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(Stroke. 2003;34:2817.)
© 2003 American Heart Association, Inc.

Original Contributions

Tissue Inhibitor of Metalloproteinases-1, -2, and -3 Polymorphisms in a White Population With Intracranial Aneurysms

Dietmar Krex, MD; Henning Röhl; Inke R. König, PhD; Andreas Ziegler, PhD; Hans K. Schackert, MD Gabriele Schackert, MD

From the Departments of Neurosurgery (D.K., G.S.) and Surgical Research (H.K.S.), University Hospital Carl Gustav Carus, University of Technology, Dresden, and Institute of Medical Biometry and Statistics (A.Z., I.R.K.), University of Lübeck, Lübeck, Germany.

Correspondence Dr Dietmar Krex, Department of Neurosurgery, Carl Gustav Carus Hospital, University of Technology, Fetscherstr 74, 01307 Dresden, Germany. E-mail krex{at}rcs.urz.tu-dresden.de

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose— Remodeling of the extracellular matrix seems to be a crucial event in the pathogenesis of cerebral aneurysms. Matrix metalloproteinases are the most important degrading enzymes in the extracellular matrix. Their activity is controlled predominantly by tissue inhibitors of metalloproteinases (TIMPs). To investigate the possible impact of genetic variants within the genes encoding TIMP-1, -2, and -3, we conducted this case-control study.

Methods— A study sample was analyzed that comprised 44 patients with intracranial aneurysms and 44, 41, and 40 controls for the analysis of TIMP-1, -2, and -3, respectively. Differences in genotype and allele frequencies of identified polymorphisms were determined. The entire coding regions and parts of the promoter sequences of the TIMP-1, -2, and -3 genes were with using the automated laser fluorescence technique.

Results— Nine polymorphisms were identified, 3 located in TIMP-1 (-19C>T, 261C>T, 372T>C), 4 in TIMP-2 (-621C>T, -596A>C, -261G>A, 303G>A), and 2 in TIMP-3 (249T>C, 261C>T), whereas -621C>T, -596A>C, and -261G>A of the TIMP-2 gene are newly identified polymorphisms. We detected no deviation from Hardy-Weinberg equilibrium in any of the groups. The C allele of the 372T>C polymorphism was more frequently found in female than in male controls (exact nominal P=0.0012). However, this finding could not be validated by analysis of a second sample of 113 controls (exact nominal P=1.0000). There were no differences in genotype and allele frequencies between any of the other groups.

Conclusions— Our analysis of the entire coding region of 3 TIMPs, which are the main inhibitors of metalloproteinase activity in the extracellular matrix, failed to show an association between genetic polymorphisms and an intracranial aneurysm. These data do not support the hypothesis that genetic variants within these genes have an impact on aneurysm development in the white population.

Key Words: connective tissue • intracranial aneurysm • polymorphism (genetics) • risk factors

	Introduction

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Ruptured intracranial aneurysms are 1 of the most severe forms of cerebrovascular disease, with a mortality approaching 40% despite modern treatment modalities.¹ Although risk factors like cigarette smoking, elevated arterial blood pressure, and female sex have been identified,^2–4 little is known about the molecular pathology of the genesis of aneurysms. Understanding the biology of cerebral aneurysm development is a prerequisite for evolving new therapeutic strategies and identifying molecular markers that may help to identify people at high risk.

There is evidence that remodeling of the extracellular matrix (ECM) plays a major role in the pathogenesis of cerebral aneurysms. The ECM is a dynamic network of proteins and proteoglycans that not only is essential for structural maintenance in many tissues but also is involved in cell adhesion and migration, as well as in cell proliferation and differentiation processes. The structural integrity of the vessel wall relies on a balance between synthesis and degradation of ECM proteins. However, increased circulating levels of proteases, which have been detected in some aneurysm patients,⁵ diminished arterial structural proteins,⁶ exaggerated expression of catalytic enzymes in the aneurysm wall,⁷ and a predominance of superoxide anion metabolites⁸ all point to an imbalance in favor of protein degrading processes in the arterial wall. Remodeling of the vascular ECM has been found to be involved in the pathogenesis of other vascular diseases like aortic aneurysm,^9,10 atherosclerosis,¹¹ and postangioplasty restenosis.^12,13 Among the degrading enzymes, the growing family of matrix metalloproteinases (MMPs) has been found to be crucial in ECM remodeling of vascular walls. An important mechanism for the regulation of the activity of MMPs is equimolar binding to a family of homologous proteins referred to as tissue inhibitors of metalloproteinases (TIMP-1 through TIMP-4) (a review is given by Brew et al¹⁴). TIMP-3, unlike the other 3 TIMPs, binds tenaciously to ECM components. Mutations in the TIMP-3 gene have been found in patients with Sorsby’s fundus dystrophy, an autosomal dominant inherited macular disorder, characterized by accumulation of abnormal deposits in the Bruch’s membrane and choroidal neovascularization.¹⁵ The most recently isolated TIMP-4 also binds to pro-MMP-2; however, so far there are no data about its clinical significance.^16,17

