GSTT1 Null Genotype Research Articles

Dual impact analysis of GSTT1 polymorphisms on the metformin response and cardiovascular risk: A novel integrated approach in type 2 diabetes mellitus management

Although genetic variations in glutathione S-transferase (GST) have been linked to type 2 diabetes mellitus (T2DM), the relationships among GSTT1 polymorphisms, metformin effectiveness, and cardiovascular risk remain unclear. This study investigated the association between the GSTT1 null genotype and the metformin monotherapy response while simultaneously assessing its impact on atherosclerotic cardiovascular disease risk. This case-control study examined 84 T2DM patients aged 30-70 years, categorized into metformin therapy responders and nonresponders. This study employed multiplex PCR for GSTT1 genotyping and utilized the pooled cohort equation for cardiovascular risk assessment, offering a comprehensive analysis of both genetic and clinical parameters. GSTT1 genetic variations were not significantly associated with metformin response (odds ratio [OR] 1.773, p=0.306) or cardiovascular risk (OR 1.086, 95% CI: 0.46-2.56, p=1.000). The analysis revealed distinct patterns in clinical parameters between the GSTT1 null and wild-type genotypes, particularly in terms of glycemic control indicators and lipid profiles, although these differences did not reach statistical significance. This study presents a novel approach by simultaneously examining both the therapeutic response and cardiovascular risk in relation to GSTT1 polymorphisms, distinguishing it from previous studies that typically focused on either aspect in isolation. These findings suggest that while genetic variations in GSTT1 may influence metabolic parameters, their direct impact on metformin effectiveness and cardiovascular risk may be more complex than previously thought.

Pharmacogenetic assessment of cytostatic therapy efficacy depending on the polymorphism of T1 and M1 glutathione-S-transferase genes in breast cancer patients

Aim. To study the effect of deletion polymorphism of the GST genes (GSTT1, GSTM1) on chemotherapy (CT) efficacy in women diagnosed with breast cancer (BC) in the Primorsky Krai. Materials and methods. The study involved 132 women with breast cancer aged 23 to 79 years (mean age 48 ± 13 years) who received chemotherapy treatment. The detection of deletion (null) genotypes of GSTM1 and GSTT1 was carried out using multiplex PCR followed by an analysis of the melting curves of the reaction products. Results. Relapse-free survival (RFS) of BC patients with the “null” GSTT1 genotype was statistically significantly higher (116.7 months (9.6 years) versus 75.8 months (6.2 years)) than in patients with the “normal” GSTT genotype. Thus, in the case of the GSTT1“null” genotype, the risk of disease relapse decreased by 2.4 times (HR = 0.418, CI = 0.191–0.915, p = 0.024). Similar to GSTT1, the DFS of patients with the GSTM1 null genotype increased from 72.7 months (6 years) to 76.1 months (6.3 years). At the same time, the risk of disease relapse in carriers of the “null” GSTM1 genotype decreased by 1.7 times (HR = 0.596, CI = 0.369–0.964, p = 0.033) compared with that in carriers of the “normal” GSTM1 genotype. Conclusions. Deletion polymorphism of the GSTT1 and GSTM1 genes has a significant impact on chemotherapy efficacy in breast cancer patients. Carriers of “null” genotypes demonstrated a higher RFS and a lower risk of developing disease relapse. Further research in this direction and validation of the data obtained may contribute to individualizing the treatment of breast cancer patients, optimizing chemotherapy regimens, and reducing the number of adverse events.

The association of combined GSTM1, GSTT1, and GSTP1 genetic polymorphisms with lung cancer risk in male Iraqi Waterpipe Tobacco (Nargila) smokers

