisms by which GST genotypes influence the development of disorders in transplant patients differ by disorder: they may participate in it by decreasing metabolism of drugs administered to patients undergoing transplantation, then exposing them to greater toxicity; by decreasing the repair ability against oxidative stress; or by encoding proteins that may be recognized as foreign, setting of an alloimmune reaction. Although some results are better established- such as GSTM1 null genotype's role in the development of toxicity events in transplant patients- others require further evidences, as GST influence on the development of pulmonary decline and posttransplant diabetes mellitus (PTDM). The importance of investigating these associations lies in a personalized medicine, in which the high-risk genotype patient has its treatment individualized and its care for prophylaxis and surveillance increased, potentially reducing this population's morbimortality.

Features of GSTM1, GSTT1 and GSTP1 Genetic Polymorphism in Nizhny Tagil Metallurgical Plant Workers with Cardiovascular Diseases

Background: The development of cardiovascular diseases is determined not only by working conditions but also by genetic characteristics of employees. Genetic GSTM1, GSTT1 and GSTP1 variations contribute to individual differences in responses to industrial chemicals and carcinogens. Objective: To study the features of the genetic polymorphism of the GSTM1, GSTT1, and GSTP1 genes in metallurgical plant workers with diseases of the cardiovascular system in the town of Nizhny Tagil, Sverdlovsk Region, Russian Federation. Materials and methods: The case cohort included 61 men aged 33 to 61 years (mean: 48.15 ± 7.50 years), working in the converter shop and suffering from heart diseases. The control cohort consisted of 29 conditionally healthy male employees, aged 23–56, of the same iron and steel works having no signs of a cardiovascular disease. The DNA was isolated from peripheral blood using a standard technique. Deletion polymorphism of GSTM1 and GSTT1 genes was determined by quantitative PCR; Ile105Val polymorphism of the GSTP1 gene was established by qPCR using a commercial test kit. Results: We observed no statistically significant differences between the cohorts for any of the studied genes. The frequency of occurrence of the combination of GSTM1 (0/0) and GSTT1 (0/0) in the cases and controls was 14 % and 11 %, respectively, but the difference was negligible. Conclusions: Our findings demonstrate that the presence of null genotypes of GSTM1, GSTT1, as well as the mutant GSTP1 allele and the associated loss of enzyme activity contribute little to the development of cardiovascular diseases in workers exposed to occupational hazards.

Analysis of the influence of glutathione S-transferase (GSTM1 and GSTT1) genes on the risk of essential hypertension

Background Essential hypertension (EH) results from a complex interaction between environmental factors and an individual’s genetic background. Aim To assess the relationship between polymorphisms in GSTM1 and GSTT1 and the risk of EH. Subjects and methods A multiplex-PCR was used to identify the genotypic profiles of GSTM1 and GSTT1 in 160 patients and 210 controls. Results The frequency of GSTM1-null genotype was higher in patients younger than 61 years when compared to those over 61 years. Interestingly, GSTT1-null was significantly associated with the risk of EH (OR 4; 95% CI 2.6–6.3; p < 0.0001). While GSTM1-null showed no trend (OR 0.7; 95% CI 0.5–1.1, p = 0.12). Individuals carrying the combined GSTT1-null/GSTM1-null were 2.4 times more at risk for hypertension compared to those harbouring the combined GSTT1-present/GSTM1-present genotype (OR 2.4; 95% CI 1.3–4.4; p = 0.005). Additionally, the presence of the combined GSTT1-null/GSTM1-present was associated with an increased risk of EH compared to GSTT1-present/GSTM1-present carriers (OR 6.75; 95% CI 3.4–13.2; p < 0.0001). Conclusion This study showed that the GSTT1-null alone or in interaction with GSTM1-present or GSTM1-null was associated with a higher risk of hypertension. Moreover, the GSTM1-null seems to be associated with the age of onset of hypertension.

GSTT1 null and rs156697 Polymorphism in GSTO2 Influence the Risk and Therapeutic Outcome of B-Acute Lymphoblastic Leukemia Patients.

IntroductionGlutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to chemotherapy in acute lymphoblastic leukemia (ALL). This case–control study investigated the association of GST gene polymorphisms with the etiology and therapeutic outcome of B-ALL among Kashmiri population.MethodsA total of 300 individuals including 150 newly diagnosed B-ALL patients and an equal number of age and gender matched controls were genotyped for five GST gene polymorphisms by polymerase chain reaction–restriction fragment length polymorphism technique (PCR-RFLP) and multiplex PCR techniques.ResultsHigher frequency of GSTT1 null, GSTO2-AG, and GSTO2-GG genotypes was observed in ALL cases compared to controls that associated significantly with ALL risk (GSTT1 null: OR = 2.93, p = 0.0001; GSTO2-AG: OR = 2.58, p = 0.01; GSTO2-GG: OR = 3.13, p = 0.01). GSTM1, GSTP1, and GSTO1 SNPs showed no significant association (p > 0.05). Combined genotype analysis revealed significant association of GSTT1 null/GSTM1 null (OR = 4.11, p = 0.011) and GSTT1 null/GSTP1-AG (OR = 4.93, p = 0.0003) with B-ALL susceptibility. Haplotype analysis of rs4925 and rs156697 revealed that carriers of CG haplotype had increased risk of B-ALL (p = 0.04). Kaplan–Meier plots revealed significantly inferior 3-year disease-free survival for GSTO2-GG carriers (p = 0.002). Multivariate analysis confirmed GSTO2-GG as an independent poor prognostic factor for DFS (HR = 4.5, p = 0.034). Among combined genotypes, only GSTT1 null/GSTP1-AG associated significantly with poorer DFS rates (p = 0.032).ConclusionThis study demonstrated that GSTT1 null individually or in combination with GSTM1null and GSTP1-AG genotypes associated with increased B-ALL risk. Also, rs156697 variant genotypes (AG and GG) associated with B-ALL, whereas the GG genotype of rs156697 influenced the treatment outcome.

Cytokinesis-block micronucleus cytome (CBMN-CYT) assay and its relationship with genetic polymorphisms in welders

Fumes generated in the welding process are composed of micrometric and nanometric particles that form when metal fumes condense. The International Agency for Research on Cancer established that many compounds derived from the welding process are carcinogenic to humans. Still, there are few studies related to the role of genetic polymorphisms. This work aimed to analyze the influence of OGG1 Ser326Cys, XRCC1 Arg280His, XRCC1 Arg194Thr, XRCC1 Arg399Gln, XRCC3 Thr241Met, GSTM1, and GSTT1 gene polymorphisms on DNA damage of 98 subjects occupationally exposed to welding fumes and 100 non exposed individuals. The results showed that individuals exposed to welding fumes with XRCC3 Thr241Thr, XRCC3 Thr241Met, and GSTM1 null genotypes demonstrated a significantly higher micronucleus frequency in lymphocytes. In contrast, individuals with XRCC1 Arg399Gln and XRCC1 Gln399Gln genotypes had significant levels of NPBs. OGG1 326 Ser/Cys, OGG1 326 Cys/Cys, XRCC1 194Arg/Thr, XRCC1 194Thr/Thr, and GSTT1 null genotypes exhibited significantly higher apoptotic values. Also, XRCC1 194Arg/Trp, XRCC1 194Thr/Thr, and GSTM1 null genotype carriers had higher necrotic levels compared to XRCC1 194Arg/Arg and GSTM1 nonnull carriers. Compositional analysis revealed the presence of iron, manganese, silicon as well as particles smaller than 2 μm that adhere to each other and form agglomerates. These results may be associated with a mixture of components, such as nitrogen dioxide, carbon monoxide, and metallic fumes, leading to significant DNA damage and cell death processes. These findings demonstrated the importance of the association between individual susceptibility and DNA damage levels due to occupational exposure to welding fumes; and constitute one of the first studies carried out in exposed workers from Colombia.

