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Carcinogenesis Advance Access originally published online on July 11, 2006
Carcinogenesis 2007 28(1):101-106; doi:10.1093/carcin/bgl124
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

CYP2E1PstI/RsaI polymorphism and interaction with tobacco, alcohol and GSTs in gastric cancer susceptibility: a meta-analysis of the literature

Stefania Boccia1,*, Angelo De Lauretis1, Francesco Gianfagna1, Cornelia M.van Duijn2 and Gualtiero Ricciardi1

1 Institute of Hygiene, Catholic University of Sacred Heart, L.go F.Vito, 1-00168 Rome, Italy
2 Department of Epidemiology and Biostatistics, Erasmus Medical Center Rotterdam, The Netherlands

*To whom correspondence should be addressed. Tel: +0039 06 35001527; Fax: +0039 06 35001522; Email: sboccia{at}rm.unicatt.it


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Studies investigating the association between cytochrome P450 2E1 (CYP2E1) 5'-flanking region (PstI/RsaI) polymorphism and gastric cancer risk report conflicting results. The rationale for this meta-analysis was to determine whether CYP2E1*2 (c2) variant allele of CYP2E1 increases gastric cancer risk, especially by interacting with smoking, alcohol and other metabolic gene polymorphisms. Two investigators independently searched the Medline and Embase databases. A qualitative scoring of papers was applied to their evaluation. Authors of the identified papers were contacted to obtain data on the mentioned co-exposures. A measurement of the biological interaction among two putative risk factors was estimated by the attributable proportion (AP) due to interaction. We identified 13 case–control studies, which included 2066 gastric cancer cases and 2754 controls. Using the random effects model, we found no association between PstI/RsaI genotype and gastric cancer risk [odds ratio (OR) = 0.97 (95% confidence interval (CI): 0.79–1.18) for c2 allele carriers and OR = 1.36 (95% CI: 0.82–2.25) for c2 homozygotes compared with homozygotes wild-type]. When only high-quality scored studies were considered, a statistically significant increased risk appeared among Asians [OR = 1.50 (95% CI: 1.16–1.94) for c2 carriers and OR = 2.62 (95% CI: 1.23–5.57) for c2 homozygotes]. No interaction was detected between CYP2E1-smoking/alcohol (AP = 0), while an AP of 60% appeared for individuals both c2 homozygotes and glutathione S-transferase M1 (GSTM1) null compared with both homozygotes wild-type. This meta-analysis suggests that the CYP2E1 PstI/RsaI polymorphism may be a risk factor for gastric cancer in Asians, and that a synergic relation among GSTM1 and CYP2E1 may account for a proportion of gastric cancer cases.

Abbreviations: AP, attributable proportion; CI, confidence interval; CYP2E1, cytochrome P450 2E1; GSTMI, glutathione S-transferase M1; OR, odds ratio


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Cytochrome P450 2E1 (CYP2E1), a member of the cytochrome P-450 superfamily, is a naturally ethanol-inducible enzyme that is mainly involved in the metabolic activation of low molecular weight compounds such as N-nitrosamines, and in alcohol metabolism (1,2). N-nitrosamines are formed endogenously in the stomach and are present in various environmental factors including tobacco smoke and some diet compounds (3). Functional CYP2E1 polymorphisms, whose expression in gastric tissues is well documented (4), might therefore impact on the susceptibility for gastric cancer, for which N-nitrosamines are suspected of having a causative role. Two point mutations in the 5'-flanking region (PstI, RsaI), which are in close linkage disequilibrium, are known to alter the transcriptional activity of the gene (1). These mutations generate the CYP2E1*1 (c1) allele and the less common CYP2E1*2 (c2) allele and have been reported to be associated with a greater risk for oral, pharyngeal (5), liver (6) and lung cancers (7,8). Recent meta-analyses reported, however, the absence of an association between these polymorphisms and oesophageal cancer (9), hepatocellular carcinoma (10) and alcoholic liver disease (11).

