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Genetic polymorphisms of glutathione S-transferase genes GSTM1, GSTT1 and risk of CHD


Mutagenesis Advance Access published March 30, 2010
Mutagenesis pp. 1–5, 2010 doi:10.1093/mutage/geq014

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

Jun Wang, LiangJian Zou, ShengDong Huang, FangLin Lu, XiLong Lang, Lin Han, ZhiGang Song and ZhiYun Xu*
Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
* To whom correspondence should be addressed. ZhiYun Xu, Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Tel: ?86-21-81873436; Fax: ?86-21-65490979; Email: zhiyunxu001@hotmail.com

Received on February 24, 2009; revised on February 24, 2010; accepted on March 2, 2010

To clarify the role of glutathione S-transferases (GSTs; GSTM1 and GSTT1) status in susceptibility to coronary heart disease (CHD), a meta-analysis of published studies was performed. A total of 19 studies including 8020 cases and 11 501 controls were included in this meta-analysis. In a combined analysis, the relative risks for CHD of the GSTM1 null and GSTT1 null polymorphisms were 1.47 [95% con?dence interval (CI): 1.08–2.01] and 1.26 (95% CI: 0.90–1.75), respectively. Three potential sources of heterogeneity including ethnicity, source of control and sample size of study were also assessed. However, no signi?cant association was found in strati?ed analyses. By pooling data from eight studies (2909 cases and 3745 controls) that considered combinations of GSTT1 and GSTM1 genotypes, a statistically signi?cant increased risk for CHD [odds ratio (OR 5 2.38, 95% CI: 1.03–5.48)] was detected for individuals with combined deletion mutations in both genes compared with positive genotypes. Results from the meta-analysis of ?ve studies on GSTs strati?ed according to smoking status showed an increased risk for individuals with null genotype (OR 5 2.21, 95% CI: 1.24–3.92 for GSTM1 and OR 5 3.29, 95% CI: 1.49–7.26 for GSTT1) versus non-null genotypes. This meta-analysis suggests that the GSTM1 null genotype may slightly increase the risk of CHD and that interaction between unfavourable GSTs genotypes may exist.

pathogenesis of atherosclerosis suggest that the occurrence of DNA alterations contribute to the multifaceted pathogenesis of the atherogenic process. In particular, deletions or mutations of gene coding for enzymes involved in the metabolism of hazardous compounds may be responsible for individual susceptibility to genotoxic factors, predisposing to the development of DNA insults (3, 4). The glutathione S-transferases (GSTs) are a gene superfamily of phase II metabolic enzymes that detoxify free radicals, particularly in tobacco smoke, products of oxidative stress and carcinogens such as benzopyrene and other polycyclic aromatic hydrocarbons (5). In addition to their role in phase II detoxi?cation, GSTs also play an important role in modulating the induction of other enzymes and proteins for cellular functions, such as DNA repair (6). GSTM1 and GSTT1 are the most extensively studied genes in the GST gene superfamily. Polymorphic deletion variants in the GSTM1 and GSTT1 genes produce either a functional enzyme (nondeletion alleles or heterozygous deletion, GSTM1-1 and GSTT1-1) or result in the complete absence of the enzyme (homozygous deletion alleles, GSTM1-null and GSTT1-null) (7). Therefore, these enzymes may be related to the risk for atherosclerosis and CHD (8). Indeed, several studies have investigated the associations between the GSTT1 and GSTM1 null genotypes and CHD susceptibility. However, these studies have yielded contradictory results, with some studies showing a signi?cant association, while others showing no such association. Such inconsistency could be due to the small effect of the polymorphism on CHD risk and the relatively small sample size in each of the published studies. We therefore performed a meta-analysis of the published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between GSTM1, GSTT1 and CHD. Materials and methods
Literature search and data extraction Papers published before the end of November 2009 were identi?ed through a search of Pubmed and Embase using the following terms ‘glutathione S-transferases’ or ‘GST’ and ‘coronary heart disease’ or ‘CHD’, without restriction on language. All references cited in these studies and previously published review articles were reviewed to identify additional work not indexed by MEDLINE. Only those studies assessing the association between the CHD and the GSTs gene polymorphisms were included. The inclusion criteria were (i) original papers containing independent data, (ii) identi?cation of CHD was con?rmed pathologically, (iii) suf?cient data to calculate the odds ratio (OR) or P-value and (iv) case–control or cohort studies. The major reasons for exclusion of studies were (i) overlapping data and (ii) case-only studies, family-based studies and review articles. For each study, the following information was extracted independently by two investigators: ?rst author’s surname, publication date, gender, ethnicity, genotyping method, cigarette smoking status, clinical characteristics, con?rmation of diagnosis, total number of cases and controls. The results were compared and disagreements were discussed and resolved with consensus. Where essential information was not presented in articles, every effort was made to contact the authors.

