Glutathione S-transferase Genotypes Research Articles

Does lung function in preschoolers help to predict asthma in later life?

The earliest respiratory function assessments, within or close to the neonatal period, consistently show correlations with lung function and with the development of asthma into adulthood. Measurements of lung function in infancy reflect the in utero period of lung development, and if early enough, show little influence of postnatal environmental exposures. Later in the preschool and school age periods, influences of the environment are superimposed on initial levels. Fetal exposures before birth such as maternal smoking during pregnancy, lead to reduced lung function and an increased risk of asthma in females particularly those with certain glutathione S-transferase genotypes. Lung function measurements later in the preschool period are also associated with development of asthma. Although lung function in preschoolers does help predict asthma in later life and these observations have increased our understanding of the physiology underlying asthma, the findings have not led to thewidespread use of lung function measurements being in preschoolers as clinical predictors of asthma due to the practicalities of testing in this age group.

The moderation effect of GSTM1/GSTT1 gene polymorphisms on the association of sperm mitochondrial DNA copy number and sperm mobility

Oxidative stress (OS) is believed to be a significant factor in the decline of semen quality, with mitochondrial DNA copy number (mtDNAcn) serving as a sensitive biomarker for both semen quality and mitochondrial dysfunction resulting from oxidative stress. While glutathione S-transferases (GSTs) are commonly known as ‘antioxidant’ enzymes, there is ongoing debate regarding the relationship between GST genotypes and semen quality. In a study involving 568 male volunteers from the outpatient department of Puyang Reproductive Medicine Center, sperm mtDNAcn, semen quality, and GSTM1/GSTT1 genotypes were analyzed to investigate the potential link between GSTM1/GSTT1 gene variations and semen quality, as well as the impact of GSTs gene variations on the connection between sperm mtDNAcn and semen quality. Adjusting for variables such as age, BMI, smoking, and alcohol consumption, it was found that mtDNAcn was significantly correlated with decreased sperm concentration and total sperm count (b = − 0.109, − 0.128, respectively; P = 0.002, 0.001, respectively). GSTM1 was associated with progressive motility (OR 0.390, 95% CI 0.218, 0.697), Straight line velocity (VSL) (OR = 0.606, 95% CI 0.385, 0.953), and Straightness (STR) (OR 0.604, 95% CI 0.367, 0.994), while GSTT1 was linked to progressive motility (OR 0.554, 95% CI 0.324, 0.944) and Beat crossover frequency (OR 0.624, 95% CI 0.397, 0.982). The GSTT1 was found to moderate the relationship between mtDNAcn and sperm motility parameters linearity (LIN), STR, and Wobble (WOB), with additive interaction effects observed between GSTT1 and mtDNAcn on LIN, STR, and WOB (P for interaction = 0.008, 0.034, 0.010, respectively). Overall, this study suggests that GSTT1 and GSTM1 gene variations may play a role in sperm motility, with GSTT1 potentially influencing the impact of oxidative stress on sperm motility.

Gene-environment interactions and colorectal cancer risk: A case-control study on xenobiotic metabolizing enzyme polymorphisms in the Jammu& Kashmir, India population

