TIMP-2 gene polymorphism is associated with intracerebral hemorrhage.
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).


CONCLUSIONS
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.
Department of Neurology, Universitatsklinikum Mannheim, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. reuter@neuro.ma.uni-heidelberg.de
Bjoern
B
Reuter
Peter
P
Bugert
Mark
M
Stroick
Simone
S
Bukow
Martin
M
Griebe
Michael G
MG
Hennerici
Marc
M
Fatar
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*
D019716:Tissue Inhibitor of Metalloproteinase-2