Glutathione S-transferase M1 polymorphism and esophageal cancer risk: An updated meta-analysis based on 37 studies

AIM: To evaluate the relationship between glutathione S-transferase M1（GSTM1） polymorphism and susceptibility to esophageal cancer（EC）.METHODS: A comprehensive search of the United States National Library of Medicine Pub Med database and the Elsevier, Springer, and China National Knowledge Infrastructure databases for all relevant studies was conducted using combinations of the following terms: "glutathione S-transferase M1", "GSTM1", "polymorphism", and "EC"（until November 1, 2014）. The statistical analysis was performed using the SAS software（v.9.1.3; SAS Institute, Cary, NC, United States） and the Review Manager software（v.5.0; Oxford, England）; crude odds ratios（ORs） with 95% confidence intervals（CIs） were used to assess the association between the GSTM1 null genotype and the risk of EC.RESULTS: A total of 37 studies involving 2236 EC cases and 3243 controls were included in this metaanalysis. We observed that the GSTM1 null genotype was a significant risk factor for EC in most populations(OR = 1.33, 95%CI: 1.12-1.57, P_{heterogeneity} < 0.000001, and I2 = 77.0%), particularly in the Asian population(OR = 1.53, 95%CI: 1.26-1.86, P_{heterogeneity}< 0.000001, and I2 = 77.0%), but not in the Caucasian population(OR = 1.02, 95%CI: 0.87-1.19, P_{heterogeneity} = 0.97, and I2 = 0%).CONCLUSION: The GSTM1 null polymorphism may be associated with an increased risk for EC in Asian but not Caucasian populations.     

谷胱甘肽S-转移酶M1、T1基因多态性与骨肉瘤易感性的Meta分析

目的 定量分析谷胱甘肽S-转移酶M1、T1(GSTM1、GSTT1)基因多态性与骨肉瘤易感性的关系.方法 检索PubMed、Embase、CNKI、维普、万方数据平台从建库到2013年2月的文献,对符合本实验纳入标准和排除标准的随机对照临床研究,运用RevMan5.0.0软件进行Meta分析.结果 共纳入3篇文献,累计样本量为914例,其中病例组202例,对照组712例.Meta分析见GSTTI位点的多态性与骨肉瘤易感性有显著关联,而GSTM1和骨肉瘤无显著关联(基因型GSTM1空白对GSTM1非空白:OR=1.21,95％ CI:0.86～1.70,P=0.27;基因型GSTT1空白对GSTT1非空白:OR=1.58,95％ CI:1.11 ～2.25,P=0.01).结论 GSTT1基因多态性与骨肉瘤相关,GSTT1空白基因型可能增加骨肉瘤的发病.     

An updating meta-analysis of the glutathione S-transferase T1 polymorphisms and colorectal cancer risk: a HuGE review

Introduction  

GSTT1 status has been extensively studied as a colorectal cancer risk factor. However, the results are inconsistent. To examine this controversy, we performed a meta-analysis to evaluate the relationship between GSTT1 polymorphism and colorectal cancer.     

Glutathione S-transferase M1 gene null genotype and gastric cancer risk in Taiwan

BACKGROUND/AIMS: Glutathione S-transferases (GST) are involved in the detoxification of many potential carcinogens and appear to play an important role in the protection from carcinogens. The association between different GSTM1 genotypes and gastric cancer risk is still controversial. The aim of this study was to determine the association between the GSTM1-null genotype and gastric cancer risk. METHODOLOGY: A retrospective, hospital-based case-control study of 123 primary gastric cancer patients and 121 healthy controls was conducted to evaluate the presence or absence of the GSTM1 gene from peripheral blood samples by a PCR-based method. RESULTS: The frequency of the GSTM1-null was 59.3% in the gastric cancer group and 45.5% in the control group. An increase in risk for gastric cancer was found among carriers of GSTM1-null genotype. The odds ratio (OR) was 1.752, with 95% confidence interval (CI) = 2.963 approximately 1.035. CONCLUSIONS: GSTM1-null polymorphism was associated with genetic susceptibility of gastric cancer in Taiwan.     

