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CLINICAL STUDY

Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease

Nicolas Lamblin, MD^*, Christophe Bauters, MD, FACC^*,*, Xavier Hermant, Jean-Marc Lablanche, MD, FACC^*, Nicole Helbecque, PhD and Philippe Amouyel, MD, PhD^*

^* Centre Hospitalier Universitaire de LilleLille Cedex, France
INSERM U508, Institut Pasteur de Lille, Lille Cedex, France

Manuscript received January 10, 2002; revised manuscript received March 6, 2002, accepted March 14, 2002.

^* Reprint requests and correspondence: Dr. Christophe Bauters, Service de Cardiologie C, Hôpital Cardiologique, CHRU de Lille, 59037 Lille Cedex, France.
cbauters{at}chru-lille.fr

	Abstract

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OBJECTIVES: Our hypothesis was that functional polymorphisms in matrix metalloproteinase (MMP) genes may act as susceptibility factors for the development of coronary aneurysms (CAs).

BACKGROUND: Different forms of remodeling have been described at the level of coronary arteries; CA, reported in 1% to 5% of patients with angiographic evidence of coronary artery disease (CAD), are one of them. Matrix metalloproteinases have been implicated in the pathogenesis of aneurysm development through increased proteolysis of extracellular matrix proteins.

METHODS: We screened 3,862 patients who underwent coronary angiography and identified 113 patients with CAD with at least one CA (CA group); these patients were matched with 226 patients with CAD without CA (control group). The –1,306 C/T MMP-2, 5A/6A MMP-3, CA-repeat MMP-9 and –82 A/G MMP-12 polymorphisms were determined.

RESULTS: The MMP-2, MMP-9 and MMP-12 polymorphisms were not associated with CA. By contrast, the 5A/5A genotype of MMP-3 was significantly more frequent in the CA group than in the control group (31% vs. 18%, p = 0.015); similarly, the MMP-3 5A allele was more frequent in the CA group (p = 0.009). Three variables were independently associated with CA: the MMP-3 5A/5A genotype (odds ratio [OR] = 2.23, 95% confidence interval [CI] [1.27 to 3.93]), a previous myocardial infarction (OR = 1.91, 95% CI [1.14 to 3.20]) and a history of aortic aneurysm (OR = 21.06, 95% CI [2.35 to 188]).

CONCLUSIONS: The MMP-3 5A allele is associated with the occurrence of CA. Our results suggest that an increased proteolysis in the arterial wall may act as a susceptibility factor for the development of CA in patients with coronary atherosclerosis.

Abbreviations and Acronyms   CA   coronary aneurysm   CAD   coronary artery disease   CI   confidence interval   MI   myocardial infarction   MMP   matrix metalloproteinase   OR   odds ratio   PCR   polymerase chain reaction   TIMP   tissue inhibitor of metalloproteinases

Studies performed in patients with aortic aneurysms may offer some insights into the general pathogenesis of aneurysms. The matrix metalloproteinases (MMPs) have been implicated in the development of aortic aneurysms through increased proteolysis of extracellular matrix proteins (6). Previous studies have found that MMP-1 (interstitial collagenase), MMP-2 (72-kD gelatinase or gelatinase A), MMP-3 (stromelysin-1), MMP-9 (92-kD gelatinase or gelatinase B) and MMP-12 (macrophage metalloelastase) are expressed in aortic aneurysms at elevated levels compared with normal vessel wall (6–10). This arsenal of MMPs has the capacity to degrade virtually all components of the extracellular matrix in the arterial wall (collagens, elastin, proteoglycans, laminin, fibronectin, etc.). On the other hand, a decreased level of tissue inhibitor of metalloproteinases (TIMP) has been reported in aortic aneurysms (9,11). Moreover, in experimental models, inhibitors of MMPs (12), MMPs gene disruption (13,14) or the overexpression of TIMP-1 (15) may block aneurysm development.

Our study hypothesis was that a genetic-mediated increased proteolysis in the arterial wall may act as a susceptibility factor for the development of CA in patients with coronary atherosclerosis. Four candidate genes were selected: MMP-2, MMP-3, MMP-9 and MMP-12. Polymorphisms described in the promoters of these four genes are functional because they exhibit different transcriptional activities in vitro (16–20) and were implicated in different in vivo studies (18,19,21–23). They may, consequently, play a role in the regulation of extracellular matrix proteolysis. Thus, we designed the present case/control study to compare allele and genotype frequencies among 113 patients with atherosclerotic CA and 226 control patients with coronary atherosclerosis but without aneurysm formation.

