GSTM1 Null Polymorphism Research Articles

GSTM1 and GSTT1 genetic polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity: an updated meta-analysis

The results of studies investigating the associations between GSTM1 and GSTT1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity (ADIH) risk exhibit much controversy. Therefore, a meta-analysis was performed in order to examine the associations between GST variants and ADIH risk. A total of 451 relevant studies were identified through the digital medical databases Medline, Embase, and CBM published up to October 2012. Thirteen individual case-control studies were eventually recruited for GSTM1 null polymorphism (including 951 ADIH cases, 1,922 controls) and 12 studies for GSTT1 null polymorphism (847 cases, 1,811 controls). Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were appropriately calculated from fixed-effects or random-effects models. Subgroup analyses were stratified by ethnicity and different treatment combinations. The overall ORs of relevant studies that exhibited elevated ADIH risk was significantly associated with GSTM1 null genotypes (OR = 1.36, 95% CI 1.04-1.79), but for the GSTT1 polymorphism, no difference was found (OR = 0.98, 95% CI 0.82-1.18). In the subgroup analyses, the pooled results showed that GSTM1 null allele carriers had a significant association with ADIH risk in East Asians and the patients who used isoniazid (INH) + rifampicin (RMP) + pyrazinamide (PZA) + ethambutol (EMB), or + streptomycin (SM) (HRZES), but the opposite result was observed for patients using HR. Moreover, the GSTT1 null genotype evaluated the susceptibility to ADIH for tuberculosis using HRZ. This meta-analysis provides evidence that there may be an increased risk of ADIH in individuals with null genotypes of GSTM1 in the total population, especially East Asians and patients receiving HRZE or HRZES. However, polymorphisms of the GSTT1 null genotype seem to have no association with susceptibility to ADIH, except for patients receiving HRZ.

Association of Glutathione S transferases Polymorphisms with Glaucoma: A Meta-Analysis

Background Glutathione S transferase (GST) polymorphisms have been considered risk factors for the development of glaucoma, including primary open angle glaucoma (POAG) and other types of glaucoma. However, the results remain controversial. In this study, we have conducted a meta-analysis to assess the association between polymorphisms of GSTM1, GSTT1 and GSTP1 and glaucoma risk.MethodsPublished literature from PubMed and other databases were retrieved. All studies evaluating the association between GSTM1, GSTT1 and GSTP1 polymorphisms and glaucoma risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model.ResultsTwelve studies on GSTM1 (1109 cases and 844 controls), ten studies on GSTT1 (709 cases and 664 controls) and four studies on GSTP1 (543 cases and 511 controls) were included. By pooling all the studies, either GSTM1 or GSTT1 null polymorphism was not associated with a POAG risk, and this negative association maintained in Caucasian. The GSTP1 Ile 105 Val polymorphism was significantly correlated with increased POAG risk among Caucasian in a recessive model (Val/Val vs. Ile/Ile+Ile/Val: OR, 1.62, 95%CI: 1.00–2.61). Interestingly, increased glaucoma risk was associated with the combined GSTM1 and GSTT1 null genotypes (OR, 2.20; 95% CI, 1.47–3.31), and with the combined GSTM1 null and GSTP1 Val genotypes (OR, 1.86; 95% CI, 1.15–3.01).ConclusionsThis meta-analysis suggests that combinations of GST polymorphisms are associated with glaucoma risk. Given the limited sample size, the associations between single GST polymorphism and glaucoma risk await further investigation.

Glutathione-S-transferase (GST) polymorphisms are associated with relapse after radical prostatectomy

