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Research Article

Association between Glutathione S-Transferase T1 Null Genotype and Gastric Cancer Risk: A Meta-Analysis of 48 Studies

  • Weiyuan Ma,

    Affiliation: Department of Dermatology, Qilu Hospital, Shandong University, Jinan, China

    X
  • Le Zhuang,

    Affiliation: Department of Dermatology, Qilu Hospital, Shandong University, Jinan, China

    X
  • Bo Han mail,

    doctor19cn@yahoo.cn

    Affiliation: Institute of Pathology, School of Medicine, Shandong University, Jinan, China

    X
  • Bo Tang

    Affiliation: Department of Oncology, Southwest Hospital, the Third Military Medical University, Chongqing, China

    X
  • Published: April 09, 2013
  • DOI: 10.1371/journal.pone.0060833

Abstract

Background

Glutathione S-transferases (GSTs) have proved to be involved in the detoxifying several carcinogens and may play an important role in carcinogenesis of cancer. Previous studies on the association between Glutathione S-transferase T1 (GSTT1) polymorphism and gastric cancer risk reported inconclusive results. To clarify the possible association, we conducted a meta-analysis of eligible studies.

Methods

We searched in the Pubmed, Embase, and Wangfang Medicine databases for studies assessing the association between GSTT1 null genotype and gastric cancer risk. The pooled odds ratio (OR) and its 95% confidence interval (95%CI) was calculated to assess the strength of the association. A total of 48 studies with a total of 24,440 individuals were ultimately eligible for meta-analysis.

Results

Overall, GSTT1 null genotype was significantly associated with increased risk of gastric cancer (Random-effect OR = 1.23, 95%CI 1.13–1.35, P OR <0.001, I2 = 45.5%). Significant association was also found in Caucasians, East Asians, and Indians (P Caucasians = 0.010; P East Asians = 0.003; P Indians = 0.017). After adjusting for other confounding variables, GSTT1 null genotype was also significantly associated with increased risk of gastric cancer (Random-effect OR = 1.43, 95%CI 1.20–1.71, P OR <0.001, I2 = 48.1%).

Conclusion

The meta-analysis provides strong evidence for the significant association between GSTT1 null genotype and increased risk of gastric cancer.

Introduction

Gastric cancer is the second most frequent cause of cancer death worldwide, and the global burden of gastric cancer continues to increase largely in economically developing countries [1], [2]. Though there are many achievements in the treatment of gastric cancer in terms of the combined therapy, novel anti-tumor agents and personalized treatments the, the survival of gastric cancer patients is still poor [3], [4]. Currently, the prevention intervention is regarded as the best option to reduce the high rated of gastric cancer mortality. Effective prevention strategies should be based on specific risk profiles of gastric cancer, including Helicobacter pylori, environmental factors, and the host genetic polymorphisms [2]. In addition, genetic susceptibility to gastric cancer has been a research focus, and identifications of risk factors for gastric cancer are important for us to understand the biology of gastric carcinogenesis and develop some effective interventions. Glutathione S-transferases (GSTs) have proved to be involved in the detoxifying several carcinogens and may play an important role in carcinogenesis of cancer [5][7]. The theta class of GSTs is encoded by the Glutathione S-transferase T1 (GSTT1) gene located on the long arm of chromosome 22 (22q11.23), and the homozygous deletion (null genotype) of GSTT1 gene causes complete absence of GST enzymes activity [8]. Previous studies on the association between Glutathione S-transferase T1 (GSTT1) polymorphism and gastric cancer risk reported inconclusive results [9][48]. To clarify the possible association, we conducted a meta-analysis of eligible studies by searching three electronic databases.

Methods

Identification of Eligible Studies

We searched in the Pubmed, Embase, and Wangfang Medicine databases for studies assessing the association between GSTT1 null genotype and gastric cancer risk. The literature strategy used the following keywords: (‘‘Glutathione S-transferase T1’’, ‘‘GSTT1’’ or ‘‘GSTT’’) and (‘‘gastric cancer’’, ‘‘gastric carcinoma’’, ‘‘stomach cancer’’ or ‘‘stomach carcinoma’’). The references of the retrieved articles were also hand searched at the same time to identify additional published articles. The references of eligible studies and relevant reviews were also checked for other literature not indexed into common databases. There was no language restriction applied in this meta-analysis. The inclusion criteria of eligible studies were as following: (1) Case-control study; (2) The cases were patients with histopathologicaly proved gastric cancer; (3) The controls were gastric cancer-free individuals; (4) Reported the frequencies of GSTT1 polymorphism in both cases and controls or the odds ratio (OR) and its 95% confidence interval (95%CI) of the association between GSTT1 null genotype and gastric cancer risk. Family-based studies and studies containing overlapping data were all excluded.