中国人谷胱甘肽-S-转移酶M1和T1基因多态性与原发性肝细胞癌的易感性

目的 探讨中国人群谷胱甘肽-S转移酶(GST) M1和T1基因多态性与原发性肝细胞癌遗传易感性的关系. 方法 通过检索PubMed和中国知网等数据库中的谷胱甘肽-S-转移酶基因多态性与原发性肝细胞癌的25篇文献,针对累计病例2788例和正常对照5548例进行Meta分析和关联性研究.对数据进行皮尔逊x2检验和异质性检验.结果 GSTM1、GSTT1空白基因型与原发性肝细胞癌易感性有统计学意义,病例对照的皮尔逊x2检验P值分别是1.8×10-11和4.6×10-11,比值比(OR值,95％ CI)分别为1.67 (1.39 ～ 2.01)和1.59 (1.29 ～ 1.96).GSTM1和GST1的交叉分析,两者均为空白基因型的OR值(95％ CI)为3.34 (2.23 ～ 5.00),明显高于GSTM1和GSTT1中有一个空白基因型的OR值,相对易感性更大;两者至少有一个空白基因型比两者均为非空白基因型能提高原发肝细胞癌发病的危险性,OR值(95％CI)是2.52 (1.87 ～ 3.38). 结论 谷胱甘肽-S-转移酶GSTM1、GSTT1的空白基因型分别是中国人群原发性肝细胞癌的易感因素,并且GSTM1和GSTT1两者联合对原发性肝癌有协同易感作用.     

XRCC1 polymorphisms and risk of colorectal cancer: a meta-analysis

Purpose  

Previous studies investigating the association between X-ray repair cross-complementation group 1 (XRCC1) polymorphisms and colorectal cancer (CRC) risk has provided inconsistent results. The aim of our study was to clarify the effects of XRCC1variants on CRC risk.     

Glutathione S-transferase M1 and P1 metabolic polymorphism and lung cancer predisposition

Individual susceptibility to different environmental agents is expected to be associated with alterations in metabolism of xenobiotics. Thus, genetic polymorphism of glutathione S-transferase (GST) can be recognized as a potential risk modifier in lung cancer development. The distribution of GSTM1 and GSTP1 genotypes was studied in a group of 138 diagnosed lung cancer patients and in 165 controls living in central Poland and RFLP-PCR technique was applied. The frequency of GSTM1 null genotype and GSTP1 Val single and duplicated alleles was similar among patients and controls. GSTM1 homozygous deletion was most prevalent in small-cell carcinoma groups (adjusted odds ratio (OR): 2.32, 95% confidence interval (CI): 0.98-5.52). In patients and controls, GSTM1A genotype was most frequent (34.1% vs. 37.0%). The estimated lung cancer risk for GSTM1 null, GSTP1 Ile/Val and GSTP1 Val/Val combined genotype was 1.44 (95% CI: 0.73-2.83), suggesting the absence of modifying effect of defective GSTM1 and GSTP1 alleles on lung cancer predisposition.     

Glutathione S-transferases M1, T1 genotypes and the risk of gastric cancer: a case-control study

AIM: Glutathione S-transferases (GSTs) are involved in the detoxification of many potential carcinogens and appear to play a critical role in the protection from the effects of carcinogens. The contribution of glutathione S-transferases M1 and T1 genotypes to susceptibility to the risk of gastric cancer and their interaction with cigarette smoking are still unclear. The aim of this study was to determine whether there was any relationship between genetic polymorphisms of GSTT1 and GSTT1 and gastric cancer. METHODS: A population based case-control study was carried out in a high-risk area, Changle County, Fujian Province, China. The epidemiological data were collected by a standard questionnaire and blood samples were obtained from 95 incidence gastric cancer cases and 94 healthy controls. A polymerase chain reaction method was used to detect the presence or absence of the GSTT1 and GSTT1 genes in genomic DNA. Logistic regression model was employed in the data analysis. RESULTS: An increase in risk for gastric cancer was found among carriers of GSTT1 null genotype. The adjusted odds ratio (OR) was 2.63 95% Confidence Interval (95% CI) 1.17-5.88, after controlling for age, gender, cigarette smoking, alcohol drinking, and fish sauce intake. The frequency of GSTT1 null genotype in cancer cases (43.16%) was not significantly different from that in controls (50.00%). However, the risk for gastric cancer in those with GSTT1 null and GSTT1 non-null genotype was significantly higher than in those with both GSTT1 and GSTT1 non-null genotype (OR = 2.77, 95% CI 1.15-6.77). Compared with those subjects who never smoked and had normal GSTT1 genotype, ORs were 1.60 (95% CI:0.62-4.19) for never smokers with GSTT1 null type, 2.33 (95% CI 0.88-6.28) for smokers with normal GSTT1, and 8.06 (95% CI 2.83-23.67) for smokers with GSTT1 null type. CONCLUSIONS: GSTT1 gene polymorphisms may be associated with genetic susceptibility of stomach cancer and may modulate tobacco-related carcinogenesis of gastric cancer.     

