ABSTRACT
BACKGROUND: Both ischemic stroke and intracerebral hemorrhage are associated with altered expression and activation of matrix metalloproteinases (MMPs). Particularly relevant are MMP-2 and MMP-9. This proteolytic effect is dampened by tissue inhibitors of metalloproteinases (TIMPs). TIMP-2 is an important endogenous inhibitor of MMP-2. Alterations in the TIMP-2 gene expression may contribute to the incidence of ischemic stroke and intracerebral hemorrhage. METHODS: TIMP-2 gene SNP -261G/A was genotyped from sequentially recruited stroke patients (n = 356, f/m 151/205, mean age 68.2 years, range 19-100 years) and gender and age matched controls (n = 253, f/m 114/139, mean age 68.5 years, range 32-92 years). The SNP -261G/A was detected after gene sequencing of 95 patients and controls. Furthermore, in a subgroup of 93 patients the serum levels of TIMP-2 were measured during the first 7 days after stroke onset and compared to the genotype. RESULTS: SNP -261G/A in the TIMP-2 gene shows an allele frequency of approximately 39.14%. Homozygosity for allele A is associated significantly with the development of ICH (p = 0.025, OR = 2.020, CI = 1.115-3.661) as compared to heterozygosity and homozygosity for allele G (recessive genotypic model). Concordantly, the serum levels of TIMP-2 showed a nonsignificant decreases, depending on the genotype (p = 0.111). CONCLUSION: We investigated a SNP 261 base pairs upstream of the start codon in exon 1 of TIMP-2. Our data suggest that carriers of homozygosity for allele A are at increased risk of developing intracerebral hemorrhage.
Subject(s)
Cerebral Hemorrhage/genetics , Polymorphism, Single Nucleotide/genetics , Tissue Inhibitor of Metalloproteinase-2/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Gene Frequency/genetics , Genetic Predisposition to Disease/genetics , Genotype , Heterozygote , Homozygote , Humans , Incidence , Male , Middle AgedABSTRACT
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.
Subject(s)
Matrix Metalloproteinase 2/genetics , Polymorphism, Single Nucleotide , Stroke/genetics , Aged , Aged, 80 and over , Case-Control Studies , Female , Genetic Predisposition to Disease , Humans , Logistic Models , Male , Matrix Metalloproteinase 2/blood , Middle Aged , Phenotype , Risk Assessment , Risk Factors , Severity of Illness Index , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Stroke/enzymology , Stroke/pathologyABSTRACT
Tirofiban is one of three glycoprotein IIb/IIIa receptor antagonists approved by the US FDA, beside abciximab and eptifibatide. The approval of tirofiban covers conservative treatment of myocardial infarction and unstable angina, as well as percutaneous coronary intervention, for which treatment with tirofiban is recommended in moderate-to-high-risk patients. The efficacy of glycoprotein IIb/IIIa antagonists in myocardial infarction indicated that these agents may also be helpful in the treatment of acute ischaemic stroke. Although experimental data are lacking, observational studies are promising. In recent years, increasing effort in studying glycoprotein IIb/IIIa antagonists has been made, mostly for treatment with abciximab. However, there is one Phase II trial that investigated treatment with tirofiban.