Data Extraction

Relevant data were extracted from all the eligible studies independently by two reviewers, and disagreements were settled by discussion and the consensus among all reviewers. The main data extracted from the eligible studies were as following: the first author, year of publication, country, ethnicity, characteristics of cases, characteristics of controls, total numbers of cases and controls, the genotype frequency of GSTT1 polymorphism, adjusted variables, and adjusted ORs and corresponding 95%CIs. Different ethnicities were mainly categorized as Caucasians, East Asians, Indians, Africans, and Mixed. If a study did not specify the ethnicity or if it was not possible to separate participants according to such phenotype, the group was termed ‘‘mixed’’. For studies including subjects of different ethnic populations, data were collected separately whenever possible and recognized as an independent study.

Quality Assessment

Quality of eligible studies in present meta-analysis was assessed using the Newcastle Ottawa scale (NOS) as recommended by the Cochrane Non-Randomized Studies Methods Working Group. This instrument was developed to assess the quality of nonrandomized studies, specifically cohort and case-control studies [49]. This scale awards a maximum of nine stars to each study: four stars for the adequate selection of cases and controls, two stars for comparability of cases and controls on the basis of the design and analysis, and three stars for the adequate ascertainment of the exposure in both the case and control groups. Given the variability in quality of eligible studies found on our initial literature search, we considered studies that met 5 or more of the NOS criteria as high quality.

Statistical Methods

The strength of the association between GSTT1 null genotype and gastric cancer risk was assessed by calculating the pooled OR with its corresponding 95%CI, and the significance of the pooled OR was determined by the Z-test. To assess the heterogeneity among the included studies more precisely, both the chi-square based Q statistic test (Cochran's Q statistic) to test for heterogeneity and the I2 statistic to quantify the proportion of the total variation due to heterogeneity were calculated [50], [51]. If obvious heterogeneity existed among those included studies (P Q statistic <0.05), the random-effect model (DerSimonian and Laird method) was used to pool the results [52]. When there was no obvious heterogeneity existed among those included studies (P Q statistic >0.05), the fixed-effect model (Mantel-Haenszel’s method) was used to pool the results [53]. Subgroup analyses were performed by ethnicity, the adjusted status of the estimates, and the quality of studies. The kinds of ethnicity were mainly defined as Caucasians, East Asians, and Indians. Publication bias was investigated with the funnel plot and its asymmetry suggested risk of publication bias. The asymmetry of funnel plots was further assessed by both the Begg’s test and the Egger’s linear regression test [54], [55]. All statistical tests for this meta-analysis were performed with STATA (version 11.0; Stata Corporation, College Station, TX). A P value less than 0.05 was considered statistically significant, and all the P values were two sided.

Results

Studies Selection and Characteristics of Eligible Studies

There were 107 relevant abstracts identified by the searching words, and 48 studies were firstly excluded after the careful review of the abstracts, leaving 59 studies for full publication review (Figure S1). Of those 59 studies, 11 studies were excluded (5 for containing overlapping data, 2 for reviews, 2 for without adequate data, and 2 for on GSTM1 polymorphism). Therefore, a total of 48 studies with a total of 24,440 individuals were ultimately eligible for meta-analysis [9][48], [56][63]. The main characteristics of those 48 studies were presented in Table 1 (Table 1). There were 25 studies from East Asians [12], [13], [16], [19][21], [23], [27][30], [33], [34], [37], [38], [44], [48], [56][63], 16 ones from Caucasians [9][11], [14], [15], [17], [22], [25], [26], [31], [32], [35], [36], [39], [43], [47], 5 from Indians [24], [41], [42], [45], [46], and the left two from the others populations [18], [40]. There were 18 studies reporting the adjusted ORs, and 5 reporting the ORs adjusted for H. pylori infection (Table 1). Multiplex-polymerase chain reaction (Multiplex-PCR) was the most common genotype method of GSTT1 polymorphism (Table 1). According to the NOS scale, there were 43 studies with high quality, and 5 with low quality (Table 1).