Mutations in genes encoding proteins necessary for detoxifying oxidative stress products have been predicted to increase susceptibility to lung cancer (LC). Despite this, the association between waterpipe tobacco smoking (WP), genetic polymorphisms, and LC risk remains poorly understood. This is the first study to explore the relationship between WP tobacco smoking and these genetic factors. Previously, we investigated the association of GSTP1 SNPs (rs1695-A/G and rs1138272-C/T) with LC in Iraqi males who smoke WP. Here, we expanded our analysis to include GSTM1 (active/null) and GSTT1 (active/null) genotypes, both individually and in combination with GSTP1 SNPs. Multiplex PCR and RFLP-PCR assays were utilized to determine the genotypes of 123 cases and 129 controls. No significant association was observed between GSTM1-null or GSTT1-null genotypes and LC risk, either separately or in combination with variant genotypes of GSTP1 (rs1695 "AG+GG" and rs1138272 "CT+TT"). However, smoking WP and carrying null genotypes elevated the risk five-fold for GSTM1-null (OR 5.17, 95 % CI 2.02–13.24, P<0.001) and three-fold for GSTT1-null (OR 3.08, 95 % CI 1.55–6.13, P=0.001) compared to non-smokers carrying active genotypes. Conversely, genotype distribution analysis based on LC histological types did not indicate an increased risk of LC. Lung cancer is a complex multifactorial disease. WP smoking and GSTs genetic polymorphisms might be associated with an increased risk of developing LC. However, our data did not confirm an association between GST polymorphisms alone and the risk of LC.

Genetic Polymorphisms in Glutathione S-Transferase (GST) Gene and Their Correlation with Toxicity of Chemotherapy in Breast Cancer Patients.

Glutathione S-Transferase (GST) is a family of phase II metabolizing enzymes contribute to detoxification and elimination of variety of endogenous as well as exogenous xenobiotics including chemotherapeutic agents. The comprehensive knowledge on the impact of genetic polymorphisms in GST) enzyme coding gene will help to understand the clinical outcomes in breast cancer patients treated with either Adriamycin or paclitaxel or combination of both. In this study we attempted to assess the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and their association with Adriamycin and Paclitaxel induced toxicity reactions in breast cancer patients. Two hundred BC patients receiving Adriamycin and Paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms in GSTM1, GSTP1 and GSTT1 gene were studied by PCR and RFLP analysis. After the univariate analysis of the genetic polymorphisms of GSTM1, GSTP1 and GSTT1 showed that GSTT1 null genotype showed significant association with neutropenia (OR=2.84, 95% CI: 1.06-7.56; p=0.036) in breast cancer patients treated with Adriamycin and GSTT1 null genotype in patients with >1 CINV toxicity confirmed significant correlation (OR=3.75, 95% CI: 1.46-9.59; p=0.005). The genetic polymorphisms of GSTP1 (exon 5) A/G heterozygous genotype was significant in grade >1 toxicity reactions of mucositis (OR=3.22, 95% CI: 1.06-9.71; p=0.037) in breast cancer patients administered with Paclitaxel chemotherapy. The findings obtained from this study proposed significant involvement of GSTT1-null genotype in hematological neutropenia toxicity in response to Adriamycin and GSTM1-null genotype showed negative association with non-hematological toxicity (bodyache) in response to Paclitaxel.

Glutathione S Transferase Theta1 and Mu1 (GSTT1 and GSTM1) Deletion Among Autistic Population of India

Introduction: Oxidative stress is an imbalance between an organism's reactive oxygen species (ROS) production and antioxidant defence capacity. Long-term oxidative stress contributes to cellular ageing and plays a role in the pathogenesis of several diseases. Several investigations indicated that oxidative stress has a role in the pathogenesis of ASD. Objectives: Present study was undertaken to record the association of GSTTT1 and GSTM1 null genotype among the autistic population of India. Methods: Genomic DNA was isolated from 108 autistic children along with healthy agematched control. The quality and quantity of the isolated genomic DNA were analysed. GSTT1 and GSTM1 null genotype was analysed using polymerase chain reaction with internal positive control. Statistical analysis was performed using SPSS 15.0. Results: Present study included 85 males and 23 females with a mean age of 11.7 ± 3.5 and 75 males and 33 females with a mean age of 11 ± 2.0 in the control group. 32 (29.6%) autistic cases showed null genotypes for GSTT1 and 21(19.4%) autistic children showed null genotypes for GSTM1. 3 (2.85%) control children showed a null genotype for GSTT1 and 5 (4.6%) control children showed a null genotype for GSTM1. The GSTT1 and GSTM1 null genotypes were observed to be significantly associated with the risk of autism (p value-0.0001, OR-14.73, 95% CI 4.35-49.90) and (p value-0.003, OR-4.731, 95% CI 1.71-13.08) respectively. Conclusion: The findings of our study suggested that GSTT1 and GSTM1 null genotype is one of the potential risk factors for autism through oxidative stress mechanism in our population.