BackgroundCancer remains a significant global health concern, with colorectal cancer (CRC) showing a rising incidence, particularly among younger populations. Most CRC cases are linked to a complex interplay of genetic and environmental factors. The cytochrome P450 (CYP) superfamily, including enzymes like CYP2A13 and CYP2A6, plays a vital role in metabolizing environmental carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and nitrosamines. Polymorphisms in these genes, alongside phase II glutathione-S-transferases (GSTs) involved in detoxification, can influence individual cancer risk. This study focuses on the association between these genetic polymorphisms and CRC risk in the Jammu & Kashmir, population, a region with high exposure to dietary and lifestyle-related carcinogens. MethodologyThis hospital-based case-control study was conducted at the Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, India between March 2019 and March 2022. The study included 246 histopathologically confirmed colorectal cancer (CRC) cases, and an equal number of matched controls based on age (±5 years), gender, and place of residence. Blood samples were collected for DNA extraction, followed by genotyping of xenobiotic-metabolizing enzyme (XME) genes, including CYP2A13, CYP2A6, and GSTs using standard PCR-RFLP and multiplex PCR methods. Statistical analyses were performed using STATA software to assess the association between gene polymorphisms and CRC risk. ResultsThe study revealed key associations between genetic and environmental factors and CRC risk. The analysis demonstrated that cases had significantly lower education levels than controls. Family history of cancer, smoking, and dietary factors like red meat and salt tea consumption were more prevalent among cases. Genetic analysis identified significant interactions between various CYP and GST genotypes, and environmental factors such as smoking, pesticide exposure, and diet, with varying effects on CRC risk. ConclusionThe research underscores the influence of genetic and environmental factors on colorectal cancer (CRC) risk. Lower educational was associated with a heightened risk of CRC. Certain genotype variants of xenobiotic metabolizing enzymes (XME) were found to increase CRC risk, particularly in conjunction with smoking, pesticide exposure, and sun-dried vegetable consumption. A family history of cancer, especially CRC, further amplified the risk. These findings emphasize the importance of developing personalized CRC prevention and screening strategies that account for gene-environment interactions.

Dose-response Relationships Between Cigarette Smoking and Breast Cancer Risk: A Systematic Review and Meta-analysis.

The possible association between cigarette smoking and breast cancer risk has been quite controversial. We conducted a systematic review and meta-analysis of all available observational studies published on the issue up to January 2020. Random-effects models were used to compute pooled relative risks (RRs) for cigarette smoking status and dose-risk relationships were evaluated using one-stage random-effects dose-response models. A total of 169 studies were selected, providing a pooled RR for breast cancer of 1.07 (95% confidence interval [CI], 1.05-1.10) for current, 1.08 (95% CI, 1.06-1.10) for former, and 1.09 (95% CI, 1.07-1.11) for ever smokers, compared to never smokers. Results were consistent in case-control and cohort studies. No meaningful differences were observed across strata of most covariates considered, nor according to relevant genetic mutations and polymorphisms (ie, BRCA mutation, N-acetyltransferase and glutathione S-transferase genotypes, and P53). Breast cancer risk increased linearly with intensity of smoking (RR 1.12; 95% CI, 1.08-1.16 for 20 cigarettes/day and 1.26; 95% CI, 1.17-1.36 for 40 cigarettes/day), and with increasing duration of smoking (RR 1.05; 95% CI, 1.03-1.08 for 20 years of smoking and 1.11; 95% CI, 1.06-1.16 for 40 years of smoking). The present large and comprehensive meta-analysis-conducted using an innovative approach for study search-supports the evidence of a causal role of tobacco smoking on breast cancer risk.

Association between Glutathione S-Transferases Gene Variants and COVID-19 Severity in Previously Vaccinated and Unvaccinated Polish Patients with Confirmed SARS-CoV-2 Infection.

As the outcome of COVID-19 is associated with oxidative stress, it is highly probable that polymorphisms of genes related to oxidative stress were associated with susceptibility and severity of COVID-19. The aim of the study was to assess the association of glutathione S-transferases (GSTs) gene polymorphisms with COVID-19 severity in previously vaccinated and unvaccinated Polish patients with confirmed SARS-CoV-2 infection. A total of 92 not vaccinated and 84 vaccinated patients hospitalized due to COVID-19 were included. The WHO COVID-19 Clinical Progression Scale was used to assess COVID-19 severity. GSTs genetic polymorphisms were assessed by appropriate PCR methods. Univariable and multivariable analyses were performed, including logistic regression analysis. GSTP1 Ile/Val genotype was found to be associated with a higher risk of developing a severe form of the disease in the population of vaccinated patients with COVID-19 (OR: 2.75; p = 0.0398). No significant association was observed for any of the assessed GST genotypes with COVID-19 disease severity in unvaccinated patients with COVID-19. In this group of patients, BMI > 25 and serum glucose level > 99 mg% statistically significantly increased the odds towards more severe COVID-19. Our results may contribute to further understanding of risk factors of severe COVID-19 and selecting patients in need of strategies focusing on oxidative stress.