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Table 1. Characteristics of 48 eligible studies in this meta-analysis.

doi:10.1371/journal.pone.0060833.t001

Meta-analysis

There was some heterogeneity among those 48 studies (I2 = 45.5%; P Q statistic <0.001), thus the random-effect model (DerSimonian and Laird method) was used to pool the results (Table 2). Overall, GSTT1 null genotype was significantly associated with increased risk of gastric cancer (Random-effect OR = 1.23, 95%CI 1.13–1.35, P OR <0.001) (Figure 1, Table 2). In the subgroup analyses by ethnicity (Caucasians, East Asians, Africans, and Indians), there was an significant association between GSTT1 null genotype and increased risk of gastric cancer in Caucasians (Random-effect OR = 1.30, 95%CI 1.06–1.59, P OR = 0.010), East Asians (Random-effect OR = 1.16, 95%CI 1.05–1.29, P OR = 0.003), and Indians (Fixed-effect OR = 1.37, 95%CI 1.06–1.77, P OR = 0.017) (Table 2). In the subgroup analysis of studies with high quality, there was an obvious association between GSTT1 null genotype and increased risk of gastric cancer (Random-effect OR = 1.23, 95%CI 1.12–1.35, P OR <0.001) (Table 2).

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Figure 1. Meta-analysis of the association between GSTT1 null genotype and gastric cancer risk.

(48 studies, Random-effect model).

doi:10.1371/journal.pone.0060833.g001
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Table 2. Meta-analysis of the association between GSTT1 null genotype and gastric cancer risk.

doi:10.1371/journal.pone.0060833.t002

After adjusting for other confounding variables, GSTT1 null genotype was still significantly associated with increased risk of gastric cancer (Random-effect OR = 1.43, 95%CI 1.20–1.71, P OR <0.001, I2 = 48.1%) (Figure 2, Table 2). Meta-analysis of ORs adjusted for H.pylori infection also showed a significant association between GSTT1 null genotype and increased risk of gastric cancer (OR = 1.34, 95%CI 1.09–1.64, P = 0.006) (Table 2).

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Figure 2. Assessment of the association between GSTT1 null genotype and gastric cancer risk by using adjusted estimates.

(18 studies, Random-effect model).

doi:10.1371/journal.pone.0060833.g002

Publication Bias

In the meta-analysis of total 48 studies, the shape of the funnel plot did not reveal any evidence of obvious asymmetry (Figure 3). In addition, both the Begg’s test and Egger’s test provided statistical evidence for the symmetry of the funnel plot (P Begg = 0.333; P Egger = 0.145). Therefore, there was no obvious risk of publication bias in the present meta-analysis.

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Figure 3. Funnel plots did not reveal any evidence of obvious asymmetry in the overall meta-analysis.

doi:10.1371/journal.pone.0060833.g003

Discussion

Previous studies on the association between GSTT1 polymorphism and gastric cancer risk reported inconclusive results. To clarify the possible association, we conducted a meta-analysis of a total of 48 studies with 24,440 individuals [9][48], [56][63]. Overall, GSTT1 null genotype was significantly associated with increased risk of gastric cancer (Random-effect OR = 1.23, 95%CI 1.13–1.35, P OR <0.001, I2 = 45.5%). Significant association was also found in Caucasians, East Asians, and Indians (P Caucasians = 0.010; P East Asians = 0.003; P Indians = 0.017). After adjusting for other confounding variables, GSTT1 null genotype was also significantly associated with increased risk of gastric cancer (Random-effect OR = 1.43, 95%CI 1.20–1.71, P OR <0.001, I2 = 48.1%). Therefore, the meta-analysis provides strong evidence for the significant association between GSTT1 null genotype and increased risk of gastric cancer.

Endogenous products and environmental factors could result in the production of reactive oxygen species (ROS) and nitrogen metabolites causing cell injury and genetic instability [64], [65]. GSTs are the most important family of phase II isoenzymes known to detoxify a variety of electrophilic compounds, including carcinogens, chemotherapeutic drugs, environmental toxins, and DNA products generated by reactive oxygen species damage to intracellular molecules, chiefly by conjugating them with glutathione [66]. GSTs play a major role in cellular antimutagen and antioxidant defense mechanisms, and these enzymes may regulate pathways that prevent damage from several carcinogens. GSTs have proved to be involved in the detoxifying several carcinogens and may play an important role in carcinogenesis of cancer [66]. These enzymes also play a crucial role in protection of DNA from oxidative damage by ROS [66]. Therefore, the polymorphisms in GSTT1 gene can causes the dysfunction of GSTs and result in less protection of DNA from damages caused by ROS [8]. The null genotype of GSTT1 gene can cause the complete absence of GST enzymes activity, which may increase the host’s susceptibility to DNA damage and some cancers. Thus, there is obvious biochemical evidence for the relationship of GSTT1 polymorphism with cancer risk [8].