The increased proteolytic activity observed in the vascular wall of aneurysm patients may be due to either an elevated activity of proteolytic enzymes or diminished activity of their inhibitors. Genetic variants of the encoding genes might result in altered enzyme activities of each protein.

We conducted this case-control study to investigate whether polymorphisms in the promoter and coding regions of the TIMP-1, -2, and -3 genes are associated with the occurrence of cerebral aneurysms in white populations.

	Subjects and Methods

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Study Population
For the analysis of TIMP-1, TIMP-2, and TIMP-3, the patient group consisted of 44 unrelated, consecutively recruited patients with intracranial aneurysms (43.7% men; mean age, 54 years [range, 23 to 72 years] and 50 years [range, 27 to 72 years] for men and women). All patients presented with at least 1 aneurysm, which was confirmed by cerebral angiography, and they were all operated on or treated by an endovascular approach between 1997 and 1998 at the Departments of Neurosurgery and Neuroradiology, respectively, at the University of Technology in Dresden. All patients were residents of the Dresden urban area. They had no history of previous subarachnoid hemorrhage, nor was there a familial history of such hemorrhages. The prevalence of risk factors like hypertension, diabetes mellitus, and cigarette smoking was 22.7%, 4.5%, and 29.5%, respectively.

The control groups consisted of 44, 41, and 40 anonymous, healthy blood donors enrolled from the same urban area for the analysis of TIMP-1, TIMP-2, and TIMP-3, respectively. Differences in sample size were due to difficulties in generating a complete sequence analysis of all 3 genes for all 44 controls. We must emphasize that the control group was enrolled from the same geographic area as the cases. Because of its historical background, Dresden is populated by a homogenous white population. In general, blood is donated by all social classes in Germany. All potential blood donors are routinely screened for disease with a questionnaire, red blood cell count, white blood cell count, and liver function parameters (details provided on request). A second control sample was recruited from the same population of blood donors and comprised another 113 (43 men, 70 women) controls for the analysis of TIMP-1. This study was approved by the local ethics committee. Informed written consent for genetic analysis was obtained from all nonanonymous individuals.

Sequence Analysis
For amplification of genomic DNA, primer pairs were designed on the basis of the genomic sequence of the TIMP genes published in GenBank (Accession NT_011584, U44381-85, NT_0115200). Primers are located in the adjacent intronic sequences of each exon, allowing analysis of exon/intron borders. In addition, 483, 676, and 418 bp of the TIMP-1, -2, and -3 promoter regions were analyzed, respectively.

Polymerase chain reaction (PCR) was performed with a thermal cycler (Perkin Elmer, Applied Biosystems GmbH). For negative control, water was used instead of genomic DNA in PCR.

PCR products were electrophoresed on an 0.8% agarose gel, and bands were cut out and eluted. Three microliters of the eluted PCR product were used in the reaction mix to which 1 µL of Thermo Sequenase Mix (Amersham Pharmacia Biotech, UK Ltd) and 1 µmol/L cyanine5 end-labeled sense primer were added. The cycling reaction also was performed with a thermocycler. Cycling products were run on A.L.F.express with denaturing 6.5% Long Ranger gels, which were run at 40 W (1000 V, 38 mA) for 4 hour. Runs were analyzed with A.L.F. Evaluation software. The primer list and details on PCR and cycling reaction conditions can be provided on request.

Analysis of the second study population for TIMP-1 polymorphisms was performed with mutation detection by melting point analysis on a real-time PCR device (LightCycler). Primers and hybridization probes were designed covering the 372T>C polymorphism. Three samples with known genotypes and a negative control were used in each run. Primer sequences and PCR conditions will be provided on request.

