Tissue inhibitor of metalloproteinases-1,-2, and-3 polymorphisms in a white population with intracranial aneurysms

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.