Nowadays, a great number of studies have been published to assess the association between GSTT1 null genotype and risks of some cancers. Currently, GSTT1 null genotype has been proven to be associated with risks of some cancers, such as lung cancer and hepatocellular carcinoma [67], [68]. The significant associations further suggest that GSTT1 null genotype can affect the individual susceptibility to common malignancies, and has important roles the carcinogenesis of some cancers.

A meta-analysis in 2010 was performed to assess the association between GSTT1 null genotype and risk of gastric cancer by including thirty-six studies with 4,357 gastric cancer cases and 9,796 controls [69]. The previous meta-analysis concluded that GSTT1 gene polymorphism may be not associated with increased gastric cancer risk among Europeans, Americans, and East Asians, and more large-scale studies based on the same racial group were needed [69]. In the present meta-analysis, we performed a updated literature search and included 12 new studies, and the total sample size (24, 440 individuals) was nearly two times of that from the previous meta-analysis. To the best our knowledge, our meta-analysis is the largest meta-analysis of the association between GSTT1 null genotype and gastric cancer risk. Therefore, compared with the previous meta-analysis, the present meta-analysis has greater statistical power and can provide a more precise assessment on the association between GSTT1 null genotype and gastric cancer risk.

Some limitations of this study should be acknowledged. Firstly, there was some heterogeneity in both the meta-analysis of total 48 studies and the subgroup analyses by ethnicity. The differences from the selection criteria of cases or controls, the adjusted confounding variables, and the ethnicity result in the heterogeneity. Secondly, most studies in the meta-analysis were retrospective design which could suffer more risk of bias owing to the methodological deficiency of retrospective studies. Those there was no obvious risk of publication bias in the present meta-analysis, the risks of other potential bias were unable to be excluded. Some misclassification bias was possible because most studies could not exclude latent gastric cancer cases in the control group. Therefore, more studies with prospective design and low risk of other bias are needed to provide a more precise estimate of the association between GSTT1 null genotype and gastric cancer risk. Finally, we could not address gene-gene and gene-environmental interactions in the association between GSTT1 null genotype and gastric cancer risk. The latter may be important for genes that code proteins with detoxifying function, but would require detailed information on exposures to various potential carcinogens and individual-level data and would be most meaningful only for common exposures that are found to be strong risk factors for the disease. Thus, more studies analyses on the gene-gene and gene-environmental interactions are needed.

In conclusion, the meta-analysis provides strong evidence for the significant association between GSTT1 null genotype and increased risk of gastric cancer. In addition, more studies with well design are needed to further assess the possible gene-gene and gene-environmental interactions in the association between GSTT1 null genotype and gastric cancer risk.

Supporting Information

Figure S1.

Flow diagram in the meta-analysis of the association between GSTT1 null genotype and gastric cancer risk.

doi:10.1371/journal.pone.0060833.s001

(TIF)

Acknowledgments

We thank all the people who give technical support and useful discussion of the paper.

Author Contributions

Conceived and designed the experiments: WM LZ BH. Performed the experiments: WM LZ BH BT. Analyzed the data: WM BH BT. Contributed reagents/materials/analysis tools: WM LZ BH. Wrote the paper: WM BH BT.

