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Polymorphisms of matrix metalloproteinases in myocardial infarction: a meta-analysis
  1. Junhong Wang1,
  2. Di Xu1,
  3. Xin Wu2,
  4. Chuanwei Zhou1,
  5. Hui Wang1,3,
  6. Yan Guo1,
  7. Kejiang Cao1
  1. 1Department of Gerontology, the first affiliated hospital of Nanjing Medical University, Nanjing, China
  2. 2Department of Clinical Laboratory Medicine, Benq Medical Center, Nanjing Medical University, Nanjing, China
  3. 3Department of Cardiology, The Shengze Hospital of Jiangsu Province, SuZhou, China
  1. Correspondence to Professor Guo Yan, Department of Gerontology, the first affiliated hospital of Nanjing Medical University, Nanjing 210029, PRC, China; guoyan51{at}hotmail.com

Abstract

Context The literature provides no clear answer as to whether matrix metalloproteinases (MMPs) polymorphisms increases risk of myocardial infarction (MI).

Objective Our purpose was to help clarify the inconsistent findings of MMPs polymorphisms and MI susceptibility and identify which MMP polymorphism might play an active role in the occurrence of MI.

Data Sources Articles were identified by a Medline search and citation tracking.

Study Selection Eligible articles were case–control studies of MMPs polymorphisms and MI which met our prespecified criteria.

Data extraction Data were independently extracted by two authors according to a predefined protocol. Incongruities were settled by consensus decision.

Results and Conclusions 18 potentially eligible articles were identified. In a combined analysis, the 5A allele of the MMP-3 5A/6A polymorphism was associated with MI (OR 1.21, 95% CI 1.01 to 1.46, p=0.04), suggesting its role in plaque rupture. In the subgroup analysis by ethnicity, significantly increased risk was found among East Asians (OR 1.39, 95% CI 1.01 to 1.91, p=0.04), whereas no significant association was detected in Caucasian populations. In addition, there were significant associations of the MMP-9 -1562CT polymorphism with MI (OR 1.14, 95% CI 1.02 to 1.27, p=0.02), whereas the heterogeneity of the studies showed no significance (I2=13.7%, p=0.32). This meta-analysis demonstrated that the MMP-3 5A/6A and MMP-9 -1562 CT polymorphisms are risk factors associated with increased MI susceptibility, but these associations vary in different ethnic populations.

  • MMPs
  • myocardial infarction
  • polymorphisms
  • cardiac remodelling
  • inflammation
  • coronary artery disease
  • cytokines
  • cardiac function
  • genetics

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Introduction

Myocardial infarction (MI) is the major cause of death by disease in the world; its physiopathology is complex at the molecular level which involves a wide variety of proteins, including the matrix metalloproteinases (MMPs). Some MMPs (such as MMP-2, MMP-3 and MMP-9) specifically attack type IV collagen, laminin and fibronectin, which are the major components of the basal lamina around blood vessels. There is evidence that the action of MMP enzymes weakens the arterial wall, contributing to the destabilisation and rupture of atheromatous plaque, finally leading to MI.1 Functional polymorphisms of MMPs have been reported to be related to the concentration of circulating MMPs,2 and over the past few decades, considerable efforts have been devoted to exploring the relationships between the MMPs polymorphisms and MI risk among various populations. However, existing studies have yielded inconsistent results. Some observations have suggested that genetic variation which affects the expression of MMPs may contribute to the occurrence of MI,3 4 whereas others reported no support for an association of MMPs polymorphisms with MI susceptibility.5–8 These disparate findings may be due partly to insufficient power, false-positive results and publication biases. The interpretation of these studies has been further complicated by the use of different populations or different control sources. To help clarify the inconsistent findings and identify which MMP polymorphism might play an active role in the occurrence of MI, we therefore conducted a comprehensive meta-analysis to quantify the overall risk of MMPs polymorphisms on developing MI.

