|Year : 2015 | Volume
| Issue : 3 | Page : 565-570
Glutathione S-transferase P1, gene-gene interaction, and lung cancer susceptibility in the Chinese population: An updated meta-analysis and review
Xue-Ming Li1, Xiao-Wei Yu2, Ye Yuan3, Ming-Zhi Pu4, Hong-Xia Zhang1, Ke-Jian Wang1, Xu-Dong Han1
1 Department of Respiration, Changzhou Traditional Chinese Medicine Hospital, Changzhou 213000, China
2 Department of Respiration, Changzhou No. 2 People's Hospital, Changzhou 213000, China
3 Department of Respiration, Nanjing University of Chinese Medicine, Nanjing 210023, China
4 Department of Respiration, Suzhou Traditional Chinese Medicine Hospital, Suzhou 215009, China
|Date of Web Publication||9-Oct-2015|
Department of Respiration, Changzhou Traditional Chinese Medicine Hospital, No. 25 Heping Road, Changzhou 213000
Source of Support: None, Conflict of Interest: None
Aim of Study: To assess the impact of glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism on the risk of lung cancer in the Chinese population, an updated meta-analysis and review was performed.
Materials and Methods: Relevant studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine published through January 22, 2015. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the associations.
Results: A total of 13 case-control studies, including 2026 lung cancer cases and 2451 controls, were included in this meta-analysis. Overall, significantly increased lung cancer risk was associated with the variant genotypes of GSTP1 polymorphism in the Chinese population (GG vs. AA: OR = 1.36, 95% CI = 1.01-1.84). In subgroup analyses stratified by geographic area and source of controls, the significant results were found in population-based studies (GG vs. AA: OR = 1.62, 95% CI: 1.13-2.31; GG vs. AG: OR = 1.49, 95% CI: 1.03-2.16; GG vs. AA + AG: OR = 1.55, 95% CI: 1.12-2.26). A gene-gene interaction analysis showed that there was an interaction for individuals with combination of GSTM1 (or GSTT1) null genotype and GSTP1 (AG + GG) mutant genotype for lung cancer risk in Chinese.
Conclusion: This meta-analysis suggests that GSTP1 Ile105Val polymorphism may increase the risk of lung cancer in the Chinese population.
Keywords: Gene-gene interaction, glutathione S-transferase P1, lung cancer, meta-analysis, polymorphism
|How to cite this article:|
Li XM, Yu XW, Yuan Y, Pu MZ, Zhang HX, Wang KJ, Han XD. Glutathione S-transferase P1, gene-gene interaction, and lung cancer susceptibility in the Chinese population: An updated meta-analysis and review. J Can Res Ther 2015;11:565-70
|How to cite this URL:|
Li XM, Yu XW, Yuan Y, Pu MZ, Zhang HX, Wang KJ, Han XD. Glutathione S-transferase P1, gene-gene interaction, and lung cancer susceptibility in the Chinese population: An updated meta-analysis and review. J Can Res Ther [serial online] 2015 [cited 2019 Aug 22];11:565-70. Available from: http://www.cancerjournal.net/text.asp?2015/11/3/565/163788
| > Introduction|| |
Lung cancer accounts for 13% (1.6 million) of the total cases and 18% (1.4 million) of the deaths in 2008 globally.  Moreover, it was the most common diagnosed cancer as well as the leading cause of cancer death in males, while the fourth most common diagnosed cancer and the second leading cause of cancer death in females.  In China, despite substantially decreasing mortality from stomach, esophagus, nasopharynx, and cervix uteri cancers, lung cancer mortality has been increasing over the past decades and continues to increase in the recent years.  The mechanisms of lung carcinogenesis have not been fully illustrated. Although epidemiological evidence suggests that exposure to tobacco-associated carcinogens is clearly implicated in its etiology,  not all smokers develop lung cancer, indicating that genetic variations and other environmental factors may play important roles in the development of lung cancer. , In recent years, the role of genetic variability on the development of lung cancer has been extensively been studied.  An important one is glutathione S-transferase P1 (GSTP1), the most abundant GST isoform in the lung, which can metabolize numerous carcinogenic compounds, including benzo[a] pyrene, a tobacco carcinogen.  GSTP1 has two single nucleotide polymorphisms that result in a change in amino acids. One of the most frequently studied polymorphism, GSTP1 exon 5 (Ile105Val), has been reported to have functional effects on the GST gene product resulting in reduced enzyme activity.  The predominant homozygous genotypes, the heterozygous genotypes, and the homozygous rare genotypes of the GSTP1 Ile105Val gene polymorphism are named the homozygous wild-type genotype (A/A), the heterozygote (A/G), and the homozygote (G/G), respectively. The first research of the association between GSTP1 Ile105Val polymorphism and lung cancer was reported by Ryberg et al. in 1997 among the Canadian population.  As a consequence, many studies analyzed the influence of GSTP1 Ile105Val polymorphism on lung cancer risk, however, no clear consensus was reached. Meta-analyses of studies on the gene in other ethnic groups have been reported elsewhere and produced conflicting results. ,,,, Given the different genetic background between the Chinese and non-Chinese populations, it is necessary to investigate the relationship of GSTP1 Ile105Val polymorphism with risk of lung cancer in Chinese population. In addition, we performed subgroup analysis stratified by geographic area and the source of control population to explore the possible effects of the gene-environment interactions, and gene-gene interaction analysis between GSTP1 and GSTM1, GSTT1 genotypes with respect to lung cancer risk.