References

  1. 1. Jemal A, Bray F (2011) Center MM, Ferlay J, Ward E, et al (2011) Global cancer statistics. CA Cancer J Clin 61 (2): 69–90. doi: 10.3322/caac.20107
  2. 2. Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ (2009) Gastric cancer. Lancet 374 (9688): 477–90. doi: 10.3322/caac.20107
  3. 3. Soerjomataram I, Lortet-Tieulent J, Parkin DM, Ferlay J, Mathers C, et al.. (2012) Global burden of cancer in 2008: a systematic analysis of disability-adjusted life-years in 12 world regions. Lancet.
  4. 4. Qiu MZ, Wang ZQ, Luo HY, Zhang DS, Zhou ZW, et al. (2011) Prognostic analysis in node-negative gastric cancer patients in China. Tumour Biol 32 (3): 489–92.
  5. 5. Oakley A (2011) Glutathione transferases: a structural perspective. Drug Metab Rev 43 (2): 138–51.
  6. 6. Strange RC, Spiteri MA, Ramachandran S, Fryer AA (2001) Glutathione-S-transferase family of enzymes. Mutat Res 482 (1–2): 21–6.
  7. 7. Bhardwaj R, Sharma PK, Jadon SP, Varshney R (2012) A combination of 2-deoxy-D-glucose and 6-aminonicotinamide induces cell cycle arrest and apoptosis selectively in irradiated human malignant cells. Tumour Biol 33 (4): 1021–30.
  8. 8. Hayes JD, Strange RC (2000) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 61 (3): 154–66. doi: 10.1159/000028396
  9. 9. Agudo A, Sala N, Pera G, Capella G, Berenguer A, et al. (2006) Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 15 (12): 2427–34. doi: 10.1159/000028396
  10. 10. Al-Moundhri MS, Alkindy M, Al-Nabhani M, Al-Bahrani B, Burney IA, et al. (2009) Combined polymorphism analysis of glutathione S-transferase M1/G1 and interleukin-1B (IL-1B)/interleukin 1-receptor antagonist (IL-1RN) and gastric cancer risk in an Omani Arab Population. J Clin Gastroenterol 43 (2): 152–6. doi: 10.1159/000028396
  11. 11. Boccia S, Sayed-Tabatabaei FA, Persiani R, Gianfagna F, Rausei S, et al.. (2007) Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population. BMC Cancer 7 206.
  12. 12. Cai L, Yu SZ, Zhang ZF (2001) Glutathione S-transferases M1, T1 genotypes and the risk of gastric cancer: a case-control study. World J Gastroenterol 7 (4): 506–9. doi: 10.1159/000028396
  13. 13. Choi SC, Yun KJ, Kim TH, Kim HJ, Park SG, et al. (2003) Prognostic potential of glutathione S-transferase M1 and T1 null genotypes for gastric cancer progression. Cancer Lett 195 (2): 169–75. doi: 10.1016/s0304-3835(03)00158-7
  14. 14. Colombo J, Rossit AR, Caetano A, Borim AA, Wornrath D, et al. (2004) GSTT1, GSTM1 and CYP2E1 genetic polymorphisms in gastric cancer and chronic gastritis in a Brazilian population. World J Gastroenterol 10 (9): 1240–5. doi: 10.1016/s0304-3835(03)00158-7
  15. 15. Deakin M, Elder J, Hendrickse C, Peckham D, Baldwin D, et al. (1996) Glutathione S-transferase GSTT1 genotypes and susceptibility to cancer: studies of interactions with GSTM1 in lung, oral, gastric and colorectal cancers. Carcinogenesis 17 (4): 881–4. doi: 10.1016/s0304-3835(03)00158-7
  16. 16. Gao CM, Takezaki T, Wu JZ, Li ZY, Liu YT, et al. (2002) Glutathione-S-transferases M1 (GSTM1) and GSTT1 genotype, smoking, consumption of alcohol and tea and risk of esophageal and stomach cancers: a case-control study of a high-incidence area in Jiangsu Province, China. Cancer Lett 188 (1–2): 95–102. doi: 10.1016/s0304-3835(03)00158-7
  17. 17. Garcia-Gonzalez MA, Quintero E, Bujanda L, Nicolas D, Benito R, et al. (2012) Relevance of GSTM1, GSTT1, and GSTP1 gene polymorphisms to gastric cancer susceptibility and phenotype. Mutagenesis 27 (6): 771–7. doi: 10.1016/s0304-3835(03)00158-7