Abstract 839: Interaction between solvent exposure and genetic susceptibility and risk for bladder cancer

Abstract Introduction: Recent studies have reported an increased bladder cancer risk with occupational exposure to organic solvents, including exposure to benzene, toluene, and xylene (BTX). The metabolism of solvents is known to be influenced by genetic susceptibility. Here, we evaluated the association between BTX and bladder cancer, stratified by genotype in known bladder cancer susceptibility loci and in variants shown to impact the metabolism of solvents. Methods: We evaluated if single-nucleotide polymorphisms (SNPs) modified the association between BTX exposure and bladder cancer risk in 1182 cases and 1408 controls from a population-based case-control study in New England. Ever and cumulative lifetime exposure to BTX was assessed using occupational histories obtained by personal interviews and exposure-oriented modules in conjunction with a job-exposure matrix. Genotyping was conducted using Illumina arrays and GSTM1 and GSTT1 deletion were determined using melt curve/copy number assays. We used multivariate logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between BTX exposure and bladder cancer, stratified by genotype and to calculate p-values for multiplicative interaction. Results: Ever exposure to BTX was more strongly associated with bladder cancer risk among individuals with the GSTT1 null (deletion) genotype (OR 3.53, 95% CI 1.26-9.89), while exposed individuals with the GSTT1 active genotype had a diminished risk (OR 1.40, 95% CI 0.93-2.10, P-interaction = 0.06). The association between benzene exposure and bladder cancer was similarly modified by GSTT1 genotype (carriers of the deletion: OR 5.19, 95% CI 1.91, 14.13; carriers of one or two copies: OR 1.22, 95% CI 0.79, 1.89, p-interaction=0.008). Conclusion: GSTT1 genotype has been shown to impair the metabolism of solvents, particularly for benzene. Here we show that bladder cancer risk is higher among those exposed to solvents who also harbor a common deletion in GSTT1, adding to the evidence of a plausible link between BTX exposures and bladder cancer risk. Citation Format: Deborah Tadesse, Nathaniel Rothman, Shuai Xie, Lauren Hurwitz, Melissa C. Friesen, Dalsu Baris, Molly Schwenn, Alison Johnson, Margaret Karagas, Debra T. Silverman, Stella Koutros. Interaction between solvent exposure and genetic susceptibility and risk for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 839.

Combined genetic polymorphisms of the GSTT1 and NRF2 genes increase susceptibility to cisplatin-induced ototoxicity: A preliminary study

ObjectiveThe genotype-phenotype relationship in cisplatin-induced ototoxicity remains unclear. By assessing early shifts in distortion product otoacoustic emission (DPOAE) levels after initial cisplatin administration, we aimed to discriminate patients’ susceptibility to cisplatin-induced ototoxicity and elucidate their genetic background. Study DesignA prospective cross-sectional study. SettingTertiary referral hospital in Japan. PatientsTwenty-six patients with head and neck cancer were undergoing chemoradiotherapy with three cycles of 100 mg/m2 cisplatin. InterventionsRepetitive pure-tone audiometry and DPOAE measurements, and blood sampling for DNA extraction were performed. Patients were grouped into early ototoxicity presence or absence based on whether DPOAE level shifts exceeded the corresponding reference limits of the 21-day test interval. Main Outcome MeasuresHearing thresholds after each cisplatin cycle, severity of other adverse events, and polymorphisms in cisplatin-induced ototoxicity-associated genes were compared. ResultsEarly ototoxicity was present in 14 and absent in 12 patients. Ototoxicity presence on DPOAEs was associated with greater progression of hearing loss in frequencies ≥2 kHz throughout therapy and with higher ototoxicity grades compared with ototoxicity absence. Ototoxicity was further associated with grade ≥2 nausea. Ototoxicity presence was genetically associated with the GSTT1 null genotype and G-allele of NFE2L2 rs6721961, whereas ototoxicity absence was associated with the GSTM1 null genotype. Dose-dependent progression of hearing loss was the greatest in the combined genotype pattern of GSTT1 null and the T/G or G/G variants of rs6721961. ConclusionEarly DPOAE changes reflected genetic vulnerability to cisplatin-induced ototoxicity. Hereditary insufficiency of the antioxidant defense system causes severe cisplatin-induced hearing loss and nausea.

