doi: 10.1161/hs0901.095382
(Stroke. 2001;32:2198.)
© 2001 American Heart Association, Inc.
Original Contributions |
Polymorphisms in Matrix Metalloproteinase-1, -3, -9, and -12 Genes in Relation to Subarachnoid Hemorrhage
From the Human Genetics Research Division (B.Z., S.D., W.M.H., I.N., S.Y.) and Clinical Neurosciences Research Division (I.G., F.I.), University of Southampton, School of Medicine (UK).
Correspondence to Dr Shu Ye, Human Genetics, Duthie Building (Mailpoint 808), Southampton General Hospital, Tremona Rd, Southampton SO16 6YD, UK. E-mailShu.Ye{at}soton.ac.uk
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Abstract |
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Background and Purpose—— Intracranial aneurysm, which underlies the vast majority of subarachnoid hemorrhage incidences, has a multifactorial etiology, and the importance of genetic factors is increasingly recognized. Development and rupture of intracranial aneurysms involve degradation and remodeling of the vascular wall matrix in which the matrix metalloproteinases (MMPs) play an important role. The possible impact of MMP gene polymorphisms on susceptibility to intracranial aneurysms is still controversial, with conflicting data from different reported studies.
Methods—— In this study we analyzed 5 different functional promoter polymorphisms in the MMP-1, MMP-3, MMP-9, and MMP-12 genes in a sample of 92 patients with aneurysmal subarachnoid hemorrhage and 158 healthy control subjects, all from southern England.
Results—— No significant difference was detected between the patient and control groups in genotype distribution of any of the polymorphisms studied.
Conclusions—— The data do not support the hypothesis that MMP gene variations influence the development of intracranial aneurysms in the population studied.
Key Words: aneurysm, intracranial • matrix metalloproteinases • microsatellite repeats • polymorphism (genetics) • subarachnoid hemorrhage
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Intracranial aneurysm, which accounts for the vast majority of subarachnoid hemorrhage incidences, has a multifactorial etiology, with cigarette smoking, female sex, hypertension, and alcohol consumption being major risk factors.1–3 A genetic component in the etiology and pathogenesis of intracranial aneurysm is being increasingly recognized.4,5 It is estimated that first-degree relatives of patients with aneurysmal subarachnoid hemorrhage have an approximately 4-fold higher risk of suffering ruptured intracranial aneurysms compared with the general population.4 However, the genetic factors for this complex disease remain incompletely defined.
Development and rupture of aneurysms involve local degradation of vascular structural proteins and remodeling of the diseased blood vessels. Elastin and collagens are major structural components of the vascular wall, and it has been suggested that elastinolysis is particularly pertinent to vessel dilatation, while collagenolysis relates to aneurysmal rupture.6 For abdominal aortic aneurysms, there is compelling evidence indicating that a number of matrix metalloproteinases (MMPs) with proteolytic activities against extracellular matrix proteins, including elastin and collagens, play an important role in these processes.6,7 It has been shown that expression of MMP-1, MMP-2, MMP-3, MMP-9, and MMP-12 is increased in abdominal aortic aneurysmal tissues compared with normal blood vessels and that development of experimental abdominal aortic aneurysms is suppressed in MMP-9–deficient animals.8–11 Less is known about the role of the MMPs in the development and rupture of intracranial aneurysms. However, increased expression and activity of several MMPs, including MMP-2, MMP-9, and MMP14, in intracranial aneurysms have been demonstrated.12,13
The promoters of the MMP-1, MMP-3, MMP-9, and MMP-12 genes contain polymorphisms.14 Some of these promoter polymorphisms have allele-specific effects on the regulation of MMP gene transcription and are associated with the development and progression of coronary heart disease and cancers and possibly abdominal aortic aneurysms.15–26 Polymorphisms in the MMP-3 and MMP-9 genes have previously been analyzed in relation to susceptibility of intracranial aneurysms, but the findings from different studies were inconsistent.26,27
To address the question as to whether MMP genotypes are genetic determinants of intracranial aneurysms, we analyzed several promoter polymorphisms in the MMP-1, MMP-3, MMP-9, and MMP-12 genes in a sample of 92 patients with aneurysmal subarachnoid hemorrhage and 158 healthy control subjects, all from southern England.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects
A cohort of 92 unrelated patients (32 male and 60 female; age range, 23 to 75 years; mean age, 50 years) of European white ancestry, who suffered from aneurysmal subarachnoid hemorrhage and received surgical treatment (removal or clipping of aneurysm in craniotomy or endovascular Guglielmi detachable coil embolization) in the Wessex Neurological Center, Southampton General Hospital, were recruited in this study. The aneurysms were located in the anterior communicating artery in 32 patients, posterior communicating artery in 23 patients, middle cerebral artery in 23 patients, posterior inferior cerebellar artery in 6 patients, basilar artery in 4 patients, and carotid artery in 4 patients. The study was approved by the South and West Local Research Ethics Committee (submission No. 170/98), and written consent was obtained from the participants. The control subjects (86 male and 72 female; age range, 3 to 63 years; mean age, 39 years) were renal or bone marrow donors from the same population in the Wessex region in England as the cases.