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Introduction Coronary heart disease (CHD), including its most severe complication, myocardial infarction, is the leading cause of death in the industrialized world (1). Traditional risk such as hypertension, diabetes mellitus, dyslipidemia and smoking can only explain approximately two-thirds of the observed clinical events. This has maintained interest in other biochemical and genetic factors that might contribute to the underlying pathophysiology of vascular disease (2). Recent studies addressing the issue of acquired DNA mutations in the

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J. Wang et al. Statistical analysis For the GSTM1 and GSTT1 gene, we estimated the risks of the null genotype on CHD compared with the non-null genotypes in the recessive model (null verses heterozygous ? wild type). The strength of the association between the GSTM1 and GSTT1 gene and CHD risk was measured by ORs with 95% con?dence intervals (CIs). Cochran’s v2 based Q-statistic test (9, 10) and I2-test (11) were performed to assess possible heterogeneity in the combined studies. If heterogeneity existed, the random effects model (the DerSimonian and Laird method) (12), which yields wider CIs, was adopted to calculate the overall OR value. Otherwise, the ?xed effects model (the Mantel–Haenszel method) was used (13). In addition, sources of heterogeneity were investigated by strati?ed meta-analyses based on ethnicity (Caucasian and non-Caucasian population), source of controls (population and hospital based) and sample size (number of cases . 250 or , 250). The method of Woolf (14) was used to contruct 95% CIs. The signi?cance of the overall OR was determined by the Z-test. Funnel plots and Egger’s linear regression test were used to assess evidence for potential publication bias (15). In order to assess the stability of the result, sensitivity analyses were performed, each study in turn was removed from the total, and the remaining were reanalysed. The analysis was conducted using Review Manager (version 5.0, The Cochrane Collaboration, Oxford, UK). The type I error rate was set at 0.05. All P-values were two tailed.

in population-based controls compared to 1.81 (95% CI: 0.77– 4.26; I2 5 97%, Pheterogeneity 5 0.00) in hospital controls. After strati?cation for sample size, we still observed positive results in big studies (data not shown). GSTT1. The meta-analysis resulted in a statistically nonsigni?cant association between GSTT1 de?ciency and CHD. The overall OR was 1.26 (95% CI: 0.90–1.75; I2 5 93%, Pheterogeneity 5 0.00) (Figure 2). No signi?cant association was found in strati?ed analyses according to ethnicity, source of controls and GSTT1 genotypes. The OR was 1.22 (95% CI: 0.96– 1.54; I2 5 49%, Pheterogeneity 5 0.06) in Caucasians and 1.20 (95% CI: 0.68–2.10; I2 5 96%, Pheterogeneity 5 0.00) in non-Caucasians. When stratifying for source of controls, an OR of 0.97 (95% CI: 0.82–1.14; I2 5 55%, P 5 0.01) and 2.09 (95% CI: 0.90–4.86; I2 5 96%, Pheterogeneity 5 0.00) resulted for null genotype, among population- and hospital-based controls, respectively. In the strati?ed analysis by sample size, no signi?cant associations were found in big studies or small studies (data not shown). Gene–gene interaction. The effect of each genotype of GSTs was independently assessed. No association was established between both the null genotype of GSTM1, GSTT1 and CHD. The data on both null genotype of GSTs among cases and controls were available in eight studies, which included 2909 cases and 3745 controls. The interaction between GSTM1 null and GSTT1 null, for which an OR of 2.38 (95% CI: 1.03–5.48; I2 5 96%, P 5 0.00) for CHD appeared in compared with individuals with the positive genotypes. Gene–environment interaction. The data on genotypes of the GSTM1 and GSTT1 among cases and controls strati?ed by smoking status were available in ?ve studies. Among smokers in all ?ve studies, individuals with the null genotype of GSTM1 or GSTT1 had a signi?cantly increased CHD risk compared to the non-null genotypes with an OR of 2.21 (95% CI: 1.24–3.92; I2 5 84%, Pheterogeneity 5 0.00) and 3.29 (95% CI: 1.49–7.26; I2 5 90%, Pheterogeneity 5 0.00), respectively. Sensitivity analyses and publication bias. Sensitivity analyses indicated that the studies by Abu-Amero et al. were the main origin of heterogeneity in overall OR. The heterogeneity was