Organ confined prostate cancer (PCa) can be cured by radical retropubic prostatectomy (RRP); however, some tumors will still recur. Current tools fail to identify patients at risk of recurrence. Glutathione-S-transferases (GSTs) are involved in the metabolism of carcinogens, hormones and drugs. Thus, genetic polymorphisms that modify the GST activities may modify the risk of PCa recurrence. We retrospectively recruited Argentine PCa patients treated with RRP to study the association between GST polymorphisms and PCa biochemical relapse after RRP. We genotyped germline DNA in 105 patients for: GSTP1 c.313A>G (p.105 Ile>Val, rs1695) by PCR-RFLP; and GSTT1 null and GSTM1 null polymorphisms by multiplex PCR. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate these associations. Patients with GSTP1 c.313GG genotype showed shorter biochemical relapse-free survival (BRFS) (P = 0.003) and higher risk for recurrence in unadjusted (Hazard ratio (HR) = 3.16, 95% confidence interval (95% CI) = 1.41-7.06, P = 0.005) and multivariate models (HR = 3.01, 95% CI = 1.13-8.02, P = 0.028). We did not find significant associations for GSTT1 and GSTM1 genotypes. In addition, we found shorter BRFS (P = 0.010) and increased risk for recurrence for patients having two or more risk alleles when we combined the genotypes of the three GSTs in multivariate models (HR = 3.06, 95% CI = 1.20-7.80, P = 0.019). Our results give support to the implementation of GSTs genotyping for personalized therapies as a novel alternative for PCa management for patients who undergo RRP. To the best of our knowledge, this is the first study that examined GST polymorphisms in PCa progression in Argentine men. Replication of our findings in larger cohort is warranted.

BMD Values and GSTM3 Gene Polymorphisms in Combination with GSTT1/GSTM1 Genes: A Genetic Association Study in Slovenian Elderly

Background: Much research suggests that oxidative stress is associated with osteoporosis development. Glutathione S-transferases mu3 (GSTM3) are an important group of detoxifying enzymes that eliminate oxidative stress-related products. Objectives: To examine the associations of functional GSTM3 gene polymorphisms (Val224Ile and insdelAGG), their haplotypes and, in combination with GSTT1-null and GSTM1-null polymorphisms, with bone mineral density (BMD) measured at femoral neck (_fn), lumbar spine (_ls) and total hip (_th) and biochemical bone turnover markers in 593 Slovenian elderly women and 119 Slovenian elderly men. Methods:GSTM3, GSTT1-null and GSTM1-null gene polymorphisms using sizing denaturing high-performance liquid chromatography, triplex PCR method or real-time PCR; BMD_fn, BMD_ls, BMD_th values using dual energy X-ray absorptiometry, and plasma osteocalcin, serum bone alkaline phosphatase and free soluble tumor necrosis factor (ligand) superfamily, member 11 (sRANKL) concentrations using a solid-phase, two-site chemiluminescent enzyme-labeled immunometric assay, radioimmunoassay or enzyme immunoassay were determined. Statistical analysis was performed using one-way and two-way ANCOVA with adjustment for potential confounders (age, height and weight). Results: The (borderline) significant differences in BMD_th and BMD_fn values between genotype subgroups of Val224Ile polymorphism of GSTM3 gene (p = 0.057 and 0.053, respectively) with the lowest BMD values among heterozygotes and between 224Ile-insAGG haplotype subgroups (p = 0.048 and 0.019, respectively) were found. Significant differences of BMD_fn between the 224Ile-delAGG haplotype subgroups were observed (p = 0.012). Association of 224Val-insAGG with BMD_fn was of borderline significance (p = 0.062). Conclusion: The results of our study demonstrate the genetic association between detoxifying enzyme GSTM3 and BMD variation, suggesting that the Val224Ile polymorphism and 224Ile-insAGG haplotype could be used for further evaluation of the impact of GSTs gene polymorphisms on osteoporosis, using larger cohorts in searching for osteoporosis risk markers.

Inter-Gene and Gene - Environment Interactions Associated with CYP1A1 and GSTM1 Gene Polymorphisms and Risk of Oral Cancer in Chhattisgarh Population, India