Despite the biological plausibility of CYP2E1 5'-flanking region polymorphism as a modulator of gastric cancer susceptibility, previously inconsistent results have appeared in the literature (12–23), probably owing to the small sample sizes and the lack of investigations of gene–environment or gene–gene interactions. To clarify the effect of CYP2E1 PstI polymorphism on the risk of gastric cancer, we have carried out a meta-analysis of the studies published until April 31, 2006. Since we would expect to find an interaction between smoking habits, alcohol consumption and other metabolic gene polymorphisms with the CYP2E1 c2 variant allele, with respect to gastric cancer risk, we performed stratified meta-analyses after collecting the original data from the published papers.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Data collection
Papers published before the end of April 2006 were identified through a search of Medline and Embase using the following terms: ‘cytochrome p450 2E1/IIE1’ or ‘CYP2E1/IIE1’, ‘gastric’ and ‘cancer’ or ‘carcinoma’, without restriction on language. A cited reference search of the retrieved articles was carried out, and further publications were also identified by reviewing the bibliographies of the retrieved articles. Articles reporting on CYP2E1 genotype identified by RsaI or PstI enzymes in cases of gastric cancer and controls were identified (12–23). If more than one article was published by the same author using the same case series, we selected the study where the most individuals were investigated. In addition, for those papers reporting only the number of CYP2E1 c2 carriers, the corresponding authors were contacted by email and fax in order to obtain the number of individuals with the homozygous variant genotype. Lastly, our submitted study was included (S. Boccia et al., manuscript submitted).

Since our a priori hypothesis was that the variant allele might affect gastric cancer risk by interacting with smoking habits, alcohol intake and glutathione S-transferase (GST) M1 and T1 polymorphisms, investigators associated with eligible studies were invited to contribute data to our effort. The corresponding authors of the published papers who reportedly collected data on the mentioned co-exposures without publishing the results in extenso were contacted by e-mail and fax. We invited them to fill in an empty table with the CYP2E1 PstI/RsaI genotype data for cases and controls stratified for smoking status/alcohol consumption/GSTM1/GSTT1 polymorphisms.

After several efforts for data collection, information on the absolute number of homozygous c2 individuals in cases and controls, and on CYP2E1 genotypes stratified for the mentioned co-exposures, have been received for all the included studies bar one and all bar three, respectively.

Quality assessment and statistical analysis
Each article was blinded with respect to the authors, institutions and journals. The articles were read and scored for quality by two independent researchers using a recently published quality score system (24), with the exception of the articles written in a non-English language (21, 23). In brief, papers were rated according to several items on the scale in relation to two areas: the effort of the study to minimize potential bias and the data analysis, with items concerning the first area having twice the weight of those evaluating data analysis. A quality score was then calculated for each paper and reported as a percentage of the met applicable criteria from the quality scale. High-quality studies were considered to be those with a value of at least 70% of the total score (19 out of 27) (12–14, 17, 22; S. Boccia et al., manuscript submitted). The same two researchers extracted the data from each article using a structured sheet and entered it into a database. The followings items were considered: year and location of the study; ethnicity; source of the control individuals; number of individuals heterozygous and homozygous for the CYP2E1 c2 allele in cases and controls; cigarette smoking status; alcohol consumption; GSTM1 and GSTT1 polymorphisms.

In carrying out the meta-analyses, random effect models were used, taking into account the possibility of heterogeneity between studies, which was tested with the I2-test and a standard {chi}2-test. The odds ratios (ORs) of gastric cancer associated with c2 allele carriers and homozygous c2 genotype for the CYP2E1 RsaI/PstI polymorphism were estimated using the homozygous wild-type (c1/c1) as the reference group. In order to detect publication bias, ORs and 95% confidence interval (CI) were plotted against standard errors in each study and the Egger test was performed (25). To determine the deviation from Hardy–Weinberg equilibrium among control populations we used a program provided on the web site http://ihg.gsf.de/cgi-bin/hw/hwa2.pl.

Sources of heterogeneity were investigated by subgroup meta-analyses based on the ethnicity (Asian and Caucasian populations) and the quality (high and low) of the studies (26). Additional subgroup meta-analyses were performed in an attempt to evaluate if heterozygous and homozygous variant genotypes of CYP2E1 RsaI/PstI polymorphism modify the risk of gastric cancer by interacting with smoking, alcohol and GSTM1 and GSTT1 polymorphisms. For these purposes, we stratified subjects (both c2 carriers and c2 homozygous) according to smoking status (ever/never smokers); alcohol consumption (users/non-users); GSTM1 and GSTT1 polymorphisms (present/null variant).