  18. 18. Gonzalez A, Ramirez V, Cuenca P, Sierra R (2004) [Polymorphisms in detoxification genes CYP1A1, CYP2E1, GSTT1 and GSTM1 in gastric cancer susceptibility]. Rev Biol Trop 52 (3): 591–600.
  19. 19. Hong SH, Kim JW, Kim HG, Park IK, Ryoo JW, et al. (2006) [Glutathione S-transferases (GSTM1, GSTT1 and GSTP1) and N-acetyltransferase 2 polymorphisms and the risk of gastric cancer]. J Prev Med Public Health 39 (2): 135–40.
  20. 20. Jing C, Huang ZJ, Duan YQ, Wang PH, Zhang R, et al. (2012) Glulathione-S-transferases gene polymorphism in prediction of gastric cancer risk by smoking and Helicobacter pylori infection status. Asian Pac J Cancer Prev 13 (7): 3325–8.
  21. 21. Katoh T, Nagata N, Kuroda Y, Itoh H, Kawahara A, et al. (1996) Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. Carcinogenesis 17 (9): 1855–9.
  22. 22. Lan Q, Chow WH, Lissowska J, Hein DW, Buetow K, et al. (2001) Glutathione S-transferase genotypes and stomach cancer in a population-based case-control study in Warsaw, Poland. Pharmacogenetics 11 (8): 655–61.
  23. 23. Luo YP, Chen HC, Khan MA, Chen FZ, Wan XX, et al. (2011) Genetic polymorphisms of metabolic enzymes-CYP1A1, CYP2D6, GSTM1, and GSTT1, and gastric carcinoma susceptibility. Tumour Biol 32 (1): 215–22. doi: 10.1016/s1055-7903(02)00245-2
  24. 24. Malik MA, Upadhyay R, Mittal RD, Zargar SA, Modi DR, et al. (2009) Role of xenobiotic-metabolizing enzyme gene polymorphisms and interactions with environmental factors in susceptibility to gastric cancer in Kashmir Valley. J Gastrointest Cancer 40 (1–2): 26–32. doi: 10.1016/s1055-7903(02)00245-2
  25. 25. Martinez C, Martin F, Fernandez JM, Garcia-Martin E, Sastre J, et al. (2006) Glutathione S-transferases mu 1, theta 1, pi 1, alpha 1 and mu 3 genetic polymorphisms and the risk of colorectal and gastric cancers in humans. Pharmacogenomics 7 (5): 711–8. doi: 10.1016/s1055-7903(02)00245-2
  26. 26. Masoudi M, Saadat I, Omidvari S, Saadat M (2009) Genetic polymorphisms of GSTO2, GSTM1, and GSTT1 and risk of gastric cancer. Mol Biol Rep 36 (4): 781–4. doi: 10.1016/s1055-7903(02)00245-2
  27. 27. Moy KA, Yuan JM, Chung FL, Wang XL, Van Den Berg D, et al. (2009) Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms and gastric cancer risk: a prospective study of men in Shanghai, China. Int J Cancer 125 (11): 2652–9. doi: 10.1016/s1055-7903(02)00245-2
  28. 28. Mu LN, Lu QY, Yu SZ, Jiang QW, Cao W, et al. (2005) Green tea drinking and multigenetic index on the risk of stomach cancer in a Chinese population. Int J Cancer 116 (6): 972–83. doi: 10.1002/ijc.21137
  29. 29. Nan HM, Park JW, Song YJ, Yun HY, Park JS, et al. (2005) Kimchi and soybean pastes are risk factors of gastric cancer. World J Gastroenterol 11 (21): 3175–81. doi: 10.1002/ijc.21137
  30. 30. Nguyen TV, Janssen MJ, van Oijen MG, Bergevoet SM, te Morsche RH, et al. (2010) Genetic polymorphisms in GSTA1, GSTP1, GSTT1, and GSTM1 and gastric cancer risk in a Vietnamese population. Oncol Res 18 (7): 349–55. doi: 10.1002/ijc.21137
  31. 31. Palli D, Polidoro S, D'Errico M, Saieva C, Guarrera S, et al. (2010) Polymorphic DNA repair and metabolic genes: a multigenic study on gastric cancer. Mutagenesis 25 (6): 569–75. doi: 10.1002/ijc.21137
  32. 32. Palli D, Saieva C, Gemma S, Masala G, Gomez-Miguel MJ, et al. (2005) GSTT1 and GSTM1 gene polymorphisms and gastric cancer in a high-risk italian population. Int J Cancer 115 (2): 284–9. doi: 10.1002/ijc.21137
  33. 33. Piao JM, Shin MH, Kweon SS, Kim HN, Choi JS, et al. (2009) Glutathione-S-transferase (GSTM1, GSTT1) and the risk of gastrointestinal cancer in a Korean population. World J Gastroenterol 15 (45): 5716–21. doi: 10.3748/wjg.15.5716