India has one of the highest incidences of oral cancer (OC) in the world. OC susceptibility is related to the polymorphism of drug-metabolising genes because they are responsible for metabolising chemical carcinogens, which are present in tobacco and alcohol. The aim of this study was to determine the potential role of drug-metabolising CYP1A1 and GSTM1 gene polymorphisms and the risk of OC in Chhattisgarh. For the assessment of association between the polymorphism of CYP1A1 and GSTM1 genes and risk of tobacco-related OC in Chhattisgarh population, we examined the prevalence of CYP1A1 and GSTM1 null polymorphisms using PCR- and restriction fragment-length polymorphism-based methods in seventy-four histologically confirmed OC patients and in seventy-four age- and sex-matched healthy controls. Demographic information and biological samples were collected by individual-informed written consent of subjects. To know the potential gene–environment interaction, analyses were conducted by stratifying the tobacco (smoking, chewing) and alcohol consumption status and odds ratio (OR) estimation was conducted using SPSS (version 16.0) software. The increased risk for OC was observed among subjects with homozygous CYP1A1 (m2/m2) genotype (OR = 1.39; 95% CI = 0.68–2.84) and GSTM1 null genotype (OR = 1.31; 95% CI = 0.69–2.50). Furthermore, the risk for OC significantly increased in subjects with the homozygous CYP1A1 (m2/m2) genotype with tobacco-chewing and alcohol-drinking history (chewer; OR = 2.08; 95% CI = 0.84–5.20; alcohol drinker; OR = 2.07; 95% CI = 0.69–6.21). The combination of CYP1A1 (m2/m2) and GSTM1 null genotypes is a significant risk for OC (OR = 2.38; 95% CI = 0.678.49, p= 0.031). Our findings indicate that the combined net effect of null mutation on CYP1A1 and GSTM1 genes along with tobacco and alcohol habit increased 2.5-fold risk of OC in Chhattisgarh population.

Candidate gene studies in gallbladder cancer: A systematic review and meta-analysis

Gallbladder cancer (GBC) is the most frequent biliary tract malignancy. Wide variations in GBC incidence and familial and epidemiological data suggest involvement of a genetic component in its etiopathogenesis. A systematic review of genetic association studies in GBC was performed by applying a meta-analysis approach and systematically reviewing PubMed database using appropriate terms. Odds ratios (ORs) and 95% confidence intervals (CIs) were appropriately derived for each gene-disease association using fixed and random effect models. Meta-regression with population size and genotyping method was also performed. Study quality was assessed using a 10-point scoring system designed from published guidelines. Following a review of 44 published manuscripts and one unpublished report, 80 candidate gene variants and 173 polymorphisms were analyzed among 1046 cases and 2310 controls. Majority of studies were of intermediate quality. Four polymorphisms with >3 separate studies were included in the meta-analysis [OGG1 (rs1052133), TP53 (rs1042522), CYP1A1 (rs1048943) and GSTM1 null polymorphism]. The meta-analysis demonstrated no significant associations of any of the above polymorphisms with GBC susceptibility except TP53 (rs1042522) polymorphism. To conclude, existing candidate gene studies in GBC susceptibility have so far been insufficient to confirm any association. Future research should focus on a more comprehensive approach utilizing potential gene-gene, gene-environment interactions and high-risk haplotypes.

Role of GSTT1 and M1 null genotypes as risk factors for B‐cell lymphoma: Influence of geographical factors and occupational exposure

The interrelationship between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. Both factors need to be considered to enable assessment of disease risk associated with a given individual under certain environmental conditions. GSTT1 and GSTM1 are two genes whose proteins are involved in the detoxification of potential carcinogens. We have studied the prevalence of GSTT1 and GSTM1 null polymorphisms using a novel PCR multiplex protocol in a group of 158 patients with B-cell lymphoma (BCL, 138 with non-Hodgkin lymphoma and 20 with Hodgkin lymphoma) and 214 healthy controls. A questionnaire regarding occupational exposure and lifestyle factors was also completed by both groups. GSTM1 null genotype showed no significant differences between patients and controls (46.9% and 55.6%, respectively). In contrast, GSTT1 null genotype was observed in 25.3% of patients and 15.4% of controls (P=0.013; OR=1.85; CI (95%):1.11-3.09), suggesting a role for the GSTT1 null genotype in the development of BCL. This effect was even more evident in females (27.5% vs. 14%: P=0.014). No significant association was observed between GST genotypes and disease risk in relation to smoking or occupational exposure.