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.

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.

Impact of Glutathione S-Transferase Polymorphisms on Busulfan Pharmacokinetics and Outcomes of Hematopoietic Stem Cell Transplantation.

Busulfan (Bu) is an alkylating drug used in many preparative regimens before hematopoietic stem cell transplantation (HSCT). It is conjugated in the liver mainly by glutathione S-transferase isoenzyme A1-1 ( GSTA1 ). Genetic polymorphisms in these isoenzymes may affect the pharmacokinetics of Bu and the clinical outcomes of HSCT. This study aimed to assess the impact of glutathione S-transferase ( GST ) genetic polymorphisms on the clearance of Bu and the clinical outcomes of patients undergoing HSCT. This single-center retrospective study included patients who received IV Bu before HSCT at Sultan Qaboos University Hospital (SQUH), Oman from January 2003 to October 2016. Genotyping for polymorphisms was performed for GSTM1 , GSTT1 , GSTA1 , and GSTP1 . Each GST polymorphism was analyzed for its impact on Bu clearance and HSCT outcomes. A total of 135 patients were included. The mean Bu clearance was 3.7 ± 0.98 mL/min/kg. Patients with GSTA1 A-513G heterozygosity (AG) were found to have a higher incidence of graft loss ( P = 0.006). Homozygous double null of GSTM1 and GSTT1 was associated with a higher incidence of acute graft versus host disease ( P = 0.04). Double non-null GSTM1 and GSTT1 and non-null GSTM1 increased the risk of mortality ( P = 0.034 and 0.021, respectively). GST genotyping before HSCT may predict HSCT outcomes. The results of this preliminary retrospective study need to be confirmed in a larger prospective study.

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.

Heavy metal-associated oxidative stress and glutathione s-transferase polymorphisms among E-waste workers in Pakistan

Increased E-waste generation during recent times has become a global concern, especially for developing countries that are at receiving end from the developed countries. Their improper handling and lacking management practices in developing countries including Pakistan are contributing enormous addition of toxicants into the environment and affecting the health of exposed workers associated with E-waste recycling activities. A systematic cross-sectional study was designed comprising workers associated with E-waste recycling activities in Peshawar city, Pakistan. The study aimed to investigate metal concentrations in dust, particulate matter and urine of exposed workers and correlate with oxidative stress and glutathione S-transferases genotypes (GSTM1 and GSTT1) that play a role in detoxification of metals in humans. A total of 120 blood samples comprising dismantlers (n = 52), repairers (n = 21), smelters (n = 17) and controls (n = 30) were collected. Results showed that metal concentrations were significantly higher in the dust (P = 0.020), particulate matter (P = 0.021) and urine samples (P = 0.00) as compared to controls. We observed significant increase in MDA (P = 0.00) and decrease in SOD (P = 0.00) and CAT (P = 0.00) levels among exposed subjects as compared to controls. Additionally, GSTT1 null genotype was more significantly associated with the dismantlers (P = 0.02). The study shows that E-waste workers are exposed to high level of toxic metals through dust and particulate matter, resulting in significant oxidative stress and related health implications, while GSTT1 null polymorphism is associated with increased susceptibility to these metals and induced health outcomes.