Glutathione S-transferase M1, T1, and P1 genotypes and rheumatoid arthritis

OBJECTIVE: To determine the effects of genetic polymorphisms of glutathione S-transferase (GST) M1, GSTT1, and GSTP on risk and severity of rheumatoid arthritis (RA) in a Korean population. METHODS: A total of 258 patients with RA and 400 disease-free controls were enrolled. GST genotypes were determined by RFLP-PCR. HLA-DRB 1 typing and further subtyping of all alleles was performed using sequence-specific oligonucleotide probe hybridization after PCR. Severity of RA among cases was assessed by Steinbrocker anatomical stage. Risk was assessed by calculating the age and sex adjusted odds ratio (OR) and 95% confidence intervals (CI). RESULTS: The OR for risk of RA with the GSTM1-null genotype was 1.40 (95% CI 1.02- 1.92, p = 0.04), and 1.86 (95% CI 1.12- 3.09, p = 0.005) among individuals without the shared epitope (SE). Among patients with RA, the OR for risk of severe RA for the GSTM1-null genotype was 2.45 (95% CI 1.04- 5.77, p = 0.02). No association was observed between the GSTT1 or GSTP1 genotypes and either risk or severity of RA. CONCLUSION: These results suggest that the deletion polymorphism of GSTM1 is associated with increased susceptibility for RA, particularly among individuals who are not carriers of the HLA-DRB 1 SE.     

GSTM1和T1基因多态性与AFT暴露和肝癌

AIM To explore the relationship between the level of aflatoxin-human serum albumin adducts and polymorphisms of glutathione S-transferase (GST) M1 and T1 and primary liver cancer (PLC).METHODS AFT-albumin adducts were measured by sandwich enzyme-linked immunosorbent assay (ELISA) and genotypes of GST M1 and T1 were determined by PCR.RESULTS Compared with those with non-null genotype of both GST T1 and M1, the odds ratio of developing PLC for those with null genotype of both GST T1 and M1 was 3.11 (95% confidence interval: 1.01-9.98; P=0.029). There was a dose-response relationship between serum level of AFT-albumin adducts and risk of PLC (χ2trend=15.42, P=0.0001). By combined genotype of GST T1 and M1, persons with null genotype of GST T1 and M1 were more likely to have higher AFT-albumin adduct level than those with other genotypes of GST T1 and M1 (F=4.57, P＜0.005). The biological gradients between serum AFT-albumin adducts level and PLC risk were observed to determine whether the persons were of null genotype of GST T1 or M1 or not. The levels of AFT-albumin adduct in Haimen residents in 1992 and 1996 were decreased significantly as against 1987 (F=6.35, P＜0.005).CONCLUSION Exposure to aflatoxin may still be one of risk factors leading to PLC endemic in Haimen population and those with null genotype of GST T1 and M1 may be at greater risk of developing PLC once they are exposed to aflatoxin.     

Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation

Hepatic venoocclusive disease (HVOD) in bone marrow transplantation (BMT) is attributed to toxicity of cytoreductive agents, especially busulfan and cyclophosphamide, in the conditioning therapy. Busulfan, as well as the metabolites of cyclophosphamide, are conjugated with glutathione (GSH), catalyzed by enzymes of the glutathione S-transferase (GST) family. To assess the impact of polymorphisms of the GST genes, GSTM1 and GSTT1, on the risk of HVOD, we evaluated 114 consecutive patients with beta-thalassemia major undergoing BMT. There was a significantly increased incidence of HVOD in patients with the GSTM1-null genotype compared with those with the GSTM1-positive genotype (46.5% vs 18.3%; P =.001). Pharmacokinetic analysis in these patients showed that the clearance of busulfan was higher and first-dose steady-state concentration was lower among those with HVOD (0.403 +/- 0.06 vs 0.33 +/- 0.071 L/h/kg, Student t test P value =.000 01; and 508 +/- 125 vs 656 +/- 255 ng/mL, t test P value =.001, respectively). We conclude that the GSTM1-null genotype predisposes to HVOD, and the sinusoidal endothelial cells and hepatocyte damage may be mediated by metabolites of busulfan through depletion of the cellular GSH pool.     