Study Course and Statistical Methods
For all variants investigated, deviations from Hardy-Weinberg equilibrium were evaluated by comparing observed and expected genotype frequencies by an exact goodness-of-fit test separately in cases and controls. Odds ratios (ORs) and exact 95% confidence intervals (CIs) were calculated to compare allele frequencies¹⁸ and genotype frequencies using the Cochrane-Armitage trend test.

Nomenclature
The location of the polymorphisms is given according to the nomenclature system recommended by Antonarakis¹⁹ and the Nomenclature Working Group 1998 (http://www.dmd.nl/mutnomen.html).

	Results

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We identified 3 polymorphisms in TIMP-1: -19C>T is located in the 5'UTR of the gene; 261C>T is in exon 4 without an effect on amino acid sequence (P87P); and 372T>C (F124F) is in exon 5. The polymorphic T allele of the -19C>T polymorphism was detected only once (frequency=0.01), whereas the polymorphic T allele of the 261C>T polymorphism was detected twice (frequency=0.02), each in the group of cases (n=44). Genotype and allele frequencies, ORs, and exact 95% CIs for the 372T>C polymorphism are presented in Tables 1 and 2. Because TIMP-1 is located on the X chromosome, men and women were considered separately. We detected no deviation from Hardy-Weinberg equilibrium in any of the groups. Allele and genotype frequencies did not differ between cases and controls (all nominal P>0.05) in either men or women. However, the C allele was found more frequently in female controls than in male controls (exact nominal P=0.0012). To validate this finding, a second sample of 113 controls (43 men, 70 women) was recruited, which ensured a power of >95% to detect the same difference. Here, allele frequencies did not differ between male and female controls (exact nominal P=1.0000).

View this table: [in this window] [in a new window]   TABLE 1. Genotype Frequencies of the TIMP-1 372T>C Polymorphism in Women

View this table: [in this window] [in a new window]   TABLE 2. Allele Frequencies of the TIMP-1 372T>C Polymorphism in the Investigated Groups

In TIMP-2, we identified 4 polymorphisms. Three of those—-261G>A, -596A>C, and -621C>T—are located in the promoter region and have not been described before. Another, 303G>A, is located in exon 3 without having an effect on the amino acid sequence (S101S). Genotype and allele frequencies of these polymorphisms are presented in Tables 3 and 4, together with ORs and exact 95% CIs. No deviation from Hardy-Weinberg equilibrium was observed in either cases or controls (all nominal P>0.05). Allele and genotype frequencies between cases and controls did not differ (all nominal P>0.05).

View this table: [in this window] [in a new window]   TABLE 3. Genotype Frequencies of TIMP-2 Polymorphisms in the Investigated Groups

View this table: [in this window] [in a new window]   TABLE 4. Allele Frequencies of TIMP-2 Polymorphisms in the Investigated Groups

TIMP-3 harbored 2 polymorphisms, 249T>C and 261C>T, both located in exon 3, and neither changes the amino acid sequence (H83H and S87S, respectively). The genotype and allele frequencies are presented in Tables 5 and 6, together with ORs and exact 95% CIs. Again, no deviation from Hardy Weinberg equilibrium and no difference between cases and controls in allele or genotype frequencies were observed (all nominal P>0.05).

View this table: [in this window] [in a new window]   TABLE 5. Genotype Frequencies of TIMP-3 Polymorphisms in the Investigated Groups

View this table: [in this window] [in a new window]   TABLE 6. Allele Frequencies of TIMP-3 Polymorphisms in the Investigated Groups

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In our study, we analyzed the entire coding region and parts of the promoter sequences of the 3 main inhibitors of MMP activity—TIMP-1, TIMP-2, and TIMP-3—in a white population with intracranial aneurysms. We identified 3 new and 6 known polymorphisms but detected no association with the occurrence of intracranial aneurysms in our study population. Except for the TIMP-1 372T>C polymorphism, differences in allele frequencies and genotypes between cases and controls rendered only a small effect, as indicated by the ORs and the 95% CIs.