GSTM1 and GSTT1 double null genotypes determining cell fate and proliferation as potential risk factors of relapse in children with hematological malignancies after hematopoietic stem cell transplantation

PurposeThis study aimed to retrospectively evaluate the genetic association of null variants of glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with hematological malignancies (HMs) undergoing busulfan (BU)- containing allogeneic hematopoietic stem cell transplantation (HSCT) and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized lymphoblastoid cell lines (LCLs) and tumor THP1 GST gene-edited cell models.MethodsGSTM1- and GSTT1-null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1-null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell death studies were conducted in GSTs- null and non-null LCLs and CRISPR–Cas9 gene-edited THP1 leukemia cell lines.ResultsCarrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76–15.42; p = 1.9 × 10–5]). BU-induced cell death preferentially in THP1GSTM1(non−null) and LCLsGSTM1(non−null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation.ConclusionThe clinical association suggests that GSTM1/GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation.

P–114 Correlation of GSTM1 polymorphism and oxidative stress with male infertility

Abstract Study question Is GSTM1 polymorphism a putative biomarker of male infertility. Is there a possible correlation between GSTM1 presence, oxidative stress and male infertility? Summary answer A possible correlation may be established between GSTM1 polymorphism, and sperm mobility and morphology. Additionally oxidative potential may also be associated with fertility. What is known already Approximately 7% of men worldwide are affected by male infertility, which contributes to 40–50% of all infertility cases. Basic sperm analysis remains the main procedure of diagnosing male infertility, although there is still doubt whether it provides accurate clinical outcomes More accurate tests are essential for the diagnosis of male infertility. Oxidative stress is involved in the etiology of male infertility, with 30% to 80% of infertile men having increased levels of sperm free radicals. Recent research has shown that oxidative stress when combined with GSTM1-null genotype negatively affected the sperm quality of infertility group compared to the control group. Study design, size, duration Ninety semen samples were collected and divided into 2 groups. The study group consisted of sperm samples from 51 men identified as infertile according to WHO guidelines(case group).Sperm samples from 39 men with normal sperm count parameters (control group) were used for the control group. Participants/materials, setting, methods For all samples a sperm diagram was performed. and DNA was extracted. Polymerase chain reaction with specific for GSTM1 gene primers followed by agarose electrophoresis was applied to detect the presence of polymorphism. The MiOXSYS method was used to detect the oxidative potential. Main results and the role of chance This study shows that in the control group the presence of polymorphism was associated with a reduced number of immobile sperm cells (p = 0,035) while it appears to affect the normal morphology of the sperm(p = 0,042). In the infertility group the presence of the gene was significantly correlated with age(p = 0.046). No statistically significant difference was observed for the presence of the polymorphism between the 2 groups.In addition, we investigated the effect of oxidative potential with the MiOXSYS system and its relationship with sperm parameters. It was found that the two groups differed significantly when measuring oxidative potential, and that oxidoreduction potential affects sperm concentration/ml, total sperm count, type B motility and viscosity in the infertile male group. Limitations, reasons for caution A larger sample size could increase the accuracy of the results. Wider implications of the findings: Studying the relation of the oxidative stress with sperm parameters may lead to the establishment of a genetic profile of increased risk of infertility, which would be of major importance especially in cases of idiopathic infertility. Trial registration number Not applicable

Genetic polymorphism of lysyl oxidase, glutathione S-transferase M1, glutathione-S-transferase T1, and glutathione S-transferase P1 genes as risk factors for lung cancer in Egyptian patients.

Lung cancer is a lethal malignancy and is affected by genetic polymorphisms that contribute to an individual's susceptibility to developing the disease. Several studies on lung cancer showed conflicting results. The aim of this study is to investigate whether individual or combined modifying effects of LOX G/A, GSTM1 active/null, GSTT1 active/null and GSTP1 Ile/Val polymorphisms are related to the risk of lung cancer in relation to smoking in the Egyptian population. This study is a hospital-based case control study that included 200 patients and 200 control subjects. Genotyping of the 4 studied genes was determined by Multiplex PCR for GSTM1 and GSTT1 and Taq man SNP assay for GSTP1 and LOX genes. The LOX G/A and GSTP1 Ile/Val in both homozygous and heterozygous variants, and the GSTM1 and GSTT1 null genotype showed significant association with lung cancer. Combination between gene polymorphism and smoking increased the risk of developing cancer by 2.7 fold in the LOX GA+AA variant, 1.9 fold in the GSTM1 null variant, 4.8 fold in the GSTT1 null variant and 4.3 fold in the GSTP1 Ile/Val+Val/Val variant. The genetic combination (LOX GA+AA/GSTT1 active, LOX GG/GSTT1 null, LOX GA+AA/GSTT1 null, LOX GA+AA/GSTP1 Ile/Ile, LOX GG/GSTP1 Ile/Val+Val/Val and LOX GA+AA/GSTP1 Ile/Val+Val/Val) led to a higher lung cancer risk, compared to the reference group. The LOX GA/AA, GSTM1 null, GSTT1 null and GSTP1 Ile/Val, Val/Val genotypes contributed to increased lung cancer susceptibility. To the best of our knowledge, this is the first study of LOX genotyping in the Egyptian population. The combination of genotypes increased the risk of cancer, indicating the importance of gene-gene interaction and giving a targeted preventive approach.