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Results Characteristics of studies A total of 19 studies were retrieved based on the search criteria for CHD susceptibility related to the GST polymorphisms. The main study characteristics were summarized in Table I. There are 19 studies with 8020 CHD cases and 11 501 controls concerning GSTM1 polymorphism and 17 studies with 7318 CHD cases and 10 361 controls concerning GSTT1 polymorphism. Meta-analysis results GSTM1. For CHD risk and the null genotype of GSTM1, our meta-analysis gave an overall OR of 1.47 (95% CI: 1.08–2.01; I2 5 95%, Pheterogeneity 5 0.00) with statistically signi?cant between-study heterogeneity (Figure 1). This analysis is based on pooling of data from a number of different ethnic populations. When stratifying for ethnicity, an OR of 1.43 (95% CI: 0.92–2.22; I2 5 93%, Pheterogeneity 5 0.00) and 1.50 (95% CI: 0.93–2.43; I2 5 96%, Pheterogeneity 5 0.00) resulted for null genotype, among Caucasians and non-Caucasians, respectively. By considering control source subgroups, the OR was 1.31 (95% CI: 0.99–1.72; I2 5 91%, Pheterogeneity 5 0.00)
Table I. Demography of the combined studies Reference Evans et al. (16) Wilson et al. (17) Li et al. (5) Wang et al. (18) Salama et al. (19) Wilson et al. (20) Palmer et al. (21) Olshan et al. (22) Masetti et al. (23) Girisha et al. (24) Tamer et al. (25) Hayek et al. (26) Abu-Amero et al. (27) Cornelis et al. (28) Kim et al. (29) Wang et al. (30) Martin et al. (31) Manfredi et al. (32) Maciel et al. (33) Year 1996 2000 2000 2001 2002 2003 2003 2003 2003 2004 2004 2006 2006 2007 2008 2008 2009 2009 2009 Country (ethnicity) Saudi Arabia UK USA USA USA South Asian UK USA Italy India Turkey UK Saudi Arabia Canada Korea Chinese USA Italy Brazil

Genotyping method PCR PCR PCR PCR PCR PCR PCR PCR PCR PCR RT-PCR PCR PCR PCR PCR PCR PCR PCR PCR

No. of cases 90 356 400 612 120 170 51 526 308 197 148 193 1054 2042 356 277 67 184 871

No. of controls 884 187 890 256 90 203 57 868 122 198 247 2399 762 2042 336 277 63 47 1577

Controls source Population Population Population Hospital Population Population Hospital Population Hospital Population Population Population Hospital Population Hospital Hospital Population Hospital Population

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Coronary heart disease susceptibility

effectively decreased after exclusion of the study (GSTM1: I2 5 60%; GSTT1: I2 5 89%). In addition, no other single study in?uenced the pooled OR qualitatively, as indicated by sensitivity analyses, suggesting that the results of this metaanalysis are stable (data not shown). Begg’s funnel plot and Egger’s test were performed to evaluate the publication bias of literatures. As shown in Figures 3 and 4, the shape of the funnel plots seemed symmetrical for both

genes, suggesting no publication bias among the studies included. The statistical results still did not show publication bias (P . 0.05, for all). Discussion Large sample and unbiased epidemiological studies of predisposition genes polymorphisms could provide insight into the

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Fig. 1. Meta-analysis of GSTM1 null genotype associated with CHD. Each box represents the OR point estimate, and its area is proportional to the weight of the study. The diamond represents the overall summary estimate, with CI represented by its width.

Fig. 2. Effect of the GSTT1 null versus present genotype the risk of CHD.

