TIMP-2 Gene Polymorphism Is Associated with Intracerebral Hemorrhage

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.

The GC + CC genotype at position -418 in TIMP-2 promoter and the -1575GA/-1306CC genotype in MMP-2is genetic predisposing factors for prevalence of moyamoya disease

“…TIMPs are the most important endogenous inhibitors of MMPs, in particular TIMP-1 and TIMP-2. Therefore, SNPs that lead to structural defects or modify the transcription rate of TIMP-2 could affect BBB breakdown and thereby influence the magnitude and/or incidence of ischemic stroke and intracranial hemorrhage [ 31 ]. SNPs can also interfere with the balance of MMPs and TIMP-2 in the absence of acute BBB disruption, thereby influencing the development and severity of atherosclerosis, white matter lesions, and small-vessel disease [ 31 ].…”

MMP-2 concentrations in stroke according to etiology: Adjusting for enzyme degradation in stored deep-frozen serum and other methodological pitfalls

“…4,7 In line with the original study design, subjects were recruited in two distinct cohorts. The first cohort comprised unselected consecutive patients with acute stroke-like symptoms, with stroke confirmed on subsequent imaging (CT scan or MRI), who consulted the Neurological Department of the Universitätsmedizin Mannheim within 24 hours of symptom onset.…”

Polymorphisms in the Promoters of the MMP-2 and TIMP-2 Genes Are Associated with Spontaneous Deep Intracerebral Hemorrhage in the Taiwan Population

“…In addition, pro-MMP-2 in vitro increased gelatinolytic activity in cerebral aneurysms [ 17 ]. One study has shown genetic variation of TIMP-2 promoter increased ICH risks, suggesting that the MMP-TIMP pathway may play a role in the susceptibility to ICH risks [ 18 ].…”