Prenatal Exposure to Parabens Affects Birth Outcomes through Maternal Glutathione S-Transferase (GST) Polymorphisms: From the Mothers and Kids Environmental Health (MAKE) Study.

Introduction: Human exposure to parabens is very common in daily life, and prenatal exposure to these chemicals is associated with poor birth outcomes. Therefore, the aim of this study was to investigate the effect of glutathione S-transferase (GST) polymorphisms on the association between prenatal exposure to parabens and birth outcomes. Methods: We conducted a multivariate analysis involving 177 subjects to determine the association between paraben concentrations and birth outcomes in mothers with GST mu 1 (GSTM1) and GST theta 1 (GSTT1) polymorphisms from 2017 to 2019. Furthermore, we determined the interactive effect between paraben levels and GSTM1/GSTT1 polymorphisms using regression analysis, in addition to a generalized linear model after stratifying GSTM1/GSTT1 genotype into three categories. Results: Methyl and propyl paraben concentrations were significantly and positively associated with birth weight (methyl, β = 116.525, 95% confidence interval (CI) = 22.460–210.590; propyl, β = 82.352, 95% CI = 9.147–155.557) in individuals with the GSTM1-null genotype. Moreover, the propyl paraben concentration was significantly associated with an increase in gestational age (β = 0.312, 95% CI = 0.085–0.539) in individuals with the GSTM1-null genotype. Conclusions: This study reported the association between prenatal paraben exposure and birth outcomes in individuals with GST polymorphisms. We found positive relationships of maternal exposure to methyl parabens with birth weight in both mothers with GSTM1 and GSTT1-null genotypes.

The association of glutathione S-transferase T1 and M1 deletions with myocardial infarction

Glutathione S-transferases (GSTs) are the family of enzymes involved in the second line of defense against oxidative stress (OS). The lack of GSTT1/GSTM1 enzyme quantity or activity, due to the presence of homozygous deletion compromises antioxidative defense resulting in OS. OS is the critical mechanism in the pathophysiology of atherosclerosis, coronary artery disease, and myocardial infarction (MI). The increase in reactive oxygen species together with the process of apoptosis plays a role in left ventricular remodeling (LVR) after MI. The associations of GSTT1 and GSTM1 gene polymorphisms with the risk of MI are inconsistent. The aim was to analyze the association of GSTT1/GSTM1 null genotypes with first MI and LVR 8 months after the MI. The study involved 330 controls and 438 consecutive patients with symptoms and signs of first MI. The subgroup of 150 MI patients was prospectively followed up for 6 months. Evidence of maladaptive LVR was obtained by 2D Doppler echocardiography 3–5 days and 6 months after the MI. A multiplex polymerase chain reaction was used to detect the deletion in GSTT1 and GSTM1 genes. GSTM1 null genotype was significantly and independently associated with first MI (adjusted OR = 1.45 95% CI 1.03–2.03, p = 0.03). Association of double null genotypes with maladaptive LVR in patients 6 months after the first MI was no longer significant after adjustment for factors that differed significantly between patients with and without maladaptive LVR. This study demonstrated the association of GSTM1 null genotypes with the risk of MI in the Serbian population.

Influence of Estrogenic Metabolic Pathway Genes Polymorphisms on Postmenopausal Breast Cancer Risk.