Genetic Polymorphism of Glutathione S-transferase and Cervical Cancer Susceptibility in Northeastern Thailand

Background: Exposure to certain carcinogens together with host genetic predisposition likely has an influence on cervical carcinogenesis. Objective: Our aim was to evaluate synergistic effects of glutathione S-transferase (GST) polymorphisms and risk behaviors (i.e., smoking and contraceptive use) on squamous cell cervical cancer (SCCA) development in northeastern Thailand. Methods: Subjects were 198 (SCCA) patients and 198 age-matched healthy controls. Multiplex PCR and PCR-RFLP were used to determine GSTT1 and GSTA1 gene polymorphism, respectively. Results: Interaction between the four polymorphic loci of GSTs (GSTM1, GSTT1, GSTP1 and GSTA1) and increased risk for cervical cancer was not observed. The three genotypes of GSTM1 consistently showed significant risks of smoking with a lower OR for the Null individuals (1.741) at around one -fourth of wild type homozygous individuals (8.000). The effects of GST polymorphisms on cervical cancer risk under the use of hormonal contraceptives apparently did not occur. Conclusions: The predisposition of smoking risk is related to the GST genotype. It is suggested that knowing one’s own genotype data will contribute to the prevention of SCCA by controlling risk habits.

Markers of Oxidative Stress and Endothelial Dysfunction Predict Haemodialysis Patients Survival

Introduction: Overall survival of patients with end-stage renal disease (ESRD) remains poor. Oxidative stress is one of the major risk factors associated with mortality in this patient group. As glutathione S-transferases (GST) are well-established antioxidants, we hypothesized that a model including GST gene polymorphisms, oxidative damage byproducts and cell adhesion markers has a prognostic role in ESRD patient survival. Methods: A prospective study of 199 patients with ESRD on haemodialysis was conducted. GST genotype, oxidative stress byproducts and cell adhesion molecules were measured in plasma. Multivariate Cox regression and Kaplan-Meier survival analyses were performed to test the predictive ability of these parameters in the 8-year follow-up period. Results: GSTM1-null genotype was associated with significantly shorter overall (HR 1.6, p = 0.018) and cardiovascular-specific (HR 2.1, p = 0.010) survival. Oxidative stress byproducts (advanced oxidation protein products [AOPP], prooxidant-antioxidant balance [PAB], malondialdehyde [MDA]) and cell adhesion molecules (soluble vascular cell adhesion molecule-1 [sVCAM-1] and soluble intercellular adhesion molecule-1 [sICAM-1]) demonstrated a significant predictive role in terms of overall and cardiovascular survival. When 6 biomarkers (GSTM1 genotype, high AOPP/PAB/MDA/­sVCAM-1/sICAM-1) were combined into a scoring model, a significantly shorter overall and cardiovascular survival was observed for patients with the highest score (p < 0.001). Conclusion: We identified a novel panel of biomarkers that can be utilized in predicting survival in ESRD patients. This biomarker signature could enable better monitoring of patients and stratification into appropriate treatment groups.

Association of Glutathione-S-Transferases M1 and T1 Deletional Variants with Development of Oral Squamous Cell Carcinoma: A Study in the South-East of Iran.

Background:The role of genetic polymorphisms in genes of Glutathione-S-transferases (GST) enzymes in susceptibility to oral cavity cancers is controversial. Oral Squamous Cell Carcinoma (OSCC) is the most common oral cavity neoplasm. Aimed to evaluate the potential impacts of two well-known null variants residing in the gene encoding GSTM1 and GSTT1 enzymes of OSCC patients in the southeast of Iran. Methods:In a case-control design, 113 individuals (50 OSCC patients, and 63 healthy subjects) were included. DNA was extracted using paraffin-embedded tissues. GST genotyping was carried out using multiplex PCR. Results:In 113 participants, 41 (36.3%) and 72 (63.7%) were males and females respectively. No significant difference was recognized for distribution of GSTM1 (P=0.11) and GSTT1 (P=0.28) null genotypes between OSCC patients (58%, and 24% respectively) and healthy controls (42.9% and 15.9% respectively). Also, no significant difference was noted regarding the frequency of GSTM1 null genotype in different histological grades, however, those patients with more aggressive disease (poorly differentiated or grade III) revealed with a significantly higher ratio (66.7%) of GSTT1 null genotype (P=0.002). The highest odds ratio for OSCC was related to combined null genotypes for GSTM1 and GSTT1 (OR=2.5, 95% CI: 0.7-9.2), however, this was not statistically significant finding (P=0.15). Conclusion:Null genotypes polymorphisms were more common in OSCC than healthy individuals. GSTT1 null genotype may be an important genetic factor in the progression of OSCC.