| > Materials and methods|| |
Search strategy and study selection
We conducted a systematic literature search for published articles regarding the association of GSTP1 polymorphism and lung cancer risk. The search included PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine databases for articles published through January 22, 2015 using a combination of the following terms: (Lung cancer or lung carcinoma or lung neoplasm) and (variant or variation or polymorphism) and (GSTP1) and (Chinese or China or Taiwan). The search was performed without any restrictions on language and focused on studies conducted in humans. In addition to the electronic database search, all reference lists of retrieved articles were reviewed manually to identify additional articles. Criteria for inclusion in the meta-analysis were: (1) Case-control or cohort studies on the association between GSTP1 polymorphism and lung cancer, (2) all patients with the diagnosis of lung cancer confirmed by pathological or histological examinations, (3) clear description of GSTP1 polymorphism in lung cancer patients and controls, and (4) all participants were Chinese. The reasons for exclusion of studies were: (1) Duplicate publications, (2) incomplete data, (3) no control, and (4) meta-analyses, letters, reviews, or editorial articles.
Information was extracted carefully from all eligible publications independently by two authors, based on the inclusion criteria above. Discrepancies between the two authors were resolved by discussion, and if a consensus was not achieved, a decision was made by all the reviewers. The title and abstract of all potentially relevant articles were screened to determine their relevance. Full articles were also scrutinized if the title and abstract were ambiguous. The following data were extracted from the identified studies: The first author, publication year, source of controls, geographic area, sample size, GSTP1 genetic polymorphism in cases and controls, and the number of subjects with gene-gene interactions.
Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between the GSTP1 polymorphism and lung cancer risk. The significance of the pooled OR was determined by the Z-test. Cochran's Q-statistic was used to assess heterogeneity, and a significant Q-statistic (P < 0.10) indicated heterogeneity across studies. If there was heterogeneity, then the random-effects model was chosen to pool the OR with 95% CI, otherwise the fixed-effects model was used. Hardy-Weinberg equilibrium was calculated by using the goodness-of-fit test, and deviation was considered when P < 0.05. Sensitivity analysis was conducted to verify stability of the meta-analysis using both models (the fixed-effect model and random-effect model). Begg's funnel plots and Egger's linear regression test were used to assess publication bias. In addition to the comparison among all subjects, we also performed stratification analyses by geographic area and the source of controls to explore the possible effects of the gene-environment interactions. In order to evaluate the presence of a biological interaction between GSTP1 and GSTT1 (or GSTM1) polymorphisms, additional gene-gene interaction analysis was performed. All the statistical analysis was conducted by using STATA statistical package (version 10, STATA, College Station, TX, USA).
| > Results|| |
Description of included studies
We identified 53 articles that examined the association between GSTP1 polymorphism and risk of lung cancer. After screening the titles and abstracts, 34 articles were excluded because they were review articles, duplicates, not Chinese, or irrelevant to the current study. Of the 19 potentially relevant articles identified for full study retrieval, one article was excluded because of insufficient genotyping data; five were excluded because they concerned subjects included in other studies. Finally, 13 case-control studies, ,,,,,,,,,,,, including 2026 lung cancer cases and 2451 controls, were involved in this meta-analysis according to the inclusion criteria. The publication year of involved studies ranged from 2002 to 2013. The flow chart of study selection is shown in [Figure 1]. The characteristics of the included studies are summarized in [Table 1].
[Table 2] lists the primary results. Overall, the variant genotypes of GSTP1 polymorphism were associated with increased risk of lung cancer in only one model [for GG vs. AA: OR = 1.36, 95% CI = 1.01−1.84, P = 0.137 for heterogeneity, [Figure 2]a]. In addition, the finding from cumulative meta-analysis showed that there was a trend of obvious association between GSTP1 GG genotype and risk of lung cancer in Chinese as data accumulated by publication year [Figure 2]b.
|Figure 2: The forest plots of all selected studies on the association between glutathione S-transferase P1 polymorphism and lung cancer risk in Chinese ((a) meta-analysis, (b) cumulative meta-analysis)|
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In the subgroup analysis based on source of controls, the results showed that the GSTP1 polymorphism was significantly related to lung cancer risk among population-based population (GG vs. AA: OR = 1.62, 95% CI: 1.13-2.31; GG vs. AG: OR = 1.49, 95% CI: 1.03-2.16; GG vs. AA + AG: OR = 1.55, 95% CI: 1.12-2.26), but not among hospital-based studies [Table 2]. In addition, we also performed stratified analysis based on the geographic area; it revealed no significant results in South China and North China [Table 2]. [Table 3] showed the OR and 95% CI of GSTP1 and GSTM1 (or GSTT1) combined genotypes in lung cancer cases and controls from two studies. There was an interaction for individuals with combination of the GSTM1 (or GSTT1) null genotype and the GSTP1 variant allele for lung cancer risk in Chinese. This indicates that the GSTM1, GSTT1 null genotype might increase lung cancer risk associated with the GSTP1 variant allele.
