Single-Nucleotide Polymorphisms of MMP-2 Gene in Stroke SubtypesFatar M.b · Stroick M.b · Steffens M.d · Senn E.b · Reuter B.b · Bukow S.b · Griebe M.b · Alonso A.b · Lichtner P.c · Bugert P.a · Meitinger T.c · Wienker T.F.d · Hennerici M.G.b
aInstitute of Transfusion Medicine and Immunology, German Red Cross Blood Service of Baden-Württemberg – Hessia, and bDepartment of Neurology, Klinikum Mannheim, University of Heidelberg, Mannheim, cInstitute of Human Genetics, GSF-National Research Centre for Environment and Health, Technical University Munich, Munich, and dInstitute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
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Article / Publication Details
Background: Matrix metalloproteinases (MMP) are expressed after ischemic stroke. These proteases are responsible for a higher incidence of hemorrhages, are correlated to size of infarction and influence the effects of recombinant tissue plasminogen activator treatment. We therefore evaluated single nucleotide polymorphisms (SNP) of MMP-2 in different subtypes of stroke patients in an association study using a case-control design. Methods: 197 stroke patients were divided according to modified TOAST criteria (small vessel disease, large vessel disease, hemorrhagic stroke and asymptomatic carotid artery stenosis) and compared to 143 controls. Clinical data like age, sex, risk factors and diagnostic results including MRI or cranial CT scans and ultrasound evaluations of intra- and extracranial arteries were obtained. Genotypes of MMP-2 (12 SNP) were compared to controls and DNA samples were analyzed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. Logistic regression analysis was performed for small vessel disease to test for interactions between markers and defined clinical risk factors. Additionally, MMP-2 serum levels obtained in the first 24 h after stroke were measured. Results: From the MMP-2 gene, 5 markers (rs1030868, rs2241145, rs2287074, rs2287076, rs7201) showed a significant association with small vessel infarcts (p < 0.05) and rs7201:g.C was identified as an independent risk factor by multivariable logistic regression analysis. MMP-2 protein levels were significantly lower in this group (174 ± 48 ng/dl) versus controls (214 ± 56 ng/dl). For other stroke subtypes, no significant association with MMP-2 SNP could be found. Conclusion: Our study demonstrates an association of the MMP-2 gene with the development of lacunar stroke, and no association of MMP-2 with other stroke subtypes.
© 2008 S. Karger AG, Basel
- Fatar M, Stroick M, Griebe M, Hennerici M: Matrix metalloproteinases in cerebrovascular diseases. Cerebrovasc Dis 2005;20:141–151.
- Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Libby P: Enhanced expression of vascular matrix metalloproteinases induced in vitro by cytokines and in regions of human atherosclerotic lesions. Ann NY Acad Sci 1995;748:501–507.
- Galis ZS, Sukhova GK, Lark MW, Libby P: Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994;94:2493–2503.
- Buja LM and Willerson JT: Role of inflammation in coronary plaque disruption. Circulation 1994;89:503–505.
- Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT: Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation 1994;90:775–778.
- Halpert I, Sires UI, Roby JD, Potter-Perigo S, Wight TN, Shapiro SD, Welgus HG, Wickline SA, Parks WC: Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc Natl Acad Sci USA 1996;93:9748–9753.
- Ghilardi G, Biondi ML, DeMonti M, Turri O, Guagnellini E, Scorza R: Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis. Stroke 2002;33:2408–2412.
- Kuroiwa T, Ting P, Martinez H, Klatzo I: The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol (Berl) 1985;68:122–129.
- Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ: Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab 1999;19:624–633.
- Kelly MA, Shuaib A, Todd KG: Matrix metalloproteinase activation and blood-brain barrier breakdown following thrombolysis. Exp Neurol 2006;200:38–49.
- Shigemori Y, Katayama Y, Mori T, Maeda T, Kawamata T: Matrix metalloproteinase-9 is associated with blood-brain barrier opening and brain edema formation after cortical contusion in rats. Acta Neurochir Suppl 2006;96:130–133.
- Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribo M, Quintana M, Alvarez-Sabin J: Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003;107:598–603.
- Fitch MT, Doller C, Combs CK, Landreth GE, Silver J: Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci 1999;19:8182–8198.
- Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC: Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 1998;29:1020–1030.
- Galis ZS, Sukhova GK, Libby P: Microscopic localization of active proteases by in situ zymography: detection of matrix metalloproteinase activity in vascular tissue. FASEB J 1995;9:974–980.
- Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR: Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci Lett 1997;238:53–56.
- Rosenberg GA, Sullivan N, Esiri MM: White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke 2001;32:1162–1168.
- Yamada T, Yoshiyama Y, Sato H, Seiki M, Shinagawa A, Takahashi M: White matter microglia produce membrane-type matrix metalloprotease, an activator of gelatinase A, in human brain tissues. Acta Neuropathol (Berl) 1995;90:421–424.
- Tost J, Gut IG: Genotyping single nucleotide polymorphisms by MALDI mass spectrometry in clinical applications. Clin Biochem 2005;38:335–350.
- Sasieni PD: From genotypes to genes: doubling the sample size. Biometrics 1997;53:1253–1261.
- Rothman KJ: No adjustments are needed for multiple comparisons. Epidemiology 1990;1:43–46.
- Nielsen DM, Ehm MG, Weir BS: Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 1998;63:1531–1540.
- Fisher CM: Lacunes: small, deep cerebral infarcts: 1965. Neurology 1998;50:841.