Glutathione S-transferase M1 and T1 polymorphisms in Turkish patients with varicocele

Several studies have shown that high oxidative stress levels are associated with varicocele. The GST (glutathione S-transferase) family of genes is critical in the protection of cells from oxidative stress because they utilise as substrates a wide variety of products of oxidative stress. The objective of this study was to assess the relationship between genetic polymorphism in GST-M1 and GST-T1 and varicocele using 109 varicocele patients and 123 controls. Varicoceles were clinically graded as Grade 1, Grade 2 and Grade 3. GST-M1 and GST-T1 genes were determined by polymerase chain reaction. Although the GST-M1 null genotype was higher in Grade 3 than in Grade 1, 2 and controls, there were no statistical differences between control group and varicocele groups according to GST-M1 and GST-T1 null genotype. Men with varicocele do not have more GST-M1 and GST-T1 null polymorphisms than men without varicocele. Additional studies are needed to assess the exact mechanism by which the varicocele corresponds to elevated ROS levels.

Polymorphisms of DNA Repair and Xenobiotic Genes Predispose to CpG Island Methylation in Non‐Neoplastic Gastric Mucosa

Genetic factors, related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to gastric carcinogenesis. CpG island hyper methylation (CIHM) is a major event in gastric carcinogenesis. We evaluated the association between XRCC1, GSTP1, GSTT1 and GSTM1 polymorphisms with CIHM status in non-neoplastic gastric mucosa. XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 415 cancer free subjects, in relation to four candidate CpG (p14, p16, DAP-kinase and CDH1) loci, assessed by Methylation-Specific-Polymerase Chain Reaction (MSP). CIHM high was defined as two or more CpG islands methylated. Significant association between XRCC1 codon 399 Gln/Gln genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.30, 95%CI = 0.13-0.71, p = .0055) and CIHM high (OR = 0.42, 95%CI = 0.19-0.97, p = .04). XRCC1 codon 399 Gin/Gln genotype also presented lower number of CIHM when compared with both Arg/Gln, and Arg/Arg + Arg/Gln genotypes (p = .02, .046, respectively) When subjects were divided according to age (>50 and <50), an association was found between GSTM1 null genotype and increased susceptibility to CIHM high in the 50 years and older generations (OR = 1.63, 95%CI = 1.01-2.62, p = .045). XRCC1 codon 399 Gln/Gln genotype is associated with reduced susceptibility to CIHM especially DAP-kinase. GSTM1 null genotype may increase the susceptibility to CIHM especially in older patients. Genetic factors, related to DNA repair or xenobiotic pathways may have a role in CIHM-related gastric carcinogenesis.

Association of GSTM1 null polymorphism with isosorbide-5-mononitrate cardiovascular response and involvement of CGRP in healthy Chinese male volunteers

To determine whether functional polymorphisms of glutathione S-transferase μ type 1 (GSTM1) and aldehyde dehydrogenase-2 (ALDH2) affect the isosorbide 5-mononitrate (IS-5-MN) response, and the role of the calcitonin gene-related peptide (CGRP) in IS-5-MN response in healthy volunteers. A two-phase, placebo-controlled study was carried out in 24 healthy Chinese volunteers with their ALDH2 and GSTM1 genotypes known. During each phase, either 20-mg IS-5-MN tablet or placebo was orally administered; blood pressure (BP), heart rate, and plasma concentration of CGRP was determined before and at several time points after drug administration. Pharmacokinetic parameters of IS-5-MN were determined. GSTM1 null individuals showed significantly lower systolic BP (SBP) and diastolic BP (DBP), and higher degree of decreases in SBP (ΔSBP) and DBP (ΔDBP) after IS-5-MN administration. GSTM1 null individuals showed significantly decreased IS-5-MN area under the plasma concentration-time curve than GSTM1 wild-type individuals (P<0.05). Plasma concentration of CGRP was increased significantly at 0.5 (P<0.01), 1 (P<0.05), and 2 h (P<0.05) after IS-5-MN administration in GSTM1 null individuals but not wild-type individuals. GSTM1 null individuals also showed significantly higher degree of percentage increase in the plasma concentration of CGRP than GSTM1 wild-type individuals at 1 h after IS-5-MN administration (P<0.05). IS-5-MN upregulated CGRP I and CGRP II mRNA expressions in cultured peripheral blood mononuclear cells, and the IS-5-MN-induced CGRP II mRNA expression was inhibited by GSTs inhibitor, ethacrynic acid. No difference in the IS-5-MN response was observed between ALDH2 genotypes. We suggest that GSTM1, but not ALDH2, may interfere with the bioactivation of IS-5-MN, and CGRP contributes to the IS-5-MN response in a GSTM1 genotype-dependent manner.