	Materials and methods

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Study population.   The study population was prospectively selected from a series of 3,862 consecutive patients who underwent coronary angiography at Centre Hospitalier Universitaire de Lille. A CA was defined as a localized or diffuse coronary dilation that exceeded the diameter of the angiographically apparently normal adjacent segments by a factor of >1.5 (3). A total of 113 patients with angiographically proven coronary atherosclerosis who had at least one CA constitute the CA group. During the same period, we randomly selected 226 patients (2:1 ratio) who presented with coronary atherosclerosis, but without CA, to form the atherosclerotic control group. All patients gave informed consent for the study.

Clinical and angiographic data
Epidemiological and clinical characteristics were collected by trained physicians. Coronary angiograms were analyzed by two experienced interventional cardiologists. The number of nonsignificant (50%) or significant (>50%) stenoses was recorded for each patient. The extent of aneurysmal disease (number of diseased segments and of diseased vessels per patient) was also noted as was the type (diffuse or focal) of CA. Aneurysmal disease was classified as focal when it involved a discrete portion of a segment with adjacent normal appearing segments on both sides and diffuse when the entire segment was dilated with no normal vessel within the segment.

The largest diameter of each aneurysmal vessel was measured by quantitative coronary angiography with use of the cardiovascular measurement system as previously described (24).

Genetic study
Blood samples were collected at the time of coronary angiography. Genomic deoxyribonucleic acid was extracted from white blood cells by a "salting out" procedure as previously described (25). Deoxyribonucleic acid fragment amplification was performed by polymerase chain reaction (PCR). Primers and PCR conditions used for MMP-3 (17,18) have been reported previously. The primers used in –1,306 C/T MMP-2 PCR (sense 5"-TGTTGGGAACGCCTGACTTCAG-3" and antisense 5"-CTGACCCCCAGTCCTATCTGCC-3"), CA-repeat MMP-9 PCR (sense 5"-GAGAGAGGAGGAGGTGGTGTAAG-3" and antisense 5"-TGACAGGCAAGTGCTGACTC-3") and in –82 A/G MMP-12 PCR (sense 5"-AAGAGCTCCAGAAGCAGTGG-3" and antisense 5"-TGAGGTGGGTAAGAGTACAATGG-3") were designed from the DNA sequence surrounding the polymorphism. Annealing temperatures were 58°C (MMP-2), 56°C (MMP-9) and 59°C (MMP-12). The –1,306 MMP-2, 5A/6A MMP-3 and the –82 A/G MMP-12 polymorphisms were detected using allele-specific oligonucleotide hybridization with the following probes (polymorphism underlined): wild-type probe 5"-AGCACTCCACCTCTT-3" and mutated probe 5"-AGCACTCTACCTCTT-3" for MMP-2 (hybridization at 40°C and washing at 42°C), 5A-probe 5"-ACATGGTTTTTCCC-3" and 6A-probe 5"-GGGAAAAAACCATG-3" for MMP-3 (hybridization at 35°C and washing at 37°C) and wild-type probe 5"-TATCAACTATGAGTCAC-3" and mutated probe 5"-ATCAACTGTGAGTCAC-3" for MMP-12 (hybridization at 43°C, washings at 47°C and 45°C, respectively). The MMP-9 polymorphism, a CA-repeat, was analyzed by PCR, and fragments were separated on 8% nondenaturated acrylamide gel, as previously described (26).

Statistical analysis
Statistical analysis was performed with SAS software, version 6.12 (SAS Institute Inc., Cary, North Carolina). Mean values ± SD were calculated for quantitative data. The quantitative variables were compared between groups with use of unpaired Student t tests. Qualitative variables were compared with use of the Pearson’s chi-square test or the Fisher exact test when necessary. Logistic regression analysis was used to determine variables that were independently associated with aneurysmal CAD. Values of p < 0.05 were considered significant.

	Results

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Except for male gender, previous MI and an history of aortic aneurysm, which were significantly more frequent in the CA group (90% vs. 80%, p = 0.017; 68% vs. 52%, p = 0.005 and 7% vs. 0.4%, p = 0.0003, respectively), the baseline characteristics were similarly distributed in both groups (Table 1).

View larger version (56K): [in this window] [in a new window]   Figure 1 Representative examples of coronary aneurysms. (A) Diffuse aneurysmal disease of the right coronary (maximal diameter: 6.8 mm). (B) Diffuse aneurysmal disease of the proximal and midleft anterior descending artery (maximal diameter: 9.3 mm). (C) Focal aneurysm of the proximal right coronary artery (arrow) (maximal diameter: 11.6 mm).