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J. Wang et al.
0 SE(log[OR])

0.1

0.2

0.3

0.4

0.5 0.1 0.2 0.5 1 2 5

OR 10

Fig. 3. Funnel plot of association between GSTM1 polymorphism and CHD overall individuals. Formal statistical criteria by Egger’s test was also performed to investigate the symmetry of the funnel plot (P 5 0.142).
0 SE(log[OR])

0.1

0.2

0.3

0.4

0.5 0.1 0.2 0.5 1 2 5

OR 10

Fig. 4. Funnel plot of association between GSTT1 polymorphism and CHD overall individuals. Formal statistical criteria by Egger’s test was also performed to investigate the symmetry of the funnel plot (P 5 0.763).

in vivo relationship between candidate genes and complex diseases. This meta-analysis, involving a total of 8020 CHD cases and 10 501 controls from 19 case–control studies, examined the association of two commonly studied polymorphisms of GST (M1 and T1) with CHD risk. Results indicated a signi?cant association between null polymorphism of GSTM1 and CHD risk, whereas the GSTT1 polymorphism (null versus non-deleted) seems unrelated to CHD risk. In meta-analysis, heterogeneity evaluation was always conducted in statistical analysis. Thus, several subgroup meta-analyses were performed according to ethnicity control source. In racial subgroups, no statistically signi?cant association between GSTM1 or GSTT1 polymorphism and CHD appeared in Caucasians and non-Caucasians. However, the Caucasian and non-Caucasian population reports in the subgroup analysis include a mixture of populations from very 4

distant countries, so the result must be interpreted with caution. No signi?cant association between variant genotypes and CHD risk was observed when the included studies were strati?ed by control source. Such result could be due to limited number of studies that had insuf?cient statistical power to detect a slight effect or may have generated a ?uctuated risk estimate. If genetic susceptibility to CHD 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 CHD than a single locus genotype. Among the 19 studies included in the present meta-analysis, eight studies investigated the interaction between GSTM1 and GSTT1 polymorphism. By pooling the collected data on GSTM1 and GSTT1 genotypes, a statistically signi?cant 2.38fold increased risk for CHD appeared for individuals with combined deletion mutations in GSTT1 and GSTM1 genes in comparison with individuals with the positive genotypes. This result suggests that in the presence of both of the two risk factors, an important number of CHD cases would occur. Cigarette smoking is a pro-in?ammatory stimulus and an important risk factor for CHD. Unfortunately, almost all the studies did not explore the interaction between GSTs genotype and smoking habits. This was probably due to the low statistical power of the individual studies to detect interactions. Our results show a signi?cant association among smokers subgroup between GSTM1, GSTT1 polymorphism and CHD risk. The results suggest that there could be an interaction between cigarette smoking and GSTs. One possible cause is that tobacco smoke-induced DNA damage causes smooth muscle cell proliferation in the intima of arteries, thereby contributing to atherosclerotic plaque formation (8). Some limitations of this meta-analysis should be addressed. Firstly, heterogeneity is a potential problem when interpreting all the results of meta-analysis. Although we minimized the likelihood by performing a careful search for published studies, using the explicit criteria for study inclusion, the signi?cant betweenstudy heterogeneity still existed in most of comparison. The presence of heterogeneity can result from differences in the age distribution, selection of controls, prevalence lifestyle factors and so on. Secondly, the three subgroup meta-analyses considering interactions between GSTM1, GSTT1 null genotype and cigarette smoking, as well as between GSTT1 null and GSTM1 null genotypes, were performed on the basis of a fraction of all the possible data to be pooled, so selection bias may have occurred and our results may be over in?ated. In this context, more reliable results can be expected if individual data are available for a pooled analysis. Thirdly, only published studies were included in this meta-analysis. Therefore, publication bias may have occurred, even though the use of a statistical test did not show it. Despite these limitations, this meta-analysis suggests that GSTM1 polymorphisms may increase the risk of CHD, but no signi?cant effect for GSTT1 polymorphisms. In addition, GSTM1 and GSTT1 polymorphisms may modulate the tobacco-related pathogenesis of CHD and the combination of unfavourable genotypes may result in an additional risk of CHD. Larger studies of different ethnic populations, especially with detailed individual information, are needed to con?rm our ?ndings. Acknowledgements
We thank Dr Alexandre Pereira, Dr Jose Geraldo Mill, Dr Steve Humphries, ? Dr Andy Olshan and Dr jose krieger for their collaboration and for making their data available for the present meta-analysis. Con?ict of interest statement: None declared.

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Coronary heart disease susceptibility

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