Estrogen metabolism plays an important role in tumor initiation and development. Lifetime exposure to high estrogens levels and deregulation of enzymes involved in estrogen biosynthetic and metabolic pathway are considered risk factors for breast cancer. The present study aimed to evaluate the impact of mutations acquisition during the lifetime in low penetrance genes that codify enzymes responsible for estrogen detoxification. Genotype analysis of GSTM1 and GSTT1 null polymorphisms, CYP1B1 Val432Leu and MTHFR C677T polymorphisms was performed in 157 samples of women with hormone-dependent breast cancer and correlated with the age at diagnosis. The majority of patients with GSTT1 null genotype and with both GSTM1 and GSTT1 null genotypes were 50 years old or more at the diagnosis (p-value = 0.021 and 0.018, respectively). Older women with GSTM1 null genotype were also carriers of the CYP1B1Val allele (p-value = 0.012). As well, GSTT1 null and CYP1B1Val genotypes were correlated with diagnosis at later ages (p-value = 0.022). Similar results were found associating MTHFR C677T and GSTT1 null polymorphism (p-value = 0.034). Our results suggest that estrogen metabolic pathway polymorphisms constitute a factor to be considered simultaneously with models for breast cancer risk assessment.

The role of polymorphisms in glutathione-related genes in asbestos-related diseases.

BackgroundThe study investigated the influence of GCLC, GCLM, GSTM1, GSTT1 and GSTP1 polymorphisms, as well as the influence of interactions between polymorphism and interactions between polymorphisms and asbestos exposure, on the risk of developing pleural plaques, asbestosis and malignant mesothelioma (MM).Subjects and methodsThe cross sectional study included 940 asbestos-exposed subjects, among them 390 subjects with pleural plaques, 147 subjects with asbestosis, 225 subjects with MM and 178 subjects with no asbestos-related disease. GCLC rs17883901, GCLM rs41303970, GSTM1 null, GSTT1 null, GSTP1 rs1695 and GSTP1 rs1138272 genotypes were determined using PCR based methods. In statistical analysis, logistic regression was used.ResultsGSTT1 null genotype was associated with the decreased risk for pleural plaques (OR = 0.63; 95% CI = 0.40–0.98; p = 0.026) and asbestosis (OR = 0.51; 95% CI = 0.28–0.93; p = 0.028), but not for MM. A positive association was found between GSTP1 rs1695 AG + GG vs. AA genotypes for MM when compared to pleural plaques (OR = 1.39; 95% CI = 1.00–1.94; p = 0.049). The interactions between different polymorphisms showed no significant influence on the risk of investigated asbestos-related diseases. The interaction between GSTT1 null polymorphism and asbestos exposure decreased the MM risk (OR = 0.17; 95% CI = 0.03–0.85; p = 0.031).ConclusionsOur findings suggest that GSTT1 null genotype may be associated with a decreased risk for pleural plaques and asbestosis, may modify the association between asbestos exposure and MM and may consequently act protectively on MM risk. This study also revealed a protective effect of the interaction between GSTP1 rs1695 polymorphism and asbestos exposure on MM risk.

Glutathione S-transferase gene polymorphic sequence variations: Association with risk and response to Imatinib among Chronic Myeloid Leukemia patients of Kashmir.

Glutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to tyrosine kinase inhibitors in chronic myeloid leukemia (CML). We aimed to analyze relation of different GST gene sequence variants with susceptibility and response to Imatinib in CML. A total of 150CML cases and equal number of age and gender matched healthy controls were genotyped for five GST polymorphisms by multiplex-PCR and PCR-RFLP techniques. BCR-ABL1 transcripts were quantified by quantitative Real Time PCR (qRT-PCR). GSTT1, GSTO1, and GSTO2 SNPs revealed no association, while as GSTM1null genotype was observed to protect against the development of CML (OR=0.53, P=.01). GSTP1 variant genotypes AG (OR=2.1, P=.003) and GG (OR=5.6, P<.001), significantly associated with increased risk of CML. Combined genotype analysis showed protective impact of GSTT1present /GSTM1null (OR=0.44, P=.003) while as GSTT1present /GSTP1-GG (OR=6.92, P<.001) and GSTM1present /GSTP1-GG (OR=6.33, P<.001), significantly increased CML risk. GSTM1null genotype individually and in combination with GSTT1present associated with superior rate of major molecular response (MMR) and event free survival (EFS) (log-rank P=.029). GSTO2-AG+GG genotype associated with significantly inferior MMR rates at 3, 6, and 12months. Also, patients with GSTO2-GG genotype showed significantly reduced EFS (log-rank P=.025). Multivariate analysis confirmed GSTM1null as a better (HR:0.19, P=.029) and GSTO2-GG genotype as an independent poor prognostic factor (HR:2.29, P=.037). GSTM1null genotype seems to have a better prognostic role while GSTP1 variants significantly increase CML risk. Also, results support a correlation between disease outcome and GSTO2 polymorphism.