Methods

Meta-analyses of observational studies present particular challenges because of inherent biases and differences in study designs. Consequently, we performed this analysis in accordance with the guidelines of the Meta-analysis of Observational Studies in Epidemiology group.9

Search strategy, study selection and data extraction

We performed a computer-based search using the PubMed database with the following search terms: combined free-text and MeSH terms relating to ‘matrix metalloproteinase (MMP) or stromelysin 1 or gelatinase or collagenase’ and ‘myocardial infarction’ and ‘polymorphism or SNP’. Publications in English until March 2011 were included. We supplemented electronic searches by hand-searching reference lists of relevant articles and reviews and by contacting experts and manufacturers involved with MMP studies. Abstracts and titles of related articles were initially scanned by a reviewer. Potentially relevant articles were then considered by at least two independent reviewers. Disagreements were resolved by discussion or upon consensus from a third or fourth reviewer. Two reviewers agreed on the inclusionary or exclusionary status of 90% of the reviewed studies. Eligibility of identified case–control studies was determined according to prespecified criteria in a two-step procedure. First, a study was provisionally selected for inclusion in the meta-analysis if the phenotype of MMPs in the patient group was related to MI. Second, specific prerequisites for inclusion were the presentation of genotype data, use of a control group without established diagnosis related to coronary disease and agreement of the genotype distribution in the control group with the Hardy–Weinberg equilibrium. Where the data from >3 similar studies were available, meta-analysis was performed.

Data analysis

Logistic regression analysis was used to examine the association between the MMPs polymorphisms and MI risk. Crude ORs with 95% CIs were used to assess the strength of association between the MMPs polymorphisms and MI susceptibility. We then used the I2 statistic to measure the extent of inconsistency among the results, and we tested heterogeneity by using the Cochran Q test.9 Because this test has poor power in the event of few studies, we considered the presence of significant heterogeneity at the 10% level of significance and values of I2 exceeding 50% as an indicator of significant heterogeneity, so that a pooled effect could be calculated with a random-effects model that was used to take into account within-study and between-study variance or, otherwise, with a fixed-effects model. To explore sources of heterogeneity, we performed several sensitivity and subgroup analyses. Publication bias was also evaluated by use of a funnel plot. All analyses were conducted with the use of Review Manager, V.4.2 (Revman, The Cochrane Collaboration) or STATA software, V.11.0 (STATA Corp).

Results

Characteristics of the included studies

The search yielded 55 reports, of which 37 were rejected (5 were review articles; 7 were non-English articles; 17 had subjects with genes other than MMPs or enrolled patients with MI or stable or unstable angina in the patient group; 1 study used non-MI coronary artery disease patients as the control; 3 papers that studied those loci did not meet the criteria of >3 similar studies and 4 articles were excluded because the genotype distribution of the control group was not in the Hardy–Weinberg equilibrium). Of the remaining 18 studies, 5 citations reported the relationship between the polymorphisms of MMP-1 -1607 1G/2G (promoter insertion–deletion single nucleotide polymorphism (SNP) rs1799750 (−1607 1G/2G)) and MI, 3 reported the SNP of MMP-2 -1306 CT (promoter SNP rs243865 (C-1306T)), 10 articles studied the MMP-3 -1612 5A/6A (promoter insertion–deletion SNP rs3025058 (−1612 5A/6A)) and 7 articles were about MMP-9 -1562 CT (promoter SNP rs3918242 (C-1562T)) polymorphism (see table 1).

Table 1

Studies investigating the association between the MMPs polymorphisms and MI risk

Meta-analysis results

The MMP-3 5A/6A polymorphism with MI

In a combined meta-analysis of the studies (9569 cases, 7264 controls), the risk of MI was significantly different between the carriers of the 5A allele (5A5A and 5A6A genotypes) and the carriers of the 6A6A homozygote (OR 1.21, 95% CI 1.01 to 1.46, p=0.04) (figure 1). There was considerable heterogeneity across the data included in the meta-analysis (I2=83.2%, p<0.00001). A random-effects meta-regression analysis identified the inclusion of study samples of different origins, namely of Caucasian and Asian descent, as a major source of heterogeneity (p<0.001). When combined effects were determined according to the origin of study participants, the risk of MI showed no significance between the 5A allele carriers and 6A6A carriers of Caucasian ancestry (OR 1.03, 95% CI 0.88 to 1.21, p=0.07) (figure 1), and an increased risk in the 5A allele carriers of Asian descent (OR 1.39, 95% CI 1.01 to 1.91, p=0.04) was observed. There were still heterogeneity among the studies from Asia (I2=87%, p<0.00001) and moderately significant heterogeneity among the studies with participants of Caucasian origin (I2=58.5%, p=0.07). A sensitivity analysis revealed that the high degree of heterogeneity among the data from subjects of Asian descent was mainly caused by the results of Yamada et al.16

Figure 1

ORs of myocardial infarction (MI) (with 95% CIs) in matrix metalloproteinase (MMP)-3 -1612 5A/6A 5A allele carriers (5A5A or 5A6A genotype) versus 6A6A genotype carriers examined in 10 studies.