Potential risk modifications of GSTT1, GSTM1 and GSTP1 (glutathione-S-transferases) variants and their association to CAD in patients with type-2 diabetes

Background Type-2 diabetes mellitus (T2DM) is a major risk factor for coronary artery disease (CAD) resulting in high morbidity and mortality. Glutathione S-transferases (GSTM1, GSTT1 and GSTP1) are known for their broad range of detoxification and in the metabolism of xenobiotics. Recent studies revealed the relationship of GSTs variants with T2DM and CAD. In this case-control study we ascertained the association of GSTs variants in association with the development of CAD in patients with T2DM. Methods From the Southern part of India, we enrolled 222 T2DM patients, 290 T2DM patients with CAD and 270 healthy controls matched for age, sex and origin. Serum lipid profiles were measured and DNA was extracted from the blood samples. Multiplex PCR for GSTM1/T1 (null polymorphism) and PCR-RFLP for GSTP1 (105 A > G), were performed for genotyping of study participants. Gene frequency and lipid profiles were statistically analyzed for disease association. Results Regression analysis showed that, GSTM1-null genotype is associated with a 2-fold increase (OR = 2.925; 95% CI = 2.078–4.119; P < 0.0001) and GSTT1-null genotype is associated with a 3-fold increase (OR = 3.114; 95% CI = 2.176–4.456; P < 0.0001) to T2DM development. Ile/Val and Val/Val genotypes of GSTP1 also showed a significant risk for T2DM (OR = 1.423, CI = 1.041–1.946; P = 0.027 and OR = 1.829, CI = 1.064–3.142; P = 0.029). Increased odds ratio showed that GSTT1-null genotype had a moderately higher occurrence in T2DM–CAD patients (OR = 1.918, 95% CI = 1.144–3.214; P = 0.014) than T2DM patients without CAD. The level of HDL has significantly decreased in GSTT1-present than in GSTT1-null genotype (43.50 ± 4.10 vs. 45.20 ± 3.90; P = 0.004) when compared with control and T2DM patients. However, LDL level showed a significant increase in GSTT1-null than GSTT1-present genotype (108.70 ± 16.90 vs. 102.20 ± 12.60; P = 0.005). Although the GSTM1-null polymorphism showed no correlation with lipid profiles among T2DM and T2DM with CAD patients, GSTT1-null polymorphism attained a statistical significance for the level of LDL (127 ± 28.20 vs. 134 ± 29.10; P = 0.039) and triglycerides in T2DM with CAD patients (182.10 ± 21.10 vs. 191.20 ± 24.10; P = 0.018). Conclusion Our work concludes that GSTM1, GSTT1 and GSTP1 variants might contribute to the development of T2DM and GSTT1 variant alone is involved in the development of T2DM associated CAD complications in the South Indian population.

Association between polymorphisms in the XRCC1 and GST genes, and CpG island methylation status in colonic mucosa in ulcerative colitis

CpG island hypermethylation (CIHM) is frequently observed in the colonic mucosa in ulcerative colitis (UC) and is deeply involved in UC-associated colorectal carcinogenesis. We evaluated the influence of common polymorphisms related to DNA repair or xenobiotic pathway (XRCC1, GSTP1, GSTT1, and GSTM1) on the individual susceptibility to CIHM status in the non-neoplastic rectal mucosa in UC patients. XRCC1 Arg399Gln and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 84 UC patients without neoplastic lesions, in relation to CIHM in the rectal mucosa of three candidate CpG loci (p14, p16, and CDH1) assessed by methylation-specific polymerase chain reaction. XRCC1 codon 399 Arg/Gln genotype (odds ratio (OR) = 0.31, 95%CI = 0.12-0.81, p = 0.017) and 399 Gln carrier (GlnGln+Arg/Gln: OR = 0.30, 95%CI = 0.12-0.76, p = 0.01) were significantly associated with reduced susceptibility to CIHM of the CDH1 promoter. GSTP1 Val carrier (Ile Val+Val/Val) also held a significantly lower susceptibility to CIHM of the p16 promoter (OR = 0.26, 95%CI = 0.08-0.86, p = 0.028). In contrast, GSTT1 present genotype (OR = 3.16, 95%CI = 1.27-7.89, p = 0.01) was significantly associated with increased susceptibility to CIHM of the same gene. XRCC1 codon 399 Gln/Gln genotype was significantly associated with lower mean number of CIHM when compared to the Arg/Arg genotype (1.53 ± 1.01 vs. 0.63 ± 1.06, p = 0.024). In addition, the GSTP1 Ile/Val carrier (Ile/Val+Val/Val) was also significantly associated with lower mean number of CIHM (1.43 ± 1.03 vs. 0.84 ± 1.07, p = 0.03). XRCC1 Arg399Gln and GSTP1 Ile104Val polymorphisms may influence the CIHM status in the rectal mucosa of UC patients and may be substantially involved in UC-associated carcinogenesis.