GSTM1 and GSTT1 null genotype increase the risk of hepatocellular carcinoma: evidence based on 46 studies

BackgroundIt is well known that hepatocellular carcinoma (HCC) has been one of the most life-threatening diseases all over the world. Plenty of internal and extrinsic factors have been proven to be related to HCC, such as gene mutation, viral hepatitis, and Nitrosamines. Though previous studies demonstrated that glutathione S-transferase (GST) genotypes are associated with HCC, the conclusions are inconsistent. Therefore, we carried on a renewed meta-analysis to expound the connection between the null GSTM1, GSTT1 polymorphisms and the risk of HCC.MethodsWe searched PubMed, Web of Science, Embase, and CNKI databases to select qualified researches which satisfied the inclusion criteria up to July 31, 2018. Finally, we selected 41 articles with 6124 cases and 9781 controls in this meta-analysis. We use ORs and 95% confidence interval (CI) to evaluate the correlation intension between the GSTM1 and GSTT1 null genes and the risk of HCC. All the statistical processes were executed by Stata (version 12.0).ResultsThe pooled analysis showed that both GSTM1 null genotypes (OR = 1.37, 95% CI = 1.18–1.59) and GSTT1 null genotypes (OR = 1.43, 95% CI = 1.23–1.66) increased the risk of HCC. And GSTM1–GSTT1 dual-null genotypes also increased the risk of HCC (OR = 1.58, 95% CI = 1.22–2.05). In the subgroup analysis, we obtained significant results among Asians when stratified by race, and the results are GSTM1 null OR = 1.44, 95% CI = (1.22–1.71), GSTT1 null OR = 1.48, 95% CI = (1.25–1.77), GSTM1–GSTT1 null OR = 1.58, 95% CI = (1.19–2.09), while we didn’t obtain significant results among Caucasians or Africans. Stratified analyses on the type of control indicated a higher risk of HCC associated with GSTM1, GSTT1 single null genotypes and GSTM1–GSTT1 dual-null genotypes in healthy people. No evidence of significant connection was discovered in chronic liver disease (CLD) except in GSTT1 single null.ConclusionsOur study indicated that an individual who carries the GSTM1, GSTT1 single null genotypes and GSTT1–GSTM1 dual-null genotypes is more likely to develop HCC.

Glutathione S-Transferase Genotype Protects against In Utero Tobacco–linked Lung Function Deficits

Rationale: In utero tobacco exposure is associated with reduced lung function from infancy. Antioxidant enzymes from the glutathione S-transferase (GST) family may protect against these lung function deficits.Objectives: To assess the long-term effect of in utero smoke exposure on lung function into adulthood, and to assess whether GSTT1 and GSTM1 active genotypes have long-term protective effects on lung function.Methods: In this longitudinal study based on a general population (n = 253), lung function was measured during infancy and at 6, 11, 18, and 24 years. GSTM1 and GSTT1 genotype was analyzed in a subgroup (n = 179). Lung function was assessed longitudinally from 6 to 24 years (n = 199).Measurements and Main Results: Exposure to maternal in utero tobacco was associated with lower FEV1 and FVC longitudinally from 6 to 24 years (mean difference, -3.87% predicted, P = 0.021; -3.35% predicted, P = 0.035, respectively). Among those homozygous for the GSTM1-null genotype, in utero tobacco exposure was associated with lower FEV1 and FVC compared with those with no in utero tobacco exposure (mean difference, -6.2% predicted, P = 0.01; -4.7% predicted, P = 0.043, respectively). For those with GSTM1 active genotype, there was no difference in lung function whether exposed to maternal in utero tobacco or not. In utero tobacco exposure was associated with deficits in lung function among those with both GSTT1-null and GSTT1-active genotypes.Conclusions: Certain GST genotypes may have protective effects against the long-term deficits in lung function associated with in utero tobacco exposure. This offers potential preventative targets in antioxidant pathways for at-risk infants of smoking mothers.