The MMP-9 -1562C/T polymorphism with MI

Unlike the results obtained from most of the studies included in this meta-analysis, our results demonstrated that the risk of MI was significantly higher in patients carrying the T allele (CT+TT genotypes) than those with the CC genotype (OR 1.14, 95% CI 1.02 to 1.27, p=0.02) (figure 2). Furthermore, there was no significant heterogeneity across the data included in the meta-analysis (I2=13.7%, p=0.32), and also, no publication bias was detected (p=0.368 (Begg's test)).

Figure 2

ORs of myocardial infarction (MI) (with 95% CIs) in T allele carriers (CT or TT genotype) of matrix metalloproteinase (MMP)-9 -1562 CT polymorphism versus CC genotype carriers examined in seven studies.

Other MMPs polymorphisms with MI

Five studies (3459 cases, 2379 controls) that identified an association between MMP-1 -1607 1G/2G polymorphism and MI risk met the above-mentioned criteria and were then included in our meta-analysis. However, no significantly increased risk of MI was seen in the patients carrying the 2G allele (1G2G+2G2G) than those with the 1G1G genotype (OR 0.96, 95% CI 0.85 to 1.09, p=0.52) (figure 3), and no significant heterogeneity across the data was seen in the meta-analysis (I2=2.2%, p=0.39). The same results were also observed in patients carrying the 1G allele in comparison to the 2G2G genotype (OR 1.07, 95% CI 0.95 to 1.2), whose heterogeneity across the data remained not significant (I2=0%, p=0.50). As for MMP-2 -1306 CT polymorphism, there were only three citations (624 cases, 662 controls) eligible for meta-analysis. And our results demonstrated that variant genotype of MMP-2 -1306 C>T may not be a risk factor for MI (OR 0.82, 95% CI 0.44 to 1.53) (figure 4).

Figure 3

ORs of myocardial infarction (MI) (with 95% CIs) in 1G allele (1G1G or 1G2G) carriers of matrix metalloproteinase (MMP)-1 -1607 1G/2G polymorphism versus 2G2G genotype carriers examined in five studies.

Figure 4

ORs of myocardial infarction (MI) (with 95% CIs) in T allele carriers (CT or TT) of matrix metalloproteinase (MMP)-2 -1306 CT polymorphism versus CC genotype carriers examined in three studies.

Discussion

To address the association between genetic variants and MI, an increasing number of articles on genetic association studies and related pooled analyses have been published. Recently, several genome-wide association studies (GWAs) have individually identified more than 20 novel SNPs located in 13 chromosomal loci with genome-wide significance for association with MI.23 24 Especially, a meta-analysis performed by the Coronary Artery Disease Genome-Wide Replication And Meta-Analysis consortium enhanced the statistical power to detect true association of those SNPs with MI by using a large combined GWAs data.23 However, these loci explain only a small proportion of the genetic variability of MI, and up to the present, no GWAs data on the association of MMPs and MI can be obtained from the published data. Meanwhile, considerable evidence has implied a role of MMPs in MI,19 22 and many genetic association studies with MMP variants have been performed, although conclusions from many of these are complicated by poor methodology, particularly small sample sizes, and by the possibility of publication bias. The most studied polymorphisms of MMPs are the MMP-3 5A/6A and the MMP-9 -1562CT.2 5–7 16