Polymorphisms of GSTM1 and GSTT1, Sun Exposure and the Risk of Melanoma: A Case-control Study

Glutathione S-transferases (GSTs) are a family of enzymes that are known to play an important role in cellular protection against oxidative stress, including the oxidative stress caused by ultraviolet radiation. This study focused on the possible involvement of GSTM1 and GSTT1 polymorphisms in risk modulation of cutaneous melanoma. Within a case-control study, the presence of the null polymorphism at GSTM1 and GSTT1 was investigated in 188 cases of cutaneous melanoma and 152 controls. Information on socio-demographic characteristics, medical history, sun exposure and pigmentary characteristics were collected for all subjects. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI). An interaction was suggested between the GSTM1 and GSTT1 "null" genotype and episodes of sunburn in childhood OR of interaction (1.65, 95% CI (95% CI) 0.27-9.94). The risk of melanoma among the subset of participants who reported sunburns in childhood and who had both null variants, was nine (OR 9.16; 95% CI 1.18-70.9). The results suggest that subjects carrying both GSTM1 and GSTT1 null polymorphisms and experiencing sunburns in childhood have an extremely high risk of melanoma.

Opposite effects of GSTM1--and GSTT1: gene deletion variants on bone mineral density.

Oxidative stress is associated with osteoporosis. The glutathione S-transferases form the major detoxifying group of enzymes responsible for eliminating products of oxidative stress. We have therefore proposed GSTM1 and GSTT1 genes as candidates for studying the genetics of osteoporosis.The aim of the present study was to examine possible association of GSTM1 and GSTT1 gene deletion polymorphisms, alone or in combination, with bone mineral density at femoral neck (BMD_fn), lumbar spine (BMD_ls) and total hip (BMD_th) in Slovenian elderly women and men. GSTM1 and GSTT1 gene deletion polymorphisms in 712 elderly people were analyzed using the triplex PCR method for the presence of GSTM1 and GSTT1 gene segments. BMD_fn, BMD_ls and BMD_th were measured by the dual-energy X-ray absorptiometry (DEXA) method. Results were analyzed using univariate statistic model adjusted for sex, body mass index (BMI) and age.Our results showed the significant differences in BMD_th, BMD_ls and BMD_fn values (p = 0.031, 0.017 and 0.023, respectively) in subgroups of GSTT1 gene deletion polymorphism. For GSTM1 gene deletion polymorphism borderline significant association was found with BMD_ls (p = 0.100). Furthermore, subjects with homozygous deletion of GSTT1 gene showed higher BMD values on all measured skeletal sites and, in contrast, subjects with homozygous deletion of GSTM1 gene showed lower BMD values. Moreover, a gene-gene interaction study showed significant association of GSTM1-null and GSTT1-null polymorphisms with BMD_ls values (p = 0.044). Carriers with a combination of the presence of GSTT1 gene and the homozygous absence of GSTM1 gene fragment were associated with the lower BMD values at all skeletal sites.The significant association of combination of GSTT1 gene presence and homozygous absence of GSTM1 gene with BMD was demonstrated, suggesting that it could be used, if validated in other studies, as genetic marker for low BMD.