In order to evaluate the presence of a biological interaction between each couple of the investigated risk factors, additional gene–gene and gene–environment interaction meta-analyses were performed by using the homozygous wild-type individuals not exposed to the environmental factor, or the homozygous wild-type individuals for both genes, as reference groups, as suggested by Botto and Khoury (27). To quantify the amount of biological interaction, the attributable proportion (AP) due to interaction was calculated using departure from additivity of effects as the criterion for interaction, as suggested by Rothman (28). The AP is the proportion of individuals among those exposed to the two interacting factors that is attributable to the interaction per se, and it is equal to 0 in the absence of biological interaction (28). When more than additive relation was evident, we additionally tested for more than multiplicative effect between the two risk factors by using a case-only meta-analysis (under the assumption of independence of the two factors in the control population) (29). Statistical analyses were carried out in RevMan program, release 4.2 (30).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Twelve case–control studies (12–23), of which two were written in a non-English language (21–23), were identified, and by adding our recently submitted study (S. Boccia et al., manuscript submitted) we had a total of 2066 gastric cancer cases and 2754 controls (Table I). Studies were carried out in Japan, China, Taiwan, Korea, Brazil and Italy. Allele and genotype frequencies in all control groups did not deviate from values predicted by Hardy–Weinberg equilibrium. Quality scores for the individual studies ranged from 56 to 81%, with 6 of the 13 studies being classified as high-quality (12–14,17, 22; S. Boccia et al., manuscript submitted), of which three were Asian and three were Caucasian. Our meta-analysis gave an overall OR of 0.97 (95% CI: 0.79–1.18) for gastric cancer risk among c2 allele carriers of CYP2E1 RsaI/PstI polymorphism and an overall OR of 1.36 (95% CI: 0.82–2.25) for c2 homozygotes (Figure 1).


Figure 1
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  		Fig. 1 Forest plots depicting the OR and 95% CI from studies examining the association between gastric cancer and CYP2E1 RsaI/PstI 5'-flanking gene polymorphisms (c2 variant allele carriers or c2 homozygotes versus c1 homozygotes), and stratified meta-analyses according to ethnicity and quality of the studies. The centre of each square represents the OR, the area of the square is the inverse of the variance and the horizontal line indicates the 95% CI. The summary OR is represented by the diamond, where its centre indicates the OR and its ends correspond to the 95% CI. I2 and p-value for {chi}2 of heterogeneity are reported for each subgroup analysis.

 


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  		Table I Studies of the CYP2E1-PstI/RsaI polymorphism and gastric cancer risk

 
When stratifying for ethnicity, an OR of 1.01 (95% CI: 0.81–1.25) and 0.72 (95% CI: 0.44–1.18) resulted for c2 carriers, while an OR of 1.44 (95% CI: 0.85–2.42) and 0.42 (95% CI: 0.05–3.85) resulted for c2 homozygotes, among Asians and Caucasians, respectively (Figure 1). When studies were stratified for quality, an overall OR of 1.15 (95% CI: 0.81–1.56) for c2 carriers and an OR of 2.14 (95% CI: 0.96–4.74) for c2 homozygotes emerged for the high-quality scored studies. These results produced a significant OR of 1.50 (95% CI: 1.16–1.94) for c2 carriers and an OR of 2.62 (95% CI: 1.23–5.57) for c2 homozygotes when only high-quality studies among Asians were considered, while the result was not significant among low-quality scored studies (data not shown).

The results of the stratified meta-analyses according to smoking status, alcohol consumption and GSTs genotypes are shown in Figures 2 and 3. The overall ORs appeared similar among each subgroup, even when further stratified by ethnicity (data not shown). On the other hand, an effect modification due to GSTM1 genotype for gastric cancer risk appeared for c2 homozygotes individuals compared with c1/c1 homozygotes. In fact, an OR of 4.93 (95% CI: 0.73–33.08) emerged for individuals both c2 homozygotes and GSTM1 null when compared with c1 homozygotes, while an OR of 1.89 (95% CI: 1.00–3.58) appeared for the same comparison among GSTM1 wild-type individuals (Figure 3).


Figure 2
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  		Fig. 2 ORs and 95% CI from the subgroup meta-analyses examining the association between gastric cancer and CYP2E1 RsaI/PstI 5'-flanking gene polymorphisms (c2 variant allele carriers or c2 homozygotes versus c1 homozygotes), according to smoking status and alcohol consumption (see Materials and methods). The centre of each square represents the OR, the area of the square is the inverse of the variance and the horizontal line indicates the 95% CI. The summary OR is represented by the diamond, where its centre indicates the OR and its ends correspond to the 95% CI. I2 and p-value for {chi}2 of heterogeneity are reported for each subgroup analysis.

 


Figure 3
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  		Fig. 3 ORs and 95% CI from the subgroup meta-analyses examining the association between gastric cancer and CYP2E1 RsaI/PstI 5'-flanking gene polymorphisms (c2 variant allele carriers or c2 homozygotes versus c1 homozygotes), according to GSTM1 and GSTT1 gene polymorphisms (see Materials and methods). The centre of each square represents the OR, the area of the square is the inverse of the variance and the horizontal line indicates the 95% CI. The summary OR is represented by the diamond, where its centre indicates the OR and its ends correspond to the 95% CI. I2 and p-value for {chi}2 of heterogeneity are reported for each subgroup analysis.