Association of Oral Submucous Fibrosis Risk with GSTM1 and GSTT1 Gene Polymorphisms.

To determine the association of GSTM1 and GSTT1 polymorphisms with oral submucous fibrosis (OSF). A case-control study. Place and Duration of the Study: Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore and Oral and Maxillofacial Surgery Department, de Montmorency, College of Dentistry/ Punjab Dental Hospital, Lahore, Pakistan, from 1st April 2019 to 31st April 2020. OSF patients were diagnosed with different clinical staging of mouth opening by Vernier caliper with the help of a professional dentist in the Department of Oral and Maxillofacial, de Montmorency, College of Dentistry, Lahore. One hundred and eight blood samples of OSF patients and 108 samples of normal controls were collected. Genomic DNA was obtained from whole-blood extraction. Multiplex PCR amplification using GSTM1, GSTT1, and β -Globin gene primers was performed. GSTM1 and GSTT1 null genotypes frequencies were found in 43.5% (47/108) and 13.9% (15/108) of controls, whereas 54.6% (59/108) and 25.9% (28/108) of OSF patients, respectively. OSF patients had a greater frequency rate of GSTM1 and GSTT1 null genotypes than controls [OR 1.56, 95% CI 0.91-2.67 (p=0.13)]and [OR 2.17, 95% CI 1.08-4.34 (p=0.04)], respectively. The GSTT1 genotype was found statistically significant with OSF (p=0.05), and risk was also determined. The cumulative effect of null genotypes of GSTM1/GSTT1 did not show any association with the controls and in OSF patients. Proportions of active and null alleles of the patient group were; 86.1%/13.9%; and in control, it was 92.6%/7.4% (OR = 2.01; CI: 0.82-4.97; p=0.18), respectively. The study determined a statistically significant association of GSTT1 gene polymorphism with OSF. Oral submucous fibrosis, GSTM1, GSTT1, Gene polymorphisms, Genetic risk.

Role of GSTM1 and GSTT1 Gene Polymorphisms on Lung Cancer Susceptibility and Effect on Platinum‐Based Chemotherapy‐Induced Toxicity in Bangladeshi Lung Cancer Patients

Background: Glutathione S‐transferases (GSTs) play a significant role in carcinogen detoxification, and hence, polymorphisms of this gene may lead to lung cancer susceptibility. Accordingly, this study is aimed at investigating GSTM1 and GSTT1 polymorphisms’ association with lung cancer risk and their effects on the toxicities of platinum‐based chemotherapy used to treat Bangladeshi lung cancer patients.Methods: The study subjects comprised 180 lung cancer patients and 200 healthy volunteers. Genetic polymorphisms of GSTM1 and GSTT1 were analyzed using a multiplex PCR–based method. Chemotherapy toxicity was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE v5.0).Results: GSTM1 null genotype was found to be significantly associated with a 1.6‐fold increased risk of lung cancer (OR = 1.60, 95%CI = 1.01–2.52, p = 0.0491), whereas no significant association was observed with GSTT1 null genotype and combined GSTM1 and GSTT1 null genotype. Moreover, no significant relationship was observed between GSTM1 and GSTT1 polymorphisms and the increased risk of platinum‐based chemotherapy‐induced toxicities in lung cancer patients.Conclusions: These findings indicated that the GSTM1 null but not GSTT1 null genotype was significantly associated with lung cancer susceptibility. These polymorphisms were not related to platinum‐based chemotherapy‐induced toxicities in Bangladeshi lung cancer patients.