  34. 34. Roth MJ, Abnet CC, Johnson LL, Mark SD, Dong ZW, et al. (2004) Polymorphic variation of Cyp1A1 is associated with the risk of gastric cardia cancer: a prospective case-cohort study of cytochrome P-450 1A1 and GST enzymes. Cancer Causes Control 15 (10): 1077–83. doi: 10.3748/wjg.15.5716
  35. 35. Ruzzo A, Canestrari E, Maltese P, Pizzagalli F, Graziano F, et al. (2007) Polymorphisms in genes involved in DNA repair and metabolism of xenobiotics in individual susceptibility to sporadic diffuse gastric cancer. Clin Chem Lab Med 45 (7): 822–8. doi: 10.3748/wjg.15.5716
  36. 36. Saadat I, Saadat M (2001) Glutathione S-transferase M1 and T1 null genotypes and the risk of gastric and colorectal cancers. Cancer Lett 169 (1): 21–6. doi: 10.3748/wjg.15.5716
  37. 37. Setiawan VW, Zhang ZF, Yu GP, Li YL, Lu ML, et al. (2000) GSTT1 and GSTM1 null genotypes and the risk of gastric cancer: a case-control study in a Chinese population. Cancer Epidemiol Biomarkers Prev 9 (1): 73–80. doi: 10.3748/wjg.15.5716
  38. 38. Setiawan VW, Zhang ZF, Yu GP, Lu QY, Li YL, et al. (2001) GSTP1 polymorphisms and gastric cancer in a high-risk Chinese population. Cancer Causes Control 12 (8): 673–81.
  39. 39. Tamer L, Ates NA, Ates C, Ercan B, Elipek T, et al. (2005) Glutathione S-transferase M1, T1 and P1 genetic polymorphisms, cigarette smoking and gastric cancer risk. Cell Biochem Funct 23 (4): 267–72.
  40. 40. Torres MM, Acosta CP, Sicard DM, Groot de Restrepo H (2004) [Genetic susceptibility and risk of gastric cancer in a human population of Cauca, Colombia]. Biomedica 24 (2): 153–62.
  41. 41. Tripathi S, Ghoshal U, Ghoshal UC, Mittal B, Krishnani N, et al. (2008) Gastric carcinogenesis: Possible role of polymorphisms of GSTM1, GSTT1, and GSTP1 genes. Scand J Gastroenterol 43 (4): 431–9.
  42. 42. Tripathi S, Ghoshal U, Mittal B, Chourasia D, Kumar S, et al. (2011) Association between gastric mucosal glutathione-S-transferase activity, glutathione-S-transferase gene polymorphisms and Helicobacter pylori infection in gastric cancer. Indian J Gastroenterol 30 (6): 257–63.
  43. 43. Wideroff L, Vaughan TL, Farin FM, Gammon MD, Risch H, et al. (2007) GST, NAT1, CYP1A1 polymorphisms and risk of esophageal and gastric adenocarcinomas. Cancer Detect Prev 31 (3): 233–6.
  44. 44. Wu MS, Chen CJ, Lin MT, Wang HP, Shun CT, et al. (2002) Genetic polymorphisms of cytochrome p450 2E1, glutathione S-transferase M1 and T1, and susceptibility to gastric carcinoma in Taiwan. Int J Colorectal Dis 17 (5): 338–43.
  45. 45. Yadav D, Chandra R, Saxena R, Agarwal D, Agarwal M, et al. (2011) Glutathione-S-transferase M1 and T1 genes and gastric cancer: a case control study in North Indian population. Gene 487 (2): 166–9.
  46. 46. Yadav DS, Devi TR, Ihsan R, Mishra AK, Kaushal M, et al. (2010) Polymorphisms of glutathione-S-transferase genes and the risk of aerodigestive tract cancers in the Northeast Indian population. Genet Test Mol Biomarkers 14 (5): 715–23.
  47. 47. Zendehdel K, Bahmanyar S, McCarthy S, Nyren O, Andersson B, et al. (2009) Genetic polymorphisms of glutathione S-transferase genes GSTP1, GSTM1, and GSTT1 and risk of esophageal and gastric cardia cancers. Cancer Causes Control 20 (10): 2031–8.
  48. 48. Zhang AP, Liu BH, Wang L, Gao Y, Li F, et al. (2011) Glutathione S-transferase gene polymorphisms and risk of gastric cancer in a Chinese population. Asian Pac J Cancer Prev 12 (12): 3421–5.