Impact of xenobiotic-metabolizing gene polymorphisms on breast cancer risk in South Indian women.

Functional variants of the xenobiotic-metabolizing genes (XMG) might modulate breast cancer (BC) risk by altering the rate of metabolism and clearance of myriad types of potent carcinogens from the breast tissue. Despite mounting evidence on the role of XMG variants on BC risk, the current knowledge regarding their influence on BC development is still fragmentary. The present study examined the candidate genetic variants in CYP1A1, NQO1, GST-T1, GST-M1, and GST-P1 in 1002 subjects (502 BC patients and 500 disease-free women). PCR-RFLP was employed to genotype the mono-nucleotide variation in CYP1A1, NQO1, and GST-P1, and allele-specific PCR was used to detect the deletion polymorphism in GST-T1 and GST-M1 genes. Regarding CYP1A1-M1 polymorphism, the heterozygous TC and mutant CC genotype conferred 1.47-fold (95% CI 1.13-1.91, p = 0.004) and 1.84-fold (95% CI 1.17-2.91, p = 0.009) elevated risk of BC. GST-T1 null genotype was associated with increased BC risk (OR 1.47; 95% CI 1.02-2.11, p = 0.037). For the NQO1 C609T variant, the mutant T allele was associated with BC risk with an odds ratio of 1.22 (95% CI 1.02-1.48, p = 0.034). Combinatorial analysis indicated that the presence of NQO1*2 (CT), CYP1A1-M1 (CC), and GST-P1 rs1695 (AG) genotypes conferred 16.7-fold elevated risk of BC (95% CI 3.65-76.85; p < 0.001). Moreover, GST-M1 null genotype was associated with the development of larger primary breast tumors. Xenobiotic-metabolizing gene polymorphisms may play a crucial role in mammary carcinogenesis in South Indian women.

Polymorphism of Glutathione Sand#8209;Transferase M1 and T1 Genes and Susceptibility to Childhood Asthma: A Study from North India

Objectives: Glutathione S-transferases (GSTs) enzymes play an important role in the xenobiotic biotransformation of endogenous or exogenous toxicants and thought to protect the airways from oxidative stress, inflammation, and genotoxicity. Polymorphisms in the GST genes may lead to an increased imbalance in antioxidant systems and may influence the pathogenesis of asthma. We examined the association of the GST gene polymorphism to ascertain whether high-risk genotypes of GSTM1/GSTT1 could influence the susceptibility to childhood asthma in the N orth Indian population. Methods: The study constituted of 100 childhood asthmatic cases and 180 age-matched controls. The GSTT1 and GSTM1 null genotypes were identified by multiplex PCR in peripheral blood DNA samples. Statistical analysis was done by using SPSS 20.0 soft ware. Results: No association was seen either the null genotype of the GSTM1 or GSTTT1 (P > 0.05); however, in atopy patients significant association were observed with null genotype of GSTT1 (OR=2.67; P<0.05) for risk of child hood asthma. In combined analysis of GSTM1/GSTT1, presence of null genotypes of GSTM1 G P<0.05) compared to positive genotypes of GSTM1 and GSTT1. When compared among gender, GSTT1 null genotype was found to be statistically significant in male (OR=2.71; P<0.005) as compared to female childhood asthmatic patients. Conclusion: In conclusion, null genotype of GSTT1 exhibits significant association for the risk of childhood asthma, especially in disease predisposition and initiation.