Association between null Genotypes of glutathione S-transferase M1 and T1 and susceptibility to systemic lupus erythematosus: A meta-analysis

Oxidative stress is involved in the development of systemic lupus erythematosus (SLE). It is well known that activity of the glutathione S-transferase superfamily has a protective effect against oxidative stress. Several studies have investigated the association between the GSTT1/GSTM1 polymorphisms and the risk of SLE with inconsistent results. The present meta-analysis was performed to investigate the association between susceptibility to SLE and the null genotypes of GSTT1 and GSTM1. Eligible publications were identified by searching several databases, 18 case-control studies with 2483 cases and 3643 controls met the inclusion criteria. The raw data of three reports have internal inconsistencies, therefore these studies were excluded from the final analysis. The results showed that the GSTM1 null genotype significantly increased the risk of SLE (OR = 1.17, 95 % CI: 1.03-1.32, p = 0.012) with no evidence of significant heterogeneity (Q = 14.53, df = 14, p = 0.411; I² = 3.4 %). The GSTT1 null genotype was not associated with the risk of SLE (OR = 0.94, 95 % CI: 0.80-1.10, p = 0.447). There was no evidence of heterogeneity between studies. The present study showed that the null genotype of GSTM1 was weakly associated with the risk of SLE.

Association of genetic polymorphism of glutathione S-transferases with colorectal cancer susceptibility in snuff (Naswar) addicts.

The current study aimed to investigate the relationship between polymorphisms in detoxifying (GSTM1, GSTT1, and GSTP1) genes and their association with colorectal cancer (CRC) in tobacco addicts of Pashtun ethnicity. Polymorphisms in the selected genes were genotyped in a case-control study consisting of 100 histologically confirmed male CRC patients and 100 birth-year and gender-matched healthy controls using the PCR-RFLP method. The GSTM1 null, and GSTT1 null genotypes were significantly contributed to the risk of CRC in the cases (OR= 3.131, 95% CI: 1.451-6.758, P = 0.004, and OR= 3.541, 95% CI: 1.716-7.306, P = 0.001, respectively), whereas the association observed for GSTP1 Val/Val (1.139, 95% CI: 0.356-3.644, P = 0.826) did not show statistical significance. The combined GSTM1 null and GSTT1 null showed a 41-fold increased risk (95% CI: 4.945-351.950, P = 0.001), while, the combined GSTM1 null and GSTP1 Ile/Val or Val/Val variant genotypes exhibited about 3-fold (95% CI: 1.196-7.414, P = 0.019) increased risk to CRC. Similarly, the combined GSTT1 null and GSTP1 Ile/Val or Val/Val variant genotypes showed about a 3-fold (95% CI: 1.285-8.101, P = 0.013) increased risk of CRC. In the combination of three GST genotypes, the GSTM1 null, GSTT1 null, and GSTP1 Ile/Val or Val/Val variant genotypes demonstrated a more than a 22-fold (95% CI: 2.441-212.106, P = 0.006) increased risk of CRC. Our findings suggest that GSTM1 and GSTT1 polymorphism and its combination with GSTP1 may be associated with CRC susceptibility in the Naswar addicted Pashtun population of Khyber Pakhtunkhwa, Pakistan.

Machine learning approaches and genetic determinants that influence the development of type 2 diabetes mellitus: a genetic association study in Brazilian patients.

This genetic association study including 120 patients with type 2 diabetes mellitus (T2DM) and 166 non-diabetic individuals aimed to investigate the association of polymorphisms in the genes GSTM1 and GSTT1 (gene deletion), GSTP1 (rs1695), ACE (rs4646994), ACE2 (rs2285666), VEGF-A (rs28357093), and MTHFR (rs1801133) with the development of T2DM in the population of Goiás, Brazil. Additionally, the combined effects of these polymorphisms and the possible differences between sexes in susceptibility to the disease were evaluated. Finally, machine learning models were integrated to select the main risk characteristics for the T2DM diagnosis. Risk associations were found for the GSTT1-null genotype in the non-stratified sample and females, and for mutant C allele of the VEGF-A rs28357093 polymorphism in the non-stratified sample. Furthermore, an association of heterozygous (AG) and mutant (GG) GSTP1 genotypes was observed when combined with GSTT1-null. Machine learning approaches corroborated the results found. Therefore, these results suggested that GSTT1 and GSTP1 polymorphisms may contribute to T2DM susceptibility in a Brazilian sample.