  49. 49. Wells G, Shea B, O’Connell D, Peterson J, Welch V, et al.. (2012) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Health Research Institute Web site.
  50. 50. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327 (7414): 557–60.
  51. 51. Cochran WG (1954) The combination of estimates from different experiments. Biometrics 10 (1): 101–29.
  52. 52. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7 (3): 177–88.
  53. 53. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22 (4): 719–48.
  54. 54. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50 (4): 1088–101.
  55. 55. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315 (7109): 629–34.
  56. 56. Shen J, Wang RT, Xing HX, Hao B (2002) Case-control study of the polymorphisms of phase I and phase II metabolic genes and stomach cancer susceptibility (Article in Chinese). Zhong Liu Za Zhi 22 (9–13).
  57. 57. Ye M, Liu J, Deng C (2003) Relationship between xenobioticmetabolizing enzyme gene polymorphisms and genetic susceptibility of gastric cancer. World Chin J Digestol 11 (9): 1314–7.
  58. 58. Zheng T, Zheng Q, Gong F, Xie Y, Wang X (2002) Gene deletion polymorphisms of GSTT1 and GSTM1 and susceptibility to stomach neoplasm. Shi Yong Zhong Liu Za Zhi 17 (3): 155–7.
  59. 59. Shen X, Pu Y, Zhang J, Zhu L (2005) The relationship between Glutathione enzyme M1, T1 genetic type and wine and tobacco habit and gastric cancer susceptibility. J ENVIRON OCCUP MED 22 (4): 325–9.
  60. 60. Li P, Feng J, Yan Y, Fu G, Shen X (2011) Screening of Susceptibility Genes and Multi-gene Risk Analysis in Gastric Cancer. J ENVIRON OCCUP MED 28 (9): 1217–9.
  61. 61. Shen XB, Zhang J, Zhu LJ, Pu YP (2004) Relationship between glutathione S-transferase M1, T1 genetic polymorphisms, smoking and alcohol consumption and susceptibility to stomach cancer (Article in Chinese). Huan Jing Yu Jian Kang Za Zhi 24 210–4.
  62. 62. Xie S, Huang X, Lu Y (2008) Glutathione sulfur transferase T1, M1 gene deletion and wine and tobacco habit and gastric cancer susceptibility in the Guangxi people. CLINICAL FOCUS 23 (19): 1393–5.
  63. 63. Qian Y, Xu YC, Shen HB, Zhou L, Yu R (2003) The relationship between CYP2E1 and GSTT1 genetic polymorphism and gastric cancer susceptibility (Article in Chinese). CHINESE JOURNAL OF PREVENTION AND CONTROL OF CHRONIC NON-COMMUNICABLE DISEASES 11 (3): 107–9.
  64. 64. Parvin S, Lee OR, Sathiyaraj G, Khorolragchaa A, Kim YJ, et al. (2012) Interrelationship between calmodulin (CaM) and H2O2 in abscisic acid-induced antioxidant defense in the seedlings of Panax ginseng. Mol Biol Rep 39 (7): 7327–38.
  65. 65. Onul A, Elseth KM, De Vitto H, Paradise WA, Vesper BJ, et al. (2012) Long-term adaptation of the human lung tumor cell line A549 to increasing concentrations of hydrogen peroxide. Tumour Biol 33 (3): 739–48.
  66. 66. Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45 51–88.
  67. 67. Chen J, Ma L, Peng NF, Wang SJ, Li LQ (2012) A meta-analysis of the relationship between glutathione S-transferases gene polymorphism and hepatocellular carcinoma in Asian population. Mol Biol Rep 39 (12): 10383–93.
  68. 68. Lourenco GJ, Silva EF, Rinck-Junior JA, Chone CT, Lima CS (2011) CYP1A1, GSTM1 and GSTT1 polymorphisms, tobacco and alcohol status and risk of head and neck squamous cell carcinoma. Tumour Biol 32 (6): 1209–15. doi: 10.1007/s13277-011-0224-z
  69. 69. Chen B, Cao L, Zhou Y, Yang P, Wan HW, et al. (2010) Glutathione S-transferase T1 (GSTT1) gene polymorphism and gastric cancer susceptibility: a meta-analysis of epidemiologic studies. Dig Dis Sci 55 (7): 1831–8. doi: 10.1007/s13277-011-0224-z