Association between esophageal cancer risk and EPHX1 polymorphisms:A meta-analysis

AIM:To summarize the relationship between p.Tyr113His and p.His139Arg polymorphisms in microsomal epoxide hydrolase(EPHX1)and risk for esophageal cancer(EC).METHODS:The MEDLINE/PubMed and EMBASE databases were searched for studies of the association between EPHX1 polymorphisms and EC risk that were published from the database inception date to April2013.A total of seven case-control studies,including seven on p.Tyr113His(cases,n=1118;controls,n=1823)and six on p.His139Arg(cases,n=861;controls,n=1571),were included in the meta-analysis.After data extraction by two investigators working independently,the meta-analyses were carried out with STATA 11.0 software.Pooled odds ratios and 95%CI were calculated using a fixed-effects model or a random-effects model,as appropriate.RESULTS:The pooled EPHX1 p.Tyr113His polymorphism data showed no significant association with EC in any of the genetic models(OR=1.00,95%CI:0.70-1.48 for Tyr/His vs Tyr/Tyr;OR=1.10,95%CI:0.77-1.57 for His/His vs Tyr/Tyr;OR=1.06,95%CI:0.75-1.49 for a dominant model;OR=1.09,95%CI:0.89-1.34 for a recessive model).Similar results were obtained from the p.His139Arg polymorphism analysis(Arg/His vs His/His:OR=1.02,95%CI:0.84-1.23;Arg/Arg vs His/His:OR=0.96,95%CI:0.60-1.54;OR=1.03,95%CI:0.78-1.37 for the dominant model;OR=0.97,95%CI:0.61-1.56 for the recessive model).Subgroup analyses for ethnicity,subtype of EC,and source of controls(population-based or hospital-based)showed trends that were consistent with the pooled analysis(reported above),with no significant associations found.CONCLUSION:This meta-analysis suggests that the p.Tyr113His and p.His139Arg polymorphisms in EPHX1may not be associated with EC development.     

Glutathione S-transferase M1 gene polymorphisms are associated with cardiac iron deposition in patients with beta-thalassemia major

Patients with beta-thalassemia (thal) major are subject to peroxidative tissue injury by iron overload. Glutathione S-transferases work as antioxidants, and their activity is determined genetically. In this study, we used multiplex polymerase chain reaction (m-PCR) to analyze polymorphisms of two endogenous antioxidant agents, glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1), and to determine their roles in 41 patients with beta-thal major. Our results showed that the GSTM1 and GSTT1 null genotypes were not associated with any incidence of endocrine dysfunction (including diabetes mellitus, hypogonadism, hypothyroidism, and growth hormone deficiency), liver function, or impaired left ventricular ejection fraction (LVEF). The GSTM1 null genotype, but not the GSTT1 null genotype, was associated with a decreased signal intensity ratio on cardiac magnetic resonance imaging (MRI). Our results suggest that genetic variations of the GSTM1 enzyme are associated with cardiac iron deposition in patients with beta-thal major.     

Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia

Interindividual differences in susceptibility to hematologic malignancies may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs) have been implicated as susceptibility genes in this context for a number of cancers. The aim of this study was to examine whether polymorphic variation in GSTs confers susceptibility to chronic lymphocytic leukemia (CLL). GSTM1, GSTT1, and GSTP1 genotypes were determined in 138 patients and 280 healthy individuals. The frequency of both GSTM1 and GSTT1 null genotypes and the GSTP1-Ile allele was higher in cases than in controls. There was evidence of a trend in increasing risk with the number of putative "high-risk" alleles of the GST family carried (P =.04). The risk of CLL associated with possession of all 3 "high-risk" genotypes was increased 2.8-fold (OR = 2.8, 95% confidence interval: 1.1-6.9). Our findings suggest that heritable GST status may influence the risk of developing CLL.