A case-control study and systematic review of the association between glutathione S-transferase genes and chronic kidney disease

BackgroundGSTM1 deletion was reported to be associated with CKD progression in cohort studies. However, the results of case‒control studies were conflicting. The association between GST genes and CKD progression needs to be studied in China. Therefore, we conducted this case‒control study and systematic review for Southwest China to outline the association between GST genes and CKD. MethodsCKD patients and healthy controls were enrolled from June 1, 2022 to 1 August 2022. Reported case‒control studies were identified by searching databases until 1 September 2022 for meta-analysis. ResultsSignificant associations were found between deletions of GSTM1 and GSTT1 and CKD risk (all P < 0.01) but not in GSTP1 rs1695 (all P > 0.05) in Southwest China. Then, we conducted a meta-analysis on 30 studies and found positive associations between deletions of GSTM1 and GSTT1 and CKD risk (all P < 0.01) but failed to find associations in GSTP1 rs1695 (all P > 0.05). Stratification analysis for ethnicity only showed a significant association in Southern Asia (P < 0.05) but not in Eastern Asia or other populations. This was different from our case‒control results. The current evidence was influenced by study quality and PCR method but not by control selection. Given the different stages of CKD patients, a subanalysis of disease stages was performed, and the results remained positive. Interestingly, we found no significant associations between DM-CKD and GST genes, which should be interpreted with caution. ConclusionWe found that GSTM1 and GSTT1 null genotypes were risk factors for CKD in China. The results of the meta-analysis were somewhat different from our results. We considered that antioxidant therapy might be useful for the treatment of these patients.

Pengembangan Metode PCR Multipleks untuk Analisis Genotipe Null Gen GSTM1/GSTT1 pada Pasien Tuberkulosis

Tuberculosis (TB) remains Indonesia's leading infectious disease. Hepatotoxicity is the most common side effect of TB first-line medication therapy in TB patients. GSTM1 and GSTT1 are glutathione S-transferase (GST) genes involved in the detoxification of various toxic compounds such as drugs. The development of fast and simple methods for null genotyping of GSTM1/GSTT1 could facilitate large pharmacogenetic studies and the clinical application of personalized drug dose adjustment according to the patient's genetic profile. The aim of this research was to develop a multiple PCR method for simultaneous amplification of GSTM1/GSTT1 genes for molecular analysis. A total of 25 samples of TB patients were used to validate the method consisting of TB patients with hepatotoxicity and without hepatotoxicity. Our result showed the genotype frequency of the GSTM1 null genotype was 90% in TB patients with hepatotoxicity and 100% in TB patients without hepatotoxicity. The frequency of the GSTT1 null genotype in TB patients with hepatotoxicity was 90%, whereas in TB patients without hepatotoxicity was 80%. The sequencing results on the positive samples showed a similarity of 99% to the GenBank NCBI. Our study was successful in detecting GSTM1 and GSTT1 null genotypes using the multiplex PCR method in TB patients. Further study needs to be done with larger sample of TB patients.

Progonostic effect of GSTM1/GSTT1 polymorphism in determining cardiovascular diseases risk among type 2 diabetes patients in South Indian population.

Cardiovascular disease (CVD) is a significant complication of type 2 diabetes mellitus (T2DM), with oxidative stress playing a significant role. Glutathione S-transferase (GST) polymorphisms - GSTM1, GSTT1 - have been linked to CVD and T2DM. The role of GSTM1 and GSTT1 in CVD development among T2DM patients in the South Indian population is investigated in this study. The volunteers were grouped as Group 1: control, Group 2: T2DM, Group 3: CVD, and Group 4: T2DM with CVD (n = 100 each). Blood glucose, lipid profile, plasma GST, MDA, and total antioxidants were measured. GSTM1 and GSTT1 were genotyped using PCR. GSTT1 plays a significant role in the development of T2DM and CVD [OR 2.96(1.64-5.33), < 0.001 and 3.05(1.67-5.58), < 0.001] while GSTM1 null genotype was not associated with disease development. Individuals with dual null GSTM1/GSTT1 genotype had the highest risk of developing CVD [3.70(1.50-9.11), 0.004]. Group 2 and 3 individuals showed higher lipid peroxidation and lower total antioxidant levels. Pathway analysis further indicated that GSTT1 significantly affects GST plasma levels. GSTT1 null genotype may be considered a contributingfactor thatincreases the susceptibility and risk of CVD and T2DM in the South Indian population.