|Table 3: Combined genotype analysis of GSTP1 and GSTT1 (or GSTM1) on risk of lung cancer in Chinese|
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Sensitive analysis and bias diagnosis
To validate the credibility of outcomes in this meta-analysis, a sensitivity analysis was performed by comparing results of random-effects and fixed-effects models. None of the results were substantially different with respect to the model type [Table 2], indicating that they were relatively stable and credible. The Begg's funnel plot and Egger's test were performed to access the publication bias of literatures. As showed in [Figure 3]a, the shape of the funnel plots did not indicate obvious asymmetry. Similarly, the Egger's test indicated no publication bias in the 13 reviewed studies [[Figure 3]b, t = 0.92, P = 0.379].
|Figure 3: Publication bias evaluation on the association between glutathione S-transferase P1 polymorphism and lung cancer risk in Chinese ((a) funnel plot, (b) Egger's test)|
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| > Discussion|| |
Since the first research of GSTP1 Ile105Val polymorphism and lung cancer in 1997,  a number of studies have been carried out to investigate the role of GSTTP1 polymorphism in the development of lung cancer in some ethnic groups, but the results are varied and inconclusive. Meta-analysis as a powerful statistical method could improve the reliability of the conflicting results about the same topic and identify the reason for the variation. So, we conducted an update meta-analysis to more precisely assess the effect of GSTP1 polymorphism on risk for lung cancer among the Chinese population, in order to lessen the impact of genetic background. Furthermore, we also performed subgroup analysis stratified by geographic area and the source of control population to explore the possible effects of the gene-environment interactions, and gene-gene interaction analysis among GSTP1, GSTM1, and GSTT1 genotypes. The results showed that there was a significant genetic effect of the GSTP1 gene polymorphism on lung cancer in the Chinese population. The cumulative meta-analysis showed a trend of a more obvious association between GSTP1 GG genotype and lung cancer in Chinese as information accumulated gradually. The sensitivity analysis confirmed the reliability and stability of the meta-analysis and no publication bias was found among studies by Egger's test. Therefore, the findings from our meta-analysis provide a strong evidence for the association between GSTP1 polymorphism and Lung cancer in the Chinese population. Our results were consistent with a previously published meta-analysis in Chinese Han population. 
When we performed stratified analyses by geographic area and source of controls, significant association with susceptibility for the development of lung cancer was found in population-based studies, whereas not found in South China, North China, and hospital-based studies. There might be some reasons could be explained; first, the hospital-based studies usually have some biases because such controls may just represent a sample of ill-defined reference population, and may not be representative of the general population. Second, for the relevant small sample size, only three hospital-based studies were included in the meta-analysis. Third, the nondifference results between South and North of China might also make attributions for, at least in part, other unknown factors such as smoking status, family history of cancer, other genetic-related respiratory diseases, as well as other related genetic polymorphisms.
The pathways of carcinogen metabolism are complex, mediated by the activity of multiple enzymes. The effect of any single gene might have a limited impact on lung cancer risk than have so far been anticipated. It is possible that the combinations of certain genotypes may be more discriminating as risk factors for lung cancer than a single locus genotype. Hence, we also investigate the possible interaction between GSTP1 and GSTT1 (or GSTM1) status and lung cancer risk in this meta-analysis. Among the 13 studies included in the present meta-analysis, two studies investigated the interaction of GSTP1-GSTT1, GSTM1 polymorphism. By pooling the collected data on GSTP1 and GSTT1, GSTM1 genotypes, it revealed that people carrying the combination of GSTM(T)1 null genotype and GSTP1 (AG + GG) mutant genotype possess prominently increased risk of lung cancer as compared to those with GSTM(T)1 present and GSTP1 (AA) wild genotype.
Some limitations of this meta-analysis should be addressed. First, we did not perform subgroup analysis on smoking status and other exposure history, because of the lack of sufficient data. Another potential limitation was that our results were based on unadjusted estimates. More precise analyses can be conducted if individual data were available, which would allow for the adjustment by other covariates, including age, sex, race, and other factors. Third, the conclusion for the gene-gene interaction analyses might be limited because of the relevant small sample size.
| > Conclusion|| |
Our meta-analysis suggests that GSTP1 Ile105Val polymorphism may increase the risk of lung cancer in the Chinese population. Concerning lung cancer with multifactorial etiology, to further evaluate gene-gene and gene-environment interactions on GSTP1 polymorphism and lung cancer, larger studies in the Chinese population with different environmental background or other risk factors are required to confirm our findings.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]