 
The computation of the AP due to interaction showed an absence of biological interaction among each pair of tested risk factors, with an AP = 0 for all of the combinations. The only one exception is represented by the interaction between CYP2E1 c2 homozygotes and GSTM1 null, for which an OR of 5.36 (95% CI: 1.01–28.47) for gastric cancer risk appeared in comparison with individuals with both wild-type genotype (data not shown). In this case an AP of 60% of gastric cancer cases among the CYP2E1 c2 homozygotes with GSTM1 null genotype appeared to be related to the biological interaction among the two unfavourable genotypes, with a more than additive effect on gastric cancer risk. Lastly, case-only meta-analysis showed no evidence of more than multiplicative effect (OR = 1.04; 95% CI: 0.69–1.80) for the association of CYP2E1 c2 homozygotes and GSTM1 null on gastric cancer risk (data not shown).

Evidence of heterogeneity appeared when all the studies were pooled, with an I2 of 51.3% and a {chi}2 P-value = 0.01 for c2 carriers, and an I2 of 47.7% and a {chi}2 P-value = 0.03 for c2 homozygotes (Figure 1). When stratified by ethnicity, the heterogeneity still remained among Asians, but disappeared when only the three high-quality Asian studies were pooled (Figure 1). No evidence of heterogeneity appeared within strata after stratification for smoking status and alcohol consumption (Figure 2), probably owing to the association between smoking and alcohol with gastric cancer risk per se. However, a high heterogeneity emerged when data were stratified by GSTs genotypes (Figure 3), maybe owing to the wide variability in the frequency of these polymorphisms among Caucasians and Asians (31).

The funnel plot and the Egger test provided evidence that effect estimates were not related to study size (P > 0.05 for both c2 carriers and c2 homozygotes; data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Among the most widely studied metabolic gene polymorphisms as susceptibility factor for gastric cancer is the CYP2E1 RsaI/PstI polymorphism. The less common c2 variant allele frequency is highly different among Asians and Caucasians, with a prevalence of ~25–50% and 5–10%, respectively (31). Since Kato et al. (15) first investigated, in 1995, a possible relationship between CYP2E1 c2 allele and gastric cancer risk, a further 11 reports mainly conducted in Asian populations have been published examining this hypothesis (12–23), with conflicting results. This led us to undertake the present meta-analysis, which aims to derive an estimate of the gastric cancer risk associated with CYP2E1 RsaI/PstI genotype. The main finding of this meta-analysis of 13 case–control studies involving 4820 subjects is that individual carriers of CYP2E1 c2 allele or c2 homozygous do not appear to have an increased risk of gastric cancer. Since the result comes from pooling data from different ethnic groups and studies of different quality, we planned a priori to perform subgroup meta-analyses based on ethnicity and study quality. Considering separately, both Caucasian and Asian populations, the association between CYP2E1 status and gastric cancer risk did not change substantially, despite it increased for c2 homozygotes among Asians. It did reach a statistically significant level, however, when only high-quality studies among Asians were considered, with a significant 1.50- and 2.62-fold increased risk for gastric cancer among c2 carriers and c2 homozygotes, respectively. The lack of significance for the association in Caucasian population might be explained by substantially lower statistical power to detect an association owing to a lower prevalence of CYP2E1 c2 carriers (5–10% against 25–50% for Asians).

As expected, there was evidence of between-study heterogeneity when all ethnic groups were pooled, which was higher still when only Asian studies were considered. However, Asian reports in the subgroup analysis include a mixture of populations from very distant countries and sometimes substantial differences in allele frequencies for the c2 allele. On the other hand, there was no evidence of heterogeneity when only high-quality Asian studies were considered.

Since CYP2E1 is presumed to confer susceptibility to gastric cancer via an interaction with carcinogens, it is interesting to note that almost all of the studies did not explore the interaction between CYP2E1 genotype and smoking habits or alcohol consumption. This was probably due to the low statistical power of the individual studies to detect interactions; however, almost all of the studies collected these data, which was utilized for this meta-analysis. By combining the collected data on PstI/RsaI genotype and smoking habits or alcohol consumption with respect to gastric cancer risk, no statistically significant results emerged from the stratified meta-analyses. Furthermore, the computation of the AP due to biological interaction was equal to 0 in both cases, thus showing that when the environmental and genetic risk factors are both present, the effect on gastric cancer seems to be no longer than additive of the separate effects. However, we cannot ignore the fact that owing to the low prevalence of c2 homozygotes in each study, even when data are pooled, the statistical power to detect an interaction remains low.