Association of Genetic and Allelic Variants of Von Willebrand Factor (VWF), Glutathione S-Transferase and Tumor Necrosis Factor Alpha with Ischemic Stroke Susceptibility and Progression in the Saudi Population.

Stroke is a key cerebrovascular disease and important cause of death and disability worldwide, including in the kingdom of Saudi Arabia (KSA). It has a large economic burden and serious socioeconomic impacts on patients, their families and the community. The incidence of ischemic stroke is probably increased by the interaction of GSTT1 and GSTM1 null genotypes with high blood pressure, diabetes and cigarette smoking. The roles of VWF, GSTs and TNF-alpha gene variations in the induction of stroke are still uncertain and require further examination. In the current study, we studied the associations of SNPs in the genes VWF, GSTs and TNF-alpha with stroke in the Saudi population. Genotyping was performed using the ARMS -PCR for TNF-alpha, AS-PCR for VWF and multiplex PCR for GSTs. The study included 210 study subjects: 100 stroke cases and 110 healthy controls. We obtained significant distributions of VWF rs61748511 T > C, TNF-alpha rs1800629 G > A and GST rs4025935 and rs71748309 genotypes between stroke cases and the healthy controls (p < 0.05). The results also indicated that the TNF-alpha A allele was associated with risk of stroke with odd ratio (OR) = 2.22 and risk ratio = RR 2.47, p < 0.05. Similarly, the VWF-TC genotype and C allele were strongly linked with stroke with OR = 8.12 and RR 4.7, p < 0.05. In addition, GSTT1 and GSTT1 null genotype was strongly associated with stroke predisposition with OR = 8.30 and RR = 2.25, p < 0.0001. We conclude that there is a possible strong association between the VWF-T > C, TNF-alpha G > A, GSTT1 gene variants and ischemic stroke susceptibility in the Saudi population. However, future well-designed and large-scale case-control studies on protein-protein interactions and protein functional studies are required to verify these findings and examine the effects of these SNPs on these proteins.

GSTs genetic polymorphism, gene-environment interaction and association with gallbladder cancer risk in North Indian population: A case-controlled study.

In the present case-controlled study, we explored the role of genetic polymorphism in three xenobiotic metabolizing genes, GSTM1, GSTT1 and GSTP1, and their association to gallbladder cancer (GBC) risk in a North Indian population. Its etiology is influenced by genetic, food habits, lifestyle, and environmental factors. GBC incidence is significantly higher in the Gangetic belt, India. Therefore, we explored the prognostic factors in the susceptibility of GBC through gene-gene and gene-environment interaction in this region. Genetic polymorphism was analyzed in 108 GBC patients from Kamala Nehru Memorial Cancer Hospital, Prayagraj and 142 matched controls. GSTM1 and GSTT1 genotypes were analyzed by multiplex PCR method, while restriction fragment length polymorphism (RFLP) was performed to analyze GSTP1 genotypes. Logistic regression analysis calculating the odds ratio (OR) and 95% confidence interval (CI) was performed to analyze the GBC risk. GSTT1 (null) genotype was at a significantly higher risk and susceptible to GBC (OR = 2.044, CI = 1.225-3.411, P = 0.006), while GSTM1 and GSTP1 genotypes did not show any association to GBC risk. After sex stratification, females diagnosed with GBC had higher GSTT1 (null) genotype (OR = 2.754, CI = 1.428-5.310, P = 0.003) compared to males. GBC patients dwelling in rural areas show higher GSTT1 (null) genotype with two-fold GBC risk (OR = 2.031, CI = 1.200-3.439, P = 0.008). Further, GBC patients with histopathology of adenocarcinoma also showed higher GSTT1 (null) genotype (OR = 2.113, CI = 1.248-3.578, P = 0.005). Gene-gene interaction between GSTT1 (non-null)/GSTP1 (Ile/Val + Val/Val), enhance the GBC risk (OR = 1.840, CI = 1.135-2.982, P = 0.013). The present study suggests that GSTT1 (null) genotype has higher susceptibility and risk towards GBC in North Indian population. Female patients, patients with histopathology of adenocarcinoma and rural dwelling GBC patients have higher GSTT1 (null) genotypes and may be at risk of developing GBC. The genotype combination GSTT1 (non-null)/GSTP1 (Ile/Val + Val/Val) has increased GBC susceptibility and may be considered as 'at risk' genotypes for GBC in North Indians.