	Discussion

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CAs.   Coronary aneurysms are defined as localized or diffuse abnormal dilation of the coronary arterial tree. In the present study, 2.9% of the patients undergoing coronary angiography had CA; previous studies have reported rates ranging between 1% and 5% (2–5). Although CA may be related to specific diseases such as heritable disorders of connective tissue or inflammatory arteritis, most cases simply coexist with coronary atherosclerosis, and it has been suggested that aneurysmal CAD does not represent a distinct clinical entity but is, rather, a variant of coronary atherosclerosis (3,4). The mechanisms by which CA may occur in response to atherosclerosis are unknown. However, as shown by Virmani et al. (4), the main histological features of CA are lipid deposition with foam cells, fibrous caps and extensive destruction of musculoelastic elements of the media; these findings are similar to those described for aortic aneurysms. Moreover, in the present study, a significant association was found between CAs and aortic aneurysms. This suggests that similar processes may, at least in part, explain the occurrence of CAs and aortic aneurysms.

Proteolysis and aneurysms
The development of aortic aneurysms is associated with inflammation, tissue-remodeling and upregulation of MMPs. Matrix metalloproteinases can degrade a variety of extracellular proteins such as elastin, collagen or proteoglycans (27). Increased levels of MMP-2, MMP-3, MMP-9 and MMP-12 have been found in the aneurysmal wall (6–10). Recently, gene disruption of MMP-9 has been found to suppress the development of experimental abdominal aortic aneurysms (13). Conversely, a decreased level of TIMP has been found in the aneurysmal wall (9,11); moreover, Allaire et al. (15) have recently reported that local expression of TIMP-1 may prevent aortic aneurysm degeneration and rupture in a rat model. Taken together, these data suggest that the proteolytic balance in the vascular wall is a key determinant of aneurysm development.

Polymorphisms of MMP-2, MMP-3, MMP-9 and MMP-12
Matrix metalloproteinase-2, MMP-3, MMP-9 and MMP-12 genes all have polymorphisms in their promoter regions associated with different transcriptional activities in vitro.

The –1,306 C/T MMP-2 polymorphism was recently described by Price et al. (16). They demonstrated that the common C T transition at position –1,306 was functional and that the C allele was associated with the higher promoter activity.

In cultured fibroblasts and vascular smooth muscle cells, the MMP-3 5A allele is associated with a higher promoter activity than the 6A allele (18); this should theoretically lead to a higher proteolytic activity in subjects carrying the 5A allele. In a recent study, Yoon et al. (21) reported a trend for a higher frequency of the 5A allele in patients with aortic aneurysms compared with control patients.

A repeat polymorphism has been identified in the promoter of MMP-9. Variation in the length of this repetitive element was shown to modulate promoter activity in an in vitro reporter assay, with the highest promoter activity being observed in constructs bearing the longest element (23 CA) (19). The 23 CA repeat allele has been identified as a susceptibility factor for intracranial aneurysms (19).

Concerning MMP-12, a common polymorphism within the promoter (A G transition at position –82) has been identified. The polymorphism influences the binding of the transcription factor AP-1; the higher binding activity of AP-1 to the MMP-12 A allele is associated with a higher MMP-12 promoter activity in in vitro experiments (20).

The present study
This is the first study looking for genetic susceptibility factors to CA. The MMP-9 and MMP-12 polymorphisms were not associated with the occurrence of CA. Although the difference was not statistically significant, the more active C allele of the MMP-2 polymorphism tended to be more frequent in cases than in controls. Our major finding was that the MMP-3 5A allele was significantly more frequent in the CA group than in the control group (p = 0.009). Moreover, by multivariate analysis, the MMP-3 genotype was an independent predictor of CA (OR = 2.23, 95% CI [1.27 to 3.93]).

The MMP-3 or stromelysin-1 is an important member of the metalloproteinase family; various cell types may produce MMP-3 in the vessel wall: fibroblasts, smooth muscle cells and macrophages (28). Increased MMP-3 activity could potentially contribute to the development of structural alterations in the vessel wall through the degradation of extracellular matrix proteins such as proteoglycans, laminin, fibronectin and collagen types III, IV, V and IX (18,27); furthermore, MMP-3 can amplify the proteolytic effect of MMP-1 and MMP-9 (29). As stated above, MMP-3 activity is increased in the wall of aortic aneurysms (6); moreover, MMP-3 activity has been colocalized with macrophages infiltrating the aneurysmal wall (30). Recently, Carrell et al. (31) examined differences in MMPs between patients with aortic aneurysm and patients with aortic atherosclerosis but without aneurysm; among a wide range of MMPs tested, only MMP-3 was overexpressed in the aortic aneurysm samples. Finally, in a recent study (14), reduced aneurysm formation has been observed in mice with MMP-3 gene inactivation.