To investigate the possible impact of gene polymorphism on the development of intracranial aneurysms, several candidate genes have been analyzed in different ethnic groups.^20–26 Enzymes of the ECM are a reasonable target, as elevated activity and /or overexpression of pro-MMP-2, MMP-2, MMP-9, and MT1-MMP in the serum of patients with cerebral aneurysms and in the aneurysm wall have been reported.^5,7,27 MMPs are the principal matrix-degrading proteinases.²⁸ The expression of most MMPs is transcriptionally regulated by various factors, whereas their activity is additionally regulated by zymogen activation and controlled by endogenous inhibitors in the serum and tissue. TIMPs are considered to be the key inhibitors of MMPs in the ECM. The functional importance of TIMPs in the pathogenesis of aneurysms has been demonstrated by Allaire et al²⁹ using a rat model for local overexpression of TIMP-1. This resulted in the maintenance of structural integrity and prevented aneurysm development. The hypothesis that TIMPs might play a role in cerebral aneurysm pathogenesis has been supported by recent findings from Peters et al,³⁰ who have reported a global gene expression analysis of a single intracranial aneurysm from a 3-year-old girl. Among the 25 most significant tags overexpressed in intracranial aneurysms, they identified TIMP-3. A genetic variant in that particular gene might be the cause of its overexpression. However, in our study, we failed to show such an association, which might be explained by the following reasons. The investigation by Peters et al is based on the analysis of a single case, a 3-year-old girl, presenting with multiple aneurysms of the middle cerebral artery, and no other clinical data are given. The incidence of cerebral aneurysms in childhood is 1% to 2% of all aneurysms.³¹ In contrast, the mean age in our study population was 52 years, which represents the decade in which most of the aneurysms are found in men, and the peak incidence in women is at an even older age.^32,33 The genesis of an aneurysm is a multifactor event. Hypertension, arteriosclerosis, and long-lasting elevated shear stress are widely accepted risk factors in the pathogenesis of spontaneous intracranial aneurysms (for a review, see Krex et al³⁴); however, these are not found in childhood. Hence, it might be argued that multiple aneurysms in early childhood are based on a pathogenesis different from that commonly found in spontaneous aneurysms of adults, eg, an inherited connective tissue disease or polycystic kidney disease. Still, our results do not exclude the possibility that TIMP-3 is involved in the pathogenesis of aneurysms.

We analyzed the first 304 bp of the TIMP-3 promoter and the first 114 bp of the 5'UTR. The first 112 bp of the promoter harbors multiple Sp1 binding sites, and a potential NF I site is located between -235 and -248.³⁵ This region has been shown to be elementary for TIMP-3 basal activity and serum inducibility.³⁵ Nevertheless, we analyzed only a part of the entire promoter region and did not screen for posttranslational modifications or epigenetic effects that might influence the expression of a gene.

TIMP-2 is an important inhibitor of MMP-2 but also of other active MMPs.³⁶ Butler et al³⁷ have shown that the specificity of TIMP-2 for MMP binding and inhibition can be modified by single amino acid mutations. These results support the hypothesis that genetic variants might be the cause for altered enzyme activities in the ECM of aneurysm walls, although our results did not substantiate this.

Wang et al³⁸ have analyzed the sequences of the TIMP-1 and TIMP-2 genes in a mixed North American and European white population with abdominal aortic aneurysm, but also in 1 individual with both aortic and intracranial aneurysms and 4 individuals with intracranial aneurysms. They identified 2 polymorphisms each in TIMP-1 and TIMP-2 and presented preliminary results of different allele frequencies of a nucleotide 573 polymorphism in the TIMP-2 gene between male controls and patients with abdominal aortic aneurysms. However, they failed to show a significant association with the phenotype, especially with cerebral aneurysms. In our study, we detected the identical polymorphisms, although we refer to a different nomenclature for the polymorphisms, and the findings of Wang et al in another ethnic group are in accordance with our results.

In conclusion, although there is growing evidence that enzymes of the ECM play a major role in the pathogenesis of intracranial aneurysms, our results failed to show that genetic variants within the coding regions of TIMP-1, -2, and -3, which might influence the biochemical properties of the enzyme, have an impact on cerebral aneurysm development. However, expression of a gene might be regulated by sequences located several kilobases upstream from the transcription start site, as shown by Dean et al³⁹ for the TIMP-1 gene, suggesting that analysis of a long promoter sequence is mandatory.

	Acknowledgments

 
This study was supported by a grant from the Deutschen Forschungsgesellschaft (1538/3-1). We are grateful to U. Neumeister for her outstanding technical assistance and to S. Faatz for her help in preparing the manuscript.

Received March 10, 2003; revision received June 11, 2003; accepted August 1, 2003.

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