If genetic susceptibility to gastric cancer is, in part, mediated through metabolic gene polymorphisms, it is possible that the combinations of certain genotypes may be more discriminating as risk factors for gastric cancer than a single locus genotype. Among the most investigated metabolic gene polymorphisms, as susceptibility factors, are GST enzymes, which are mainly involved in the detoxification of several different xenobiotics (32). Two recent meta-analyses indicated that individuals with both GSTM1 and GSTT1 null genotypes are at higher risk for gastric cancer; however, no risk emerged when the two unfavourable genotypes were considered separately (24,33). Among the 13 studies included in the present meta-analysis, only one study (19) investigated the interaction between CYP2E1 PstI/RsaI and GSTM1 polymorphisms, even though nearly half of the studies collected data on GSTM1 and GSTT1 status for cases and controls. By pooling the collected data on CYP2E1 PstI/RsaI and GSTM1/GSTT1 genotypes, a statistically significant 5.36-fold increased risk for gastric cancer appeared for individuals both CYP2E1 c2 homozygotes and GSTM1 null, compared with individuals with both homozygous wild genotypes. On the basis of the definition of biological interaction among two component causes, our result suggests that nearly 60% of gastric cancer cases among individuals both CYP2E1 c2 homozygotes and GSTM1 null are caused through a mechanism in which the two risk factors act under biological dependence in the same causal mechanism of disease (28). In other words, in the absence of either of the two risk factors, an important number of gastric cancer cases would not occur.

In interpreting the results, the main limitation of the study should be considered. First, only published studies were included in the meta-analysis; therefore, publication bias may have occurred, even though the use of a statistical test did not show it. Secondly, the subgroup meta-analyses considering interactions between CYP2E1 genotype and smoking habits/alcohol consumption and gene–gene interactions did not include all of the studies because a small number of authors, three and one, respectively, could not share their original data, so selection bias may have occurred, and our results should be confirmed with the inclusion of the missing data. Furthermore, when the analysis was restricted to c2 homozygotes individuals, we had a low power to detect an interaction because of the low prevalence of c2 homozygotes in each study, so the results need to be confirmed with a larger sample size. Thirdly, our meta-analysis is based on unadjusted estimates, while a more precise analysis could be performed if individual data were available, which would allow for an adjustment estimate (by age and sex). To be made, however, this approach requires the authors of all of the published studies to share their data. Fourthly, the quality score of the individual studies included in our meta-analysis was assessed on the basis of efforts to minimize the potential for selection bias, misclassification related to exposure, collection of data on potential confounders and method of statistical analysis. It is known that a validated quality assessment system does not currently exist (34), and it is evident that our quality scale has a subjective component. Despite these limitations, assessment of the quality of individual studies used in our meta-analysis allowed us to see that pooling high-quality scored studies resulted in higher risk estimates than did the pooling of low-quality scored studies. If high-quality scored studies are more likely to yield valid information than low-quality studies, we can conclude that, on the basis of the currently available data, an additional risk of gastric cancer for CYP2E1 c2 carriers and c2 homozygotes may exist especially amongst Asians.

Despite all these remarks, some interesting conclusions have emerged. From the results of this quantitative meta-analysis, which combined the data from 4820 people (2066 cases and 2754 controls), it appears that CYP2E1-PstI/RsaI polymorphism may be a risk factor for gastric cancer in Asian populations, and particularly for individual homozygotes for the unfavourable gene variant. In addiction, a synergic relation among GSTM1 and CYP2E1 unfavourable variant genotypes might account for a proportion of gastric cancer cases. Since more than half of the included studies were based on a limited number of cases (<100) it is critical that larger and well-designed multicentric studies based on the same ethnic group confirm our results.


   Acknowledgments
 
We are indebted to Dr Ling-Ling Hsieh, Dr Mei Ye, Dr Jaw-Town Lin, Dr Haruhiko Sugimura, Dr Heon Kim, Dr Takahiko Katoh, Dr Ines Nobuko Nishimoto, Dr Toshiro Takezaki and Ana Elizabete Silva for collaboration and availability to share their data for the present meta-analysis. We are grateful to Wendy Morotti for the linguistic revision of the final manuscript.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received May 31, 2006; accepted July 7, 2006.


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