Assessment of cumulative evidence for the association between glutathione S-transferase polymorphisms and lung cancer: application of the Venice interim guidelines

There is an overwhelming abundance of genetic association studies available in the literature, which can often be collectively difficult to interpret. To address this issue, the Venice interim guidelines were established for determining the credibility of the cumulative evidence. The objective of this report is to evaluate the literature on the association of common glutathione S-transferase (GST) variants (GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphism) and lung cancer, and to assess the credibility of the associations using the newly proposed cumulative evidence guidelines. Information from the literature was enriched with an updated meta-analysis and a pooled analysis using data from the Genetic Susceptibility to Environmental Carcinogens database. There was a significant association between GSTM1 null and lung cancer for the meta-analysis (meta odds ratio=1.17, 95% confidence interval: 1.10-1.25) and pooled analysis (adjusted odds ratio=1.10, 95% confidence interval: 1.04-1.16), although substantial heterogeneity was present. No overall association between lung cancer and GSTT1 null or GSTP1 Ile105Val was found. When the Venice criteria was applied, cumulative evidence for all associations were considered 'weak', with the exception of East Asian carriers of the G allele of GSTP1 Ile105Val, which was graded as 'moderate' evidence. Despite the large amounts of studies, and several statistically significant summary estimates produced by meta-analyses, the application of the Venice criteria suggests extensive heterogeneity and susceptibility to bias for the studies on association of common genetic polymorphisms, such as with GST variants and lung cancer.

Glutathione S-transferase M1, T1, and P1 Polymorphisms and Ovarian Cancer Risk: A Meta-Analysis

Cytosolic glutathione S-transferase (GST) comprises multiple isoenzymes that catalyze reactions between glutathione and lipophilic compounds with electrophilic centers, resulting in the neutralization of toxic compounds, xenobiotics, and products of oxidative stress. Several studies have examined whether GST polymorphisms (GSTM1 null/present genotype, GSTT1 null/present genotype, and GSTP1 Ile105Val) represent risk factors for ovarian cancer, as they all may denote reduced enzyme activity. This meta-analysis aimed to examine the associations between the aforementioned polymorphisms and ovarian cancer risk. The MEDLINE database was searched up to September 2009 using the appropriate terms. Case-control studies with no mutually overlapping populations were selected. Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. Meta-regression with publication year was also performed. Eight studies regarding GSTM1 null polymorphism status (2357 cases and 3044 controls), 6 studies concerning GSTT1 null polymorphism (1923 cases and 2759 controls), and 3 studies on GSTP1 Ile105Val were included in the meta-analysis. The GSTM1 null genotype was not associated with an increased risk for ovarian cancer (pooled OR, 1.031; 95% confidence interval, 0.867-1.226; random effects). The GSTT1 null genotype was not associated with an increased ovarian cancer risk (pooled OR, 0.934; 95% confidence interval, 0.804-1.086; random effects); similarly, no significant associations were demonstrated for GSTP1 Ile105Val. The examined GSTM1, GSTT1, and GSTP1 genotype polymorphisms do not seem to confer any additional risk for ovarian cancer. Given that the studies included in this meta-analysis involve mainly white populations, these results cannot be extrapolated on other populations, and additional data are needed for future race-specific analyses.

Simultaneous Genotyping of GSTT1 and GSTM1 Null Polymorphisms by Melting Curve Analysis in Presence of SYBR Green I

Due to their ability to metabolize xenobiotics, glutathione S-transferases (GSTs) play an important role in cellular protection. GST family members mu (GSTM1) and theta (GSTT1) exhibit a common polymorphism that results in the complete deletion of the gene (null allele). Homozygous deletions, which result in the absence of the enzyme, are considered a risk factor for several diseases, including cancer. We report a simple, low cost, and high throughput assay for the simultaneous analysis of the GSTM1 and GSTT1 null polymorphisms in a single step. The assay is based on multiplex real-time PCR in the presence of SYBR Green I and genotype discrimination by melting curve analysis in a LightCycler. We have genotyped 792 samples to compare this new approach with conventional PCR followed by gel electrophoresis. Comparison of the methods gave a good agreement, with kappa values of 0.88 for GSTM1 and 0.64 for GSTT1. Reanalysis of discrepant samples indicated that absence of amplification of the larger GSTT1 fragment by conventional PCR accounted for most of the discrepancies. Moreover, the improved amplification efficiency of the real-time PCR results in a significant reduction of missing values. Due to its simplicity and low cost, this assay is well suited for the rapid analysis of GST-null genotypes in studies that involve large number of samples.