Glutathione S-transferase (GSTM1 and GSTT1) polymorphisms' relationship between glycemic control of diabetic mothers and their infants

ObjectiveTo evaluate the glutathione S-transferase genetic variants (GSTM1 and GSTT1) in pregnant mothers with gestational diabetes mellitus (GDM) and the degree of glycemic control.BackgroundPrevious research has declared that GDM affects both the mother and the baby during pregnancy and in the long term.Patients and methodsTo reach the goal of this research, a case–control study was designed. A total of 80 pregnant women were divided into two groups: (a) patients group (40 patients had GDM during the third trimester of pregnancy) and (b) control group (40 apparently healthy pregnant women). All participants were subjected to detailed history taking, complete general examination of all body systems, laboratory investigations, and molecular genetic study.ResultsWe found that there was a statistically significant difference in GSTT1-0 null genotype rates between mothers with GDM and controls (P = 0.04). However, there was no difference in the frequencies of GSTM1 null genotypes between mothers with GDM and controls (P = 0.112). GSTM1 was more prevalent in infants of diabetic mothers (IDM), with a significantly difference between IDM and controls regarding GSTM1 null genotypes (P = 0.04). This difference was positively associated with higher levels of respiratory rates above normal limits and low 1 min APGAR score.ConclusionOur study reveals that GSTM1-0 null genotype in IDM was positively correlated with the unfavorable presentation among affected newborns who are carriers of this polymorphism.

GSTM1 Modulates Expression of Endothelial Adhesion Molecules in Uremic Milieu.

Deletion polymorphism of glutathione S-transferase M1 (GSTM1), a phase II detoxification and antioxidant enzyme, increases susceptibility to end-stage renal disease (ESRD) as well as the development of cardiovascular diseases (CVD) among ESRD patients and leads to their shorter cardiovascular survival. The mechanisms by which GSTM1 downregulation contributes to oxidative stress and inflammation in endothelial cells in uremic conditions have not been investigated so far. Therefore, the aim of the present study was to elucidate the effects of GSTM1 knockdown on oxidative stress and expression of a panel of inflammatory markers in human umbilical vein endothelial cells (HUVECs) exposed to uremic serum. Additionally, we aimed to discern whether GSTM1-null genotype is associated with serum levels of adhesion molecules in ESRD patients. HUVECs treated with uremic serum exhibited impaired redox balance characterized by enhanced lipid peroxidation and decreased antioxidant enzyme activities, independently of the GSTM1 knockdown. In response to uremic injury, HUVECs exhibited alteration in the expression of a series of inflammatory cytokines including retinol-binding protein 4 (RBP4), regulated on activation, normal T cell expressed and secreted (RANTES), C-reactive protein (CRP), angiogenin, dickkopf-1 (Dkk-1), and platelet factor 4 (PF4). GSTM1 knockdown in HUVECs showed upregulation of monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in the regulation of monocyte migration and adhesion. These cells also have shown upregulated intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). In accordance with these findings, the levels of serum ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) were increased in ESRD patients lacking GSTM1, in comparison with patients with the GSTM1-active genotype. Based on these results, it may be concluded that incubation of endothelial cells in uremic serum induces redox imbalance accompanied with altered expression of a series of cytokines involved in arteriosclerosis and atherosclerosis. The association of GSTM1 downregulation with the altered expression of adhesion molecules might be at least partly responsible for the increased susceptibility of ESRD patients to CVD.

Polymorphisms of the GSTT1 and GSTM1 genes in polycystic ovary syndrome.

This study aimed to investigate the deletion polymorphisms of the genes of the glutathione S-transferase family GSTT1 and GSTM1 in patients with Polycystic Ovarian Syndrome (PCOS), comparing them with a control population. Blood was collected from 219 women (110 with PCOS and 109 controls) and genomic DNA was extracted. For the analysis of polymorphisms, the technique used was multiplex PCR. In the statistical analysis, the chi-square test and multiple logistic regression were used. There is no association between the GSTM1 null and GSTT1 null genotypes with PCOS when analyzed separately (P = 0.616 and P = 0.188). The analysis of the combined genotypes showed differences between the groups (P < 0.05), evidencing that the genotypic combination GSTT1 positive and GSTM1 negative is more frequent among patients. In the multivariate analysis, smoking was more frequent in the control group (OR = 0.22; 95% CI - 0.87-0.57; P = 0.002) while the presence of a family history of PCOS (OR = 2, 96; 95% CI - 1.54-5.68; P = 0.001) was more frequent in women with PCOS. In the studied sample, the deletion polymorphisms of the GSTT1 and GSTM1 genes isolated are not associated with PCOS, but in combination, they may be implicated in the etiology of the condition.