Determination of Genotypes
Blood DNA samples were prepared by the standard salt precipitation method.28 The methods used to type the MMP-1 1G/2G, MMP-3 5A/6A, MMP-9 C-1562T, and MMP-12 A-82G polymorphisms have been described previously.17,21,29,30 Briefly, the DNA sequence containing the relevant polymorphic site was amplified by polymerase chain reaction (PCR), and the amplicon was digested with an appropriate restriction enzyme that cleaves only 1 of the 2 alleles. The digests were then subjected to gel electrophoresis and visualized by Vistra green or ethidium bromide staining.
The method described by St Jean et al31 was adopted with modification to type the MMP-9 microsatellite polymorphism. Briefly, the PCR conditions and primer sequences were as described by St Jean et al, but in this study the forward primer was labeled with a fluorescent tag (Fam) and the PCR amplicons were sized by the GeneScan method with an ABI Prism 310 Genetic Analyzer (Applied Biosystems).
The sequences of PCR primers used in the aforementioned assays are described in Table 1. All PCR reactions were performed in 96-well microplates, and 2 negative control reactions without template DNA were included in each microplate. No PCR product was detected from any of the negative control reactions. The assays were repeated in 10% of the samples, and the results were consistent.
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Statistical Analyses
We performed 
2 tests to examine differences in genotype and allele frequencies between patients and controls. For 2 by 2 tables, Fisher’s exact test was performed when the table had a cell with an expected frequency of <5. Yates corrected 2 was calculated for all other 2 by 2 tables. For 2 by k tables, Pearson 2 was calculated.32 A P-value of <0.05 was taken as statistically significant.
Power calculation was as follows: On the basis of the frequencies of the rarer allele in the control group being 0.472, 0.497, 0.168, and 0.134 for the MMP-1 1G/2G, MMP-3 5A/6A, MMP-9 C-1562T, and MMP-12 A-82G polymorphisms, respectively, the sample size in this study would allow detecting a relative risk by allele of 2.0 for MMP-1 and MMP-3 and a relative risk of 2.3 for MMP-9 and MMP-12, with a power of 70% at the 0.05 significance level.
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Results |
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To investigate whether sequence variation in MMP genes influenced susceptibility of intracranial aneurysm, we analyzed 5 polymorphisms in 4 different MMP genes in 92 patients with aneurysmal subarachnoid hemorrhage and 158 control subjects. These polymorphisms were as follows: (1) 1G/2G polymorphism located at nucleotide position -1607 relative to the transcription start site in the promoter region of the MMP-1 gene; (2) 5A/6A polymorphism at nucleotide position -1612 in the promoter of the MMP-3 gene; (3) C-1562T polymorphism in the MMP-9 gene promoter; (4) A-82G polymorphism in the promoter of the MMP-12 gene; and (5) (CA)n microsatellite polymorphism from position -90 in the MMP-9 gene promoter. The former 4 were single nucleotide polymorphisms, and the last was a microsatellite polymorphism. All of these polymorphisms had previously been shown to influence the transcriptional activity of their respective gene promoter in an allele-specific manner.16,17,21,23,27,33
The genotype and allele frequencies in patients and controls are presented in Tables 2 and 3. There was no statistically significant difference between the patient and control groups in genotype distribution of any of the polymorphisms studied (P=0.881 for the MMP-1 -1607 1G/2G polymorphism; P=0.871 for the MMP-3 -1612 5A/6A polymorphism; P=0.308 for the MMP-9 C-1562T polymorphism; P=0.847 for the MMP-9 microsatellite; and P=0.709 for the MMP-12 A-82G polymorphism). All genotype distributions were consistent with Hardy-Weinberg equilibrium.