Deletion and Single Nucleotide Polymorphisms in Common Glutathione-S Transferases Contribute to Colorectal Cancer Development

Glutathione-S transferases (GSTs) are xenobiotic-conjugation enzymes involved in the detoxification process of heterocyclic aromatic amines and polycyclic aromatic hydrocarbons, widely recognized risk factors of colorectal cancer (CRC) development. Polymorphism in GSTs often leads to alteration or complete lack of enzyme activity, which might have an effect on CRC carcinogenesis. Aim of this study was to investigate GST gene variants as risk factors in patients with CRC. A total of 523 CRC patients administered for surgical resection and 400 matched controls were included. Deletion polymorphism of GSTs M1 and T1 was investigated by polymerase chain reaction. Single nucleotide polymorphism of GST A1 and P1 was investigated by restriction fragment length polymorphism method. The association between GST genotype and risk of CRC development was found in carriers of GSTT1-null and GSTP1-variant genotypes individually (p = 0.050 and p = 0.016, respectively). Furthermore, statistically significant association was found when combination of GSTP1-variant genotype with any of other three common GST genotypes was analyzed with respect to CRC susceptibility. Additionally, patients with combined GSTM1-null/GSTT1-null/GSTA1 low-activity/GSTP1-variant genotype showed 2.71-fold increased risk of developing CRC (p = 0.037). This study supports hypothesis that GST polymorphisms might have an important role in the process of the CRC development. Additionally, GSTM1-null/ GSTT1-null/ GSTA1 low-activity/ GSTP1-variant genotype could be combination of GST genotypes whose carriers are more prone to CRC development.

Interaction of Glutathione S-Transferase M1, T1, and P1 Genes With Early Life Tobacco Smoke Exposure on Lung Function in Adolescents

Glutathione S-transferase (GST) genes are involved in the management of oxidative stress in the lungs. We aimed to determine whether they modify the associations between early life smoke exposure and adverse lung health outcomes. The Melbourne Atopy Cohort study (a high-risk birth cohort) enrolled 620 children and followed them prospectively from birth. We recorded perinatal tobacco smoke exposure, asthma, and lung function at 12 (59%) and 18 years (66%) and genotyped for GSTM1, GSTT1, and GSTP1 (69%). GST genotypes were found to interact with tobacco smoke exposure on lung function outcomes (P interaction≤ .05). Only among children with GSTT1 null genotypes was exposure to mother's, father's, or parental tobacco smoke in early life associated with an increased risk of reductions in prebronchodilator (BD) FEV1 and FVC at both 12 and 18 years. These associations were not seen in children with GSTT1 present. Similarly, only among children with GSTM1 null genotypes was exposure to father's or parental smoking associated with reductions in pre- and post-BD FEV1 and FVC at 18 years. Only among children with Ile/Ile genotypes of GSTP1 was exposure to mother's smoking associated with increased risk of reduced FEV1 at 18 years, but this was not the case among children with Val/Val or Ile/Val genotypes. Our study provides evidence of interaction between early tobacco smoke exposure and GST genotypes on lung function. Carriers of GST null mutations and GSTP1 Ile/Ile alleles may be more susceptible when exposed to tobacco smoke in early life. These findings support stronger recommendations to protect all infants from tobacco smoke exposure. Australian and New Zealand Clinical Trials Registry; No.: ACTRN12609000734268; URL: http://www.anzctr.org.au/.