- Armstrong CA, Bevan SN, Gormley KT, Markus HS, Koblar SA: Tissue plasminogen activator –7351C/T polymorphism and lacunar stroke. Stroke 2006;37:329.
- Gormley K, Bevan S, Markus HS: Polymorphisms in genes of the renin-angiotensin system and cerebral small vessel disease. Cerebrovasc Dis 2007;23:148–155.
- Hassan A, Gormley K, O’Sullivan M, Knight J, Sham P, Vallance P, Bamford J, Markus H: Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke 2004;35:654–659.
- Gormley K, Bevan S, Hassan A, Markus HS: Polymorphisms in genes of the endothelin system and cerebral small-vessel disease. Stroke 2005;36:1656–1660.
- Markus HS, Barley J, Lunt R, Bland JM, Jeffery S, Carter ND, Brown MM: Angiotensin-converting enzyme gene deletion polymorphism: a new risk factor for lacunar stroke but not carotid atheroma. Stroke 1995;26:1329–1333.
- Zhang JH, Kohara K, Yamamoto Y, Nakura J, Tabara Y, Fujisawa M, Katagi R, Miki T: Genetic predisposition to neurological symptoms in lacunar infarction. Cerebrovasc Dis 2004;17:273–279.
- Chamorro A, Revilla M, Obach V, Vargas M, Planas AM: The –174G/C polymorphism of the interleukin 6 gene is a hallmark of lacunar stroke and not other ischemic stroke phenotypes. Cerebrovasc Dis 2005;19:91–95.
- Revilla M, Obach V, Cervera A, Davalos A, Castillo J, Chamorro A: A –174G/C polymorphism of the interleukin-6 gene in patients with lacunar infarction. Neurosci Lett 2002;324:29–32.
- Tachikawa H, Tsuda M, Onoe K, Ueno M, Takagi S, Shinohara Y: Alpha-1-antichymotrypsin gene A1252G variant (ACT Isehara-1) is associated with a lacunar type of ischemic cerebrovascular disease. J Hum Genet 2001;46:45–47.
- Furuta A, Ishii N, Nishihara Y, Horie A: Medullary arteries in aging and dementia. Stroke 1991;22:442–446.
- Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC: Subcortical ischaemic vascular dementia. Lancet Neurol 2002;1:426–436.
- Mulvany MJ: Small artery remodeling and significance in the development of hypertension. News Physiol Sci 2002;17:105–109.
- D’Armiento J: Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction. Trends Cardiovasc Med 2002;12:97–101.
- Derosa G, D’Angelo A, Ciccarelli L, Piccinni MN, Pricolo F, Salvadeo S, Montagna L, Gravina A, Ferrari I, Galli S, Paniga S, Tinelli C, Cicero AF: Matrix metalloproteinase-2, -9, and tissue inhibitor of metalloproteinase-1 in patients with hypertension. Endothelium 2006;13:227–231.
- Song W and Ergul A: Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: relation to vessel size. Cardiovasc Diabetol 2006;5:3.
- Thrailkill KM, Bunn RC, Moreau CS, Cockrell GE, Simpson PM, Coleman HN, Frindik JP, Kemp SF, Fowlkes JL: Matrix metalloproteinase-2 dysregulation in type 1 diabetes. Diabetes Care 2007;30:2321–2326.
- Derosa G, D’Angelo A, Tinelli C, Devangelio E, Consoli A, Miccoli R, Penno G, Del Prato S, Paniga S, Cicero AF: Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in diabetic and healthy subjects. Diabetes Metab 2007;33:129–134.
- Chandler S, Coates R, Gearing A, Lury J, Wells G, Bone E: Matrix metalloproteinases degrade myelin basic protein. Neurosci Lett 1995;201:223–226.
- Esiri MM, Wilcock GK, Morris JH: Neuropathological assessment of the lesions of significance in vascular dementia. J Neurol Neurosurg Psychiatry 1997;63:749–753.
- Akiguchi I, Tomimoto H, Suenaga T, Wakita H, Budka H: Alterations in glia and axons in the brains of Binswanger’s disease patients. Stroke 1997;28:1423–1429.
- Anthony DC, Ferguson B, Matyzak MK, Miller KM, Esiri MM, Perry VH: Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. Neuropathol Appl Neurobiol 1997;23:406–415.
- Ravens JR: Vascular changes in the human senile brain. Adv Neurol 1978;20:487–501.
- Duvernoy HM, Delon S, Vannson JL: Cortical blood vessels of the human brain. Brain Res Bull 1981;7:519–579.
- Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA: Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 2007;27:697–709.
- Vukasovic I, Tesija-Kuna A, Topic E, Supanc V, Demarin V, Petrovcic M: Matrix metalloproteinases and their inhibitors in different acute stroke subtypes. Clin Chem Lab Med 2006;44:428–434.
- Horstmann S, Kalb P, Koziol J, Gardner H, Wagner S: Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke 2003;34:2165–2170.
- Chang DI, Hosomi N, Lucero J, Heo JH, Abumiya T, Mazar AP, del Zoppo GJ: Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J Cereb Blood Flow Metab 2003;23:1408–1419.
- Djonov V, Cresto N, Aebersold DM, Burri PH, Altermatt HJ, Hristic M, Berclaz G, Ziemiecki A, Andres AC: Tumor cell specific expression of MMP-2 correlates with tumor vascularisation in breast cancer. Int J Oncol 2002;21:25–30.
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