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01 September 2014: Special Reports
Association Between GSTM1 Null Genotype and Coronary Artery Disease Risk: A Meta-Analysis
Mei Yang ABCDEF , Jing Zhao ABCDEF , Lin Xing ABCD , Li Shi ABCD
DOI: 10.12659/MSM.890876
Med Sci Monit 2014; 20:1550-1555
Call: +1.631.470.9640
Mon - Fri 10:00 am - 02:00 pm EST
01 September 2014: Special Reports
Association Between GSTM1 Null Genotype and Coronary Artery Disease Risk: A Meta-Analysis
Mei Yang ABCDEF , Jing Zhao ABCDEF , Lin Xing ABCD , Li Shi ABCD
DOI: 10.12659/MSM.890876
Med Sci Monit 2014; 20:1550-1555
Abstract
BACKGROUND: We conducted a meta-analysis to assess the association between polymorphisms of GSTM1 null genotype and coronary artery disease (CAD) risk.
MATERIAL AND METHODS: Published literature from PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) were retrieved before March 2014. All studies reporting adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of CAD risk were included.
RESULTS: A total of 13 case-control studies, including 5453 cases and 5068 controls, were collected. There was a significant association between GSTM1 null genotype and CAD risk (adjusted OR=1.26; 95% CI, 1.11–1.43; I^2=3%). When stratified by ethnicity, a significantly elevated risk was observed in whites. In the subgroup analysis according to disease type, a significantly increased myocardial infarction (MI) risk was observed. Subgroup analysis of smoking status showed an increased CAD risk in smokers.
CONCLUSIONS: Our results indicate that GSTM1 null genotype is associated with an increased CAD risk.
Keywords: Coronary Artery Disease - genetics, Case-Control Studies, Genetic Association Studies, Genetic Predisposition to Disease, Glutathione Transferase - genetics, Polymorphism, Genetic, Risk Factors
Background
Coronary artery disease (CAD) is the leading health problem worldwide and is the leading cause of mortality in the United States. The role of DNA oxidative stress in the pathogenesis of atherosclerosis and its association with increased production of reactive oxygen species has been well established [1]. The mutagenic activities of cigarette smoke chemicals can cause DNA adducts in target tissues and oxidative modification and progression of atherosclerotic lesions. The glutathione S-transferases (GSTs) are a gene superfamily of phase II metabolic enzymes that detoxify free radicals, particularly in tobacco smoke [2].
Material and Methods
PUBLICATION SEARCH:
We conducted a literature search before February 2014 in PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases without restrictions. Combination of the following terms were applied: ‘coronary heart disease’ OR ‘coronary artery disease’ OR ‘myocardial infarction’ OR ‘acute coronary syndrome’ OR ‘ischemic heart disease’ OR ‘cardiovascular disease’ OR ‘major adverse cardiac event’ OR ‘CHD’ OR ‘CAD’ OR ‘MI’ OR ‘ACS’ OR ‘IHD’ OR ‘MACE’; ‘Glutathione S-transferases’ OR ‘GSTM1; ‘polymorphism’ OR ‘variant’ OR ‘genetic’ OR ‘mutation’. We also conducted a manual search to find other articles based on references identified in the individual articles.
INCLUSION CRITERIA AND DATA EXTRACTION:
We included articles if they met all the following criteria: (1) evaluation of
Data were extracted by 2 authors independently. In case of conflicting evaluations, an agreement was reached following a discussion; if agreement could not be reached, another author was consulted to resolve the debate. The following information was extracted from each study: first author, year of publication, ethnicity, age, sex, disease type, sample size, smoking status, covariates, adjusted Ors, and the corresponding 95% CIs of CAD risk.
STATISTICAL ANALYSIS:
For the GSTM1 gene, we estimated the risk of the null genotype on CAD compared with the non-null genotypes in the recessive model (null verses heterozygous + wild type). The strength of the association between the GSTM1 gene and CAD risk was measured by ORs with 95% CIs. The ORs with corresponding 95% CIs from individual studies were pooled using random-effects models. Heterogeneity between the studies was quantified using the Cochran Q test in combination with the I2 statistic, which represents the percentage of variability across studies that is attributable to heterogeneity rather than to chance. Heterogeneity among studies was considered significant when P was less than 0.1 for the Q-test or when the I2 value was greater than 50%. Subgroup analyses were stratified by ethnicity, disease type, smoking status, and covariates of adjustment. Cumulative meta-analysis was performed. Sensitivity analysis was further performed by excluding single studies sequentially to assess the impact of the individual study on the pooled estimate. Funnel plots and Egger’s regression test were undertaken to assess the potential publication bias [16]. Data analysis was performed using STATA 12 (StataCorp LP, College Station, Texas, USA).
Results
STUDY CHARACTERISTICS:
We ultimately identified a total of 13 articles reporting the relationship between GSTM1 null genotype and CAD risk [3–15]. A total of 5453 cases and 5068 controls were included in this meta-analysis. Table 1 summarized the main characteristics of those included studies. There were 8 case-control studies from white populations and 5 case-control studies from Asian populations.
QUANTITATIVE DATA SYNTHESIS:
The evaluations of the association between GSTM1 polymorphism and CAD risk are summarized in Table 2. The null genotype of GSTM1 was associated with a significantly increased risk of CAD when compared with present genotype (adjusted OR=1.26; 95% CI 1.11–1.43; I2=3%; Figure 1). When stratified by ethnicity, a significantly elevated risk was observed in whites (OR=1.22; 95% CI 1.06–1.41; I2=0%) but not in Asians (OR=1.20; 95% CI 0.85–1.71; I2=50%). In the subgroup analysis according to disease type, a significantly increased myocardial infarction (MI) risk was observed (OR=1.19; 95% CI 1.01–1.40; I2=0%). Subgroup analysis of smoking status showed that increased risks were found in smokers (OR=1.97; 95% CI 1.59–2.44; I2=4%) but not in non-smokers (OR=1.20; 95%CI, 0.96–1.51; I2=0%). When we limited the meta-analysis to studies that controlled for confounders such as age, sex, smoking, diabetes, hypertension, family history, and dyslipidemia, a significant association between GSTM1 null genotype and CAD risk remained.
As shown in Figure 2, significant associations were evident with each addition of more data over time. The results showed that the pooled ORs tended to be stable. A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set to the pooled ORs, and the corresponding pooled ORs were not materially altered (Figure 3).
Funnel plot and Egger’s test were performed to assess the publication bias of the literature. The shape of the funnel plot did not reveal any evidence of obvious asymmetry (data not shown). Egger’s test did not find evidence of publication bias (
Discussion
The present meta-analysis, including 5453 cases and 5068 controls from 13 case-control studies, explored the associations of
Previous studies have shown that individuals with
Our study has some strengths. First, it was the first meta-analysis to report the adjusted ORs between
Some limitations in this meta-analysis should be addressed. First, the number of studies included in our meta-analysis remained small. Thus, publication bias may exist, although the funnel plots and Egger’s linear regression tests indicated no remarkable publication bias. Second, lack of the original data of the eligible studies limited the evaluation of the effects of the gene-environment interactions in CAD development. Third, no prospective studies have addressed this association between
Conclusions
This meta-analysis supports an association between
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