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Discussion |
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The development of aneurysms is associated with weakening of the blood vessel wall, which might result from inherent defects of structural molecules, although mutations in the type III collagen gene have been shown to be rare causes of aortic and intracranial aneurysms.34,35 There is also accumulating evidence indicating that overdegradation of vascular structural proteins by proteinases is an important mechanism involved in the development and rupture of aneurysms.7 The present study sought to ascertain whether polymorphisms in MMP genes influence the susceptibility of intracranial aneurysms. All polymorphisms analyzed in this study are located in the regulatory regions of the MMP genes and have been shown to influence the transcriptional activity of the respective MMP gene promoter. For example, the 5A allele of the MMP-3 5A/6A polymorphism possesses a greater transcriptional activity than the 6A allele, which appears to be due to preferential binding of a transcription repressor to the latter.16,36 Similarly, the insertion of a guanine nucleotide in the 2G allele of the MMP-1 1G/2G polymorphism creates a core binding site for transcription factor Ets, leading to a significantly higher promoter activity.23 Accordingly, ovarian and endometrial tumor tissues in individuals with the 2G/2G genotype express increased levels of MMP-1.24,25 Allelic effects on transcriptional activity have also been demonstrated for the MMP-9 C-1562T and MMP-12 A-82G polymorphisms, the latter being located immediately adjacent to an AP-1 consensus element bound by transcription factors c-Fos and c-Jun.17,21
The multiallelic (CA)n microsatellite polymorphism in the MMP-9 gene has a bimodal distribution of allele frequencies, with the first peak at the (CA)14 allele (with 14 tandem repeats of CA dinucleotide) and the second peak at the (CA)21, (CA)22, and (CA)23 alleles.31 It has been shown by the reporter gene assays that in fibroblasts (HT1080), an MMP-9 promoter encompassing 14 CA repeats has only 60% of the transcriptional activity of a promoter with 23 repeats.27 Differences in promoter activity between alleles have also been detected in esophageal carcinoma cells, with a promoter containing 14 CA repeats having only 50% of the activity of a promoter with 21 CA repeats.33 The (CA)n region has also been shown to interact with a nuclear protein in electrophoretic mobility shift assays, with the strength of nuclear protein binding being dependent on the number of CA repeats present.27,33
While some of the aforementioned polymorphisms have been consistently shown to be associated with susceptibility and progression of coronary artery disease or cancers in a number of studies,15,17–25,37–39 there have been only 2 reported studies on MMP gene polymorphisms in relation to intracranial aneurysm with conflicting results. In a case-control study of 76 patients and 93 controls from western Pennsylvania, the MMP-9 gene (CA)n microsatellite polymorphism was found to be associated with susceptibility of intracranial aneurysm, with lower frequencies of alleles (CA)14 and (CA)22 but higher frequencies of alleles (CA)21 and (CA)23 in cases than in controls (P=0.02).27 In a study of 57 cases and 174 controls from Finland, however, no association between this MMP-9 gene polymorphism and intracranial aneurysm was detected, nor was there any association of intracranial aneurysm with the MMP-3 5A/6A polymorphism.26 The results of the present study of 92 patients with aneurysmal subarachnoid hemorrhage and 158 controls from southern England are consistent with the findings of the aforementioned study in Finland26 and do not support the hypothesis that MMP gene variations are genetic determinants of intracranial aneurysms. There are several possibilities that might explain the different findings of the study in western Pennsylvania compared with the latter 2 studies. These include the possibility that MMP-9 genotypes influence the susceptibility of intracranial aneurysms only in certain populations and the possibility that a false-positive signal was obtained in the study of western Pennsylvania in the United States because of potential genetic heterogeneity of the population.