Because the MMP-3 5A allele is associated with the higher promoter activity (18), it is tempting to speculate that an increased proteolysis in the vessel wall may act as a susceptibility factor for the development of CA. The observation by Yoon et al. (21) that the 5A allele was more frequent in patients with aortic aneurysms compared with control patients is consistent with our results. Although our results do not imply that MMP-3 plays a role in CA, one attractive hypothesis would be that the higher production of MMP-3 associated with the 5A allele may lead to an increased remodeling process of coronary arteries in response to atherosclerosis. Previously published studies on the MMP-3 5A/6A polymorphism tend to support this hypothesis; while the 5A allele has been associated with acute coronary syndromes (22) (a situation in which increased proteolysis may also be important), the less active 6A allele has been associated with angiographic progression of CAD (17,18) or restenosis after balloon angioplasty (23) (two situations in which decreased proteolysis and subsequent matrix deposition may play a role). Finally, the recent observation that high circulating levels of MMP-3 are associated with coronary lesions in Kawasaki disease (32) also supports an important role for MMP-3 in the pathogenesis of CAs.

We observed that CA was independently associated with MI; this finding is concordant with previously published studies (2,3). The mechanisms underlying this association are unknown, but at least two plausible hypotheses can be advanced. First, CA have been associated with abnormal blood flow (33), which may increase the risk of thrombus formation with subsequent embolization or in situ thrombosis; recent studies have also suggested that the aneurysmal wall may be a source of thrombogenic substances (34). Second, as discussed above, CA development may simply reflect an increased proteolytic activity in the arterial wall. This increased proteolysis could theoretically predispose to an increased risk of plaque rupture and a subsequent acute coronary event (1).

A history of aortic aneurysm was more frequently observed in the CA group. This finding should be interpreted with caution because it was not the primary objective of our study; moreover, systematic screening for aortic aneurysm was not performed. However, the fact that a history of aortic aneurysm was significantly more frequent in the CA group (OR = 21.06, 95% CI [2.35 to 188]) suggests that both processes share common physiopathologic mechanisms that are likely to be determined on a patient-related basis rather than on a lesion-(local) related basis. A recent study showing an ubiquitous elevation of MMP-2 expression in the vasculature of patients with abdominal aneurysms supports this hypothesis (35). Patients with multiple aneurysms (i.e., aortic, coronary or other locations) would indeed be interesting candidates for future research on genetic risk factors for atherosclerotic aneurysmal disease. In addition, a prospective study should be designed to test whether systematic screening for asymptomatic aortic aneurysm is a beneficial and cost-effective strategy in patients with CAs.

Study limitations
The association of an MMP polymorphism with CA does not necessary imply that the genetic variation is, in itself, responsible for the increased risk of CA. In addition, the increased levels of MMPs in the aneurysmal wall may depend not only on an increased synthesis from more active alleles but also on an increased infiltration of MMPs producing cells such as monocytes and macrophages. However, the present study benefited from a prospective recruitment and from a candidate gene approach. We selected four genes on the basis of their relevance in the pathophysiology of aneurysms, and all the polymorphisms selected for this study exhibit different transcriptional activities in vitro.

Finally, although our study clearly supports an association between the MMP-3 genotype and CA, the limited number of patients with CA does not allow us to exclude an influence of the other polymorphisms on this abnormal form of remodeling; thus, our findings should be taken as hypothesis-generating rather than conclusive. With a statistical power of 80% and a significance value of 0.05, the sample size of this study allowed us to detect a 9% difference in the frequency of the MMP-2 T allele, a 6% difference in the frequency of the MMP-9 (CA) 23 allele and a 7% difference in the frequency of the MMP-12 G allele. However, we prospectively analyzed 3,862 coronary angiography procedures to select the CA group; the design of larger studies would imply a multicentric recruitment.

	Conclusions

Top Abstract Materials and methods Results Discussion Conclusions References

 
The MMP-3 5A allele is associated with the occurrence of CA. This supports the hypothesis that an increased proteolysis in the arterial wall may act as a susceptibility factor for the development of CA in patients with coronary atherosclerosis although other mechanisms cannot be excluded.

	References

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