Genetic polymorphisms of glutathione S-transferase genes GSTM1, GSTT1 and risk of coronary heart disease

To clarify the role of glutathione S-transferases (GSTs; GSTM1 and GSTT1) status in susceptibility to coronary heart disease (CHD), a meta-analysis of published studies was performed. A total of 19 studies including 8020 cases and 11 501 controls were included in this meta-analysis. In a combined analysis, the relative risks for CHD of the GSTM1 null and GSTT1 null polymorphisms were 1.47 [95% confidence interval (CI): 1.08-2.01] and 1.26 (95% CI: 0.90-1.75), respectively. Three potential sources of heterogeneity including ethnicity, source of control and sample size of study were also assessed. However, no significant association was found in stratified analyses. By pooling data from eight studies (2909 cases and 3745 controls) that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for CHD [odds ratio (OR = 2.38, 95% CI: 1.03-5.48)] was detected for individuals with combined deletion mutations in both genes compared with positive genotypes. Results from the meta-analysis of five studies on GSTs stratified according to smoking status showed an increased risk for individuals with null genotype (OR = 2.21, 95% CI: 1.24-3.92 for GSTM1 and OR = 3.29, 95% CI: 1.49-7.26 for GSTT1) versus non-null genotypes. This meta-analysis suggests that the GSTM1 null genotype may slightly increase the risk of CHD and that interaction between unfavourable GSTs genotypes may exist.

GSTT1andGSTM1polymorphisms and myelodysplastic syndrome risk: a systematic review and meta‐analysis

Glutathione-S-transferace polymorphisms may make hematopoietic lineage cells susceptible to genotoxicity following exposure to heavy metals or benzene. We conducted a systematic review and meta-analysis to define the effect of GSTM1 and GSTT1 null polymorphisms on MDS risk. We searched the PubMed and SCOPUS databases to identify peer-reviewed published case-control studies investigating the association between GSTT1 and/or GSTM1 null genotypes and development of MDS. Between-study heterogeneity was assessed using Cochran's Q statistic and the I(2) statistic. Odds ratios from individual studies were pooled using fixed and random effects models. Thirteen studies were considered eligible for the GSTT1 meta-analysis (1471 cases, 1907 controls) and 10 were considered eligible for the GSTM1 meta-analysis (1161 cases, 1668 controls). For the GSTT1 polymorphism, there was moderate between study heterogeneity (p(Q) = 0.01; I(2) = 52.3%) and the null genotype was significantly associated with increased risk of MDS development, random effects OR = 1.43 (95% CI, 1.09-1.89); p = 0.01. For the GSTM1 polymorphisms there was moderate between-study heterogeneity (p = 0.07; I(2) = 43.1%) and the random effects OR = 1.02 (95% CI, 0.82-1.28) was non-significant (p = 0.85). The GSTT1 null genotype is a significant risk factor for MDS development. Gene-environment interactions need to be further explored.

PXII-24 Analysis of rhinovirus/enterovirus infections associated with paediatric hospitalisations

Due to their ability to metabolize xenobiotics, glutathione S-transferases (GSTs) play an important role in cellular protection. GST family members μ (GSTM1) and θ (GSTT1) exhibit a common polymorphism that results in the complete deletion of the gene (null allele). Homozygous deletions, which result in the absence of the enzyme, are considered a risk factor for several diseases, including cancer. We report a simple, low cost, and high throughput assay for the simultaneous analysis of the GSTM1 and GSTT1 null polymorphisms in a single step. The assay is based on multiplex real-time PCR in the presence of SYBR Green I and genotype discrimination by melting curve analysis in a LightCycler. We have genotyped 792 samples to compare this new approach with conventional PCR followed by gel electrophoresis. Comparison of the methods gave a good agreement, with κ values of 0.88 for GSTM1 and 0.64 for GSTT1. Reanalysis of discrepant samples indicated that absence of amplification of the larger GSTT1 fragment by conventional PCR accounted for most of the discrepancies. Moreover, the improved amplification efficiency of the real-time PCR results in a significant reduction of missing values. Due to its simplicity and low cost, this assay is well suited for the rapid analysis of GST-null genotypes in studies that involve large number of samples.