CYP19A1 TC/CC Polymorphism, along with Deletion of GSTM1 and GSTT1 Genes, Strongly Influences Female Infertility Risk.

Oxidative stress has a fundamental role in the pathophysiology of various conditions, like infertility. This case-control study was performed to assess the potential role of CYP19A1, GSTM1, and GSTT1 in modifying individual predisposition to female infertility. Genotyping of 201 women with established infertility and 161 fertile female controls was performed, and statistical associations were analyzed. For carriers of GSTM1 null genotype along with CYP19A1 C allele, there is a significant association with female infertility risk (OR 7.023; 95% CI (3.627-13.601; p < 0.001), and, also for carriers of GSTT1 null genotype along with the CYP19A1 TC/CC genotype (OR 24.150; 95% CI (11.148-52.317; p < 0.001). A positive association with female infertility risk for carriers of the C allele in CYP19A1 and null genotypes in GTSM1 (OR 11.979; 95% CI (4.570-31.400; p < 0.001) or GSTT1 (OR 13.169; 95% CI (4.518-38.380; p < 0.001) was found. When both GSTs are deleted, the risk of developing female infertility is significant, independently of the CYP19A1 genotype; when all the presumed high-risk genotypes are present, we found a significant association with female infertility risk (OR 47,914; 95% CI (14,051-163,393; p < 0.001).

Genetic polymorphisms in phase II metabolizing enzymes in alcoholic and idiopathic chronic pancreatitis: Indian scenario.

To study polymorphisms in glutathione-S-transferases (GST-T1, GST-M1, GST-P1) and uridine-5'-diphosphate-glucuronosyl-transferases (UGT1A7) genes and the risk of developing chronic pancreatitis (CP) associated with these polymorphisms. This study included 49 alcoholic and 51 idiopathic chronic pancreatitis patients, 50 alcohol addicts and 50 healthy controls. Polymorphism(s) in GST-T1 and GST-M1 genes were assessed by multiplex polymerase chain reaction (PCR), while PCR-radiofrequency lesioning (RFLP) was employed to assess the same in GST-P1 and UGT1A7 genes. The differences in polymorphism frequency between groups and the risk of developing pancreatitis were assessed by the odds ratio. Strong association of the null genotype of GST-T1 with CP susceptibility was observed. Alcoholics with the Val allele of GST-P1 have higher chances of having pancreatitis. Idiopathic pancreatitis patients with higher age at the onset of pain were found to have the null genotype of GST-M1. Alcoholics with the null genotype of the GST-T1 gene and the Valine allele of the GST-P1 gene are at a higher risk of developing CP. Thus, genotyping of these genes may serve as an important screening tool for the identification of high-risk groups among alcoholics.

Impact of GSTT1 and GSTM1 Polymorphisms in the Susceptibility to Philadelphia Negative Chronic Myeloid Leukaemia.

Our research aimed to clarify the role of genetic polymorphisms in GST (T1 and M1) in the development of Ph-ve CML. We report on a case-control study with 126 participants, divided into 26 patients with Ph-ve CML (57.7% male, 42.3% female) and 100 healthy volunteers (51% male, 49% female) with no medical history of cancer as a control population. All Ph-ve CML patients were diagnosed according to standard hematologic and cytogenetic criteria based on CBC, confirmed by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) to determine the presence or absence of the BCRABL gene, followed by bone marrow (BM) examination. Of the 26 studied cases, 50% had the GSTT1 null genotype against 21% of the control group, a statistically significant difference (CI= 1.519 - 9.317; p-value= 0.004). The GSTM1 null genotype was detected in 23.1% of cases and 35% of controls, a difference not statistically significant (OR= 0.557; CI= 0.205-1.515; p-value= 0.252). The distribution of GSTT1 and GSTM1 polymorphisms was also examined according to gender, age and ethnic grouping; these findings revealed no statistically significant differences. Our study reveals a strong correlation between GSTT1 polymorphism and Ph-ve CML, whereas the data for GSTM1 polymorphisms indicates no role in the initial development of the disease. More studies are required to further clarify these and other genes' roles in disease development.