Effects of GST null genotypes on individual susceptibility to atherosclerotic cardiovascular diseases: a meta-analysis

Some genetic association studies tried to investigate potential associations between glutathione S-transferase (GST) null genotypes and atherosclerotic cardiovascular diseases (ASCVD). However, the results of these studies were not consistent. Thus, we performed the present meta-analysis to explore associations between GST null genotypes and ASCVD in a larger pooled population. Systematic literature research was performed in PubMed, Web of Science, and Embase to identify eligible studies. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the strength of associations. Totally 47 studies were included for analyses. Pooled analyses suggested that GSTM1 (p = .007, OR = 1.29, 95%CI 1.07–1.56) and GSTP1 (p = .01, OR = 1.28, 95%CI 1.06–1.55) null genotypes were significantly associated with individual susceptibility to ASCVD in overall population. Further subgroup analyses revealed similar positive results for GSTM1 null genotype in South Asians and patients with coronary artery disease (CAD). No other significant results were observed for GST null genotypes in overall and subgroup analyses. In conclusion, our meta-analysis suggested that GSTM1 and GSTP1 null genotypes could impact individual susceptibility to ASCVD. These results suggested that these variations could be used to identify individuals at higher susceptibility to ASCVD.

Genotype of Null Polymorphisms in Genes GSTM1, GSTT1, CYP1A1, and CYP1A1*2A (rs4646903 T>C)/CYP1A1*2C (rs1048943 A>G) in Patients with Larynx Cancer in Southeast Spain.

Simple SummaryEpidemiological studies have shown that individual susceptibility to cancer is mediated by genetic and environmental factors. The aim of the present study is to evaluate the individuals’ metabolic genetic susceptibility to toxic habits (smoking and alcohol consumption) by detecting polymorphisms CYP1A1 rs1048943 T>C and CYPA1A2 rs4646903 A>G, and null polymorphisms in GSTM1 and GSTT1 genotypes, comparing a group of healthy control subjects with a population of larynx cancer patients from southeastern Spain. As results patients with larynx cancer present more gene GSTM1 and GSTT1 null polymorphisms, and CYP1A1 rs4646903 T>C polymorphisms.Background: some types of cancer have been associated with the presence of single nucleotide polymorphisms (SNPs) of some genes that encode enzymes: glutathione-S transferase (GST), whose alteration leads to loss of function and a lower capacity to eliminate toxic GSTM1 and GSTT1 null genotypes; SNPs causing loss of function of CYP1A1 or CYP1A1–2 cytochrome P450 enzymes related with a lower capacity to deactivate hydrocarbons related to smoking, which involves a higher risk of developing some smoking-dependent cancers including larynx cancer. Objective: to compare the presence of null SNPs in genes GSTM1, GSTT1, and CYP1A1 rs 4646903 T>C, and CYP1A1–2 RS1048943 A>G in patients with hypopharyngeal and larynx cancer with a healthy control group. Materials and method: The study included a total of 80 patients with hypopharyngeal and laryngeal cancer and 23 healthy subjects. Genomic DNA was obtained from saliva samples, determining genotype GSTM1 (present +, or null −), GSTT1 (present + or null −). Polymorphisms (SNP) in CYP1A1 T>C (present + CC, or absent − TC/TT), and CYP1A1–2 A>G (present + GG, or absent − AG/AA). Results: the mean age of patients with larynx cancer was 62 years and of control subjects 63 years. Of the total sample, over 95% were men, and over 90% were smokers. The presence of null genotypes for GTM1 was 50% in patients with larynx cancer (p = 0.042), while GSTT1 was 88.75% (p = 0.002). CYP1A1 rs4646903 T>C polymorphisms were detected in 100% of cases of larynx cancer and 17.39% of healthy subjects (p > 0.001). Conclusions: patients with larynx cancer present more gene GSTM1 and GSTT1 null polymorphisms, and CYP1A1 rs4646903 T>C polymorphisms.