Effect of glutathione S-transferase genetic polymorphisms on busulfan pharmacokinetics and veno-occlusive disease in hematopoietic stem cell transplantation: A meta-analysis.

This meta-analysis was conducted to derive an integrated conclusion about the influence of glutathione S-transferase (GST) genetic polymorphisms on busulfan pharmacokinetic (PK) parameters and veno-occlusive disease (VOD). Studies which analysed the effect of GST genetic polymorphisms on area under the curve (AUC), clearance (CL) or VOD were searched for and selected. A pooled analysis was conducted using Comprehensive Meta-Analysis programme. Nineteen studies were included in this meta-analysis. GSTA1*B and GSTM1 null genotypes significantly decreased CLIV of busulfan (standardized difference in means (SDM)=-1.103; P=0.019 and SDM=-0.418; P=0.002, respectively). GSTA1*B significantly increased AUCIV of busulfan (SDM=0.832; P=0.046), whereas GSTM1 did not (SDM=0.155; P=0.478). The PK parameters of oral busulfan did not differ according to GST genotype. GSTA1, GSTM1 and GSTP1 were not significantly associated with VOD occurrence. GSTA1 and GSTM1 genotypes affected CLIV of busulfan, but only GSTA1 affected AUCIV . There was no significant difference in the PK parameters of oral busulfan (CLPO and AUCPO ) and VOD when only GST genotypes were considered.

The diagnostic potential of glutathione S-transferase (GST) polymorphisms in patients with colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers in the world. Despite improvements in screening for early diagnosis, CRC is one of the leading causes of cancer deaths. The aim of the study was to determine a potential association between the frequency of GSTM1 and GSTT1 null genotypes and the risk of CRC in the Polish population. Moreover, we analyzed the clinical parameters with the glutathione S-transferase (GST) gene polymorphisms in patients with CRC. The study was conducted on 512 Caucasians, including 279 patients (105 women and 174 men) with CRC. DNA from peripheral blood was extracted and the multiplex polymerase chain reaction (PCR) technique was used for glutathione S-transferase theta (GSTT1) and mu (GSTM1) gene deletion genotyping. We found no statistically significant differences in the frequency of the GST gene polymorphisms in patients with CRC and controls. The prevalence of the GSTM1*0 variant in the test subjects was higher than in controls (45.9% vs 42.9%; p > 0.05). The frequency of the GSTT1*0 variant was also higher in patients with CRC compared to the control population (21.1% vs 18.9%; p > 0.05). In addition, the effect of the GSTM1 and GSTT1 polymorphisms on the incidence of CRC was also analyzed. There was a slight, but not statistically significant, increase of the risk of colon cancer for the GSTM1*0 and GSTT1*0 variants. Moreover, we examined the GST genotype due to the cancer TNM classification and the location of the primary tumor. Statistically significant differences in the distribution of the GSTT1*0 and GSTT1*1 genotypes in both the stage and the location of the primary tumor were observed. It is suggested that the GSTT1 polymorphism may have an impact on the severity of the tumor and its location.

Variants in genes coding for glutathione S-transferases and asthma outcomes in children.

Our hypothesis was that children with mutations in genes coding for glutathione S-transferases (GST) have worse asthma outcomes compared with children with active type genotype. Data were collected in five populations. The rs1695 single nucleotide polymorphism (GSTP1) was determined in all cohorts (3692 children) and GSTM1 and GSTT1 null genotype were determined in three cohorts (2362 children). GSTT1 null (but not other genotypes) was associated with a minor increased risk for asthma attack and there were no significant associations between GST genotypes and asthma severity. Interactions between GST genotypes and SHS exposure or asthma severity with the study outcomes were nonsignificant. We find no convincing evidence that the GST genotypes studied are related to asthma outcomes.