The promoter of human MMP-3 contains a common deletion/insertion polymorphism, characterised by runs of five or six adenosines, 1612 bp upstream from the start site of transcription, which is also known as 5A/6A polymorphism.4 The MMP-3 6A6A genotype is suggested to be associated with atherosclerosis, and the 5A allele with plaque rupture.25 On meta-analysis of published studies, we found a marked association between the 5A allele and MI (OR 1.21, 95% CI 1.01 to 1.46, p=0.04), suggesting its possible role in plaque rupture. This result was in good agreement with data from a prior meta-analysis of the association between 5A/6A polymorphism and MI.3 However, there was still some difference between the two studies. First, three studies included in that meta-analysis were not eligible because the genotype distribution of the control of group was not consistent with the Hardy–Weinberg equilibrium26 27 or the control group with non-MI coronary artery disease patients did not meet our criteria.25 In addition, more data from Caucasian population studies were included in our meta-analysis.5 7 15 17 With more diverse ethnic background samples added in, the conclusions might be more reliable. Although the overall result of the present meta-analysis suggested an association of MMP-3 5A/6A polymorphism with MI, the combination of samples from Caucasian and Asian descent contributed significantly to the high degree of heterogeneity across the studies. Therefore, when the risk of MI was estimated according to ancestry, that is, Caucasian or Asian, we observed that significantly increased risk of MI was still seen in patients carrying the 5A allele in Asians (OR 1.39, 95% CI 1.01 to 1.91, p=0.04). Meanwhile, nonsignificant results with slight trends of increased risk of MI were observed in Caucasian population (OR 1.03, 95% CI 0.88 to 1.21, p=0.71). This ethnicity-related heterogeneity may reflect the striking differences that exist in the allele frequencies of MMP-3 5A/6A between populations of Caucasian and other ethnic group.5 Rockman et al28 reported that increased frequency of the 5A allele to approximately 50% was seen in Europeans but not elsewhere, including Asians, where the frequency of the 5A allele is ∼15%. In addition, after the studies were stratified by ethnicity, the heterogeneity remained highly significant across the studies in Asians. This heterogeneity may be due to the study of Yamada et al16 whose genotype distribution was greatly different from those in the control group of other studies.7 11 15 When excluding this study from our meta-analysis in Asians, no significant heterogeneity across the studies was then observed (I2 =17.2%, p=0.31, date not shown).

Of the many MMPs, MMP-9 might play an important role in matrix degradation and the subsequent rupture of the atherosclerotic plaques, owing to its broad substrate specificity and distal position in the matrix proteolytic cascade. Previous reports demonstrated that, unlike other MMPs, active synthesis of MMP-9 was detected in lesion of coronary atherectomy specimens from patients with unstable angina but not those with stable angina.29 These observations lead to the suggestion that MMP-9 might play an important role in the rupture of atherosclerotic plaques. Zhang et al22 described a functional -1562CT polymorphism in the promoter region of MMP-9. Further transfection experiments indicated that the T allele had higher activity and carriers of the T allele had greater levels of MMP-9 mRNA and protein.30 Data from seven studies were combined in our meta-analysis to investigate the association between MMP-9 -1562CT polymorphism and MI. In contrast to most of the studies included in our meta-analysis, which failed to confirm an association between the T allele and MI, our results demonstrated a close association between the T allele of MMP-9 and MI (OR 1.14, CI 1.02 to 1.27, p=0.02). Furthermore, the heterogeneity across the data included in the meta-analysis was not significant (I2=13.7%, p=0.32), which indicated that the relatively small sample sizes may be the reason for previous results of non-association in T allele and MI susceptibility. However, as only few clinical observations confirmed the association between this SNP and MMP-9 level,30 whether this is a functional SNP or not still requires more clinical observations, large genetic association studies or GWAs data to provide a precise estimate of this association and rule out possible modest causal effects.

Our meta-analysis of studies associating the MMP-1 -1607 1G/2G and MMP-2 -1562 CT polymorphisms with MI found no evidence of associations. The insertion of a guanine (G) at the -1607 bp in the MMP-1 promoter region creates the sequence 5′-GGA-3′, which has higher transcriptional activity than that with 1G allele. The MMP-1 promoter 1G/2G polymorphism has been shown to be associated with the progression of melanoma. However, this meta-analysis and previous reports did not find significant association of MMP-1 promoter 1G/2G polymorphism and susceptibility to MI. Therefore, we might draw the conclusion that MMP-1 1G/2G polymorphism may not play an important role in the occurrence of MI. Additionally, as the number of studies examining the association with polymorphisms in other MMP genes is limited, no meta-analysis of these data was possible.

In summary, this meta-analysis suggests a role of MMP-3 5A/6A and MMP-9 -1602 CT polymorphisms in the occurrence of MI. However, conclusions are limited by poor methodology in many studies. For future studies, strict selection of patients, well-matched controls, larger sample size and GWAs will be required. Moreover, gene–gene and gene–environment interactions should also be considered in future studies.

References

Footnotes

  • Funding This work was supported by the National Natural Science Foundation of China (NSFC 30900602 to Dr Wang Junhong).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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