There are a number of regulatory mechanisms that can influence the ultimate impact of an MMP on extracellular matrix degradation. These at least include the following: (1) regulation of transcription, (2) activation of latent MMPs, and (3) inhibition of MMP activity by tissue inhibitors of metalloproteinases (TIMPs) and other inhibitors such as 
2-macroglobulin and 1-antitrypsin.40,41 Thus, although the present study did not indicate that ruptured intracranial aneurysms are predisposed by MMP gene promoter polymorphisms that influence MMP gene transcription, the results are not incompatible with an important role of MMPs and TIMPs in the aneurysm formation and rupture, since other factors can also lead to an imbalance between MMPs and TIMPs in the vascular wall. There is evidence indicating that infiltration of inflammatory cells into the adventitia, with subsequent elaboration of MMPs, may contribute to rapid growth and rupture of aneurysms.42 It has also been shown in animal models that local overexpresssion of TIMP-1 prevents aneurysm rupture.43
In addition to MMPs, other proteinases such as elastase, a member of the serine proteinase family, have also been implicated in the pathogenesis of aneurysms. Animal studies have demonstrated that cigarette smoking increases elastase activity in the aortic wall44 and that topical application of elastase to the arterial wall causes saccular aneurysm formation and rupture.45 In humans, the levels of elastase and the ratios of elastase versus 1-antitrypsin are higher in patients with ruptured or unruptured intracranial aneurysms than in controls.46,47 In addition, compared with unruptured aneurysms, ruptured aneurysms have higher elastase activities in the artery wall,46 whereas serum 1-antitrypsin activity, which is influenced by smoking, is lower in patients with ruptured aneurysms than in those with unruptured aneurysms.48 Taken together, these studies suggest that elastase/1-antitrypsin imbalance in cigarette smokers may also contribute to aneurysm formation and/or rupture.
In conclusion, the results of the present study do not support an influence of MMP gene variations on susceptibility of intracranial aneurysms in the population studied. Further studies should focus on achieving power to detect possible smaller allelic relative risk (<2) and should use wider panels of polymorphisms to represent other possible haplotypes of these genes.
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Acknowledgments |
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This work was supported by project grant D08 from Hope (formerly Wessex Medical Trust). Dr Zhang is a Wessex Medical Trust Senior Research Fellow. Dr Ye thanks the British Heart Foundation for support on studies of MMP genes (PG/98183 and PG/98192). Dr Day is a Lister Institute Research Professor and thanks the UK Medical Research Council (program grant G9828424) and Wessex Medical Trust for support for our facilities.
Received March 7, 2001; revision received May 15, 2001; accepted May 31, 2001.
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J. A. Iniesta, R. Gonzalez-Conejero, C. Piqueras, V. Vicente, and J. Corral Platelet GP IIIa Polymorphism HPA-1 (PlA) Protects Against Subarachnoid Hemorrhage Stroke, October 1, 2004; 35(10): 2282 - 2286. [Abstract] [Full Text] [PDF]
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Y.B.W.E.M. Roos, G. Pals, P.M. Struycken, G.J.E. Rinkel, M. Limburg, J.C. Pronk, J.S.P. van den Berg, J.A.F.M. Luijten, P.L. Pearson, M. Vermeulen, et al. Genome-Wide Linkage in a Large Dutch Consanguineous Family Maps a Locus for Intracranial Aneurysms to Chromosome 2p13 Stroke, October 1, 2004; 35(10): 2276 - 2281. [Abstract] [Full Text] [PDF]
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E. Ribourtout and J. Raymond Gene Therapy and Endovascular Treatment of Intracranial Aneurysms Stroke, March 1, 2004; 35(3): 786 - 793. [Abstract] [Full Text] [PDF]
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J. Montaner, I. Fernandez-Cadenas, C. A. Molina, J. Monasterio, J. F. Arenillas, M. Ribo, M. Quintana, P. Chacon, A. L. Andreu, and J. Alvarez-Sabin Safety Profile of Tissue Plasminogen Activator Treatment Among Stroke Patients Carrying a Common Polymorphism (C-1562T) in the Promoter Region of the Matrix Metalloproteinase-9 Gene Stroke, December 1, 2003; 34(12): 2851 - 2855. [Abstract] [Full Text] [PDF]
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C. Grond-Ginsbach, H. Schnippering, I. Hausser, R. Weber, I. Werner, H. H. Steiner, N. Luttgen, O. Busse, A. Grau, and T. Brandt Ultrastructural Connective Tissue Aberrations in Patients With Intracranial Aneurysms Stroke, September 1, 2002; 33(9): 2192 - 2196. [Abstract] [Full Text] [PDF]
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