Tissue Inhibitor of Metalloproteinases-1, −2, and −3 Polymorphisms in a White Population With Intracranial Aneurysms

Abstract

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 (Ϫ19CϾT, 261CϾT, 372TϾC), 4 in TIMP-2 (Ϫ621CϾT, Ϫ596AϾC, Ϫ261GϾA, 303GϾA), and 2 in TIMP-3 (249TϾC, 261CϾT), whereas Ϫ621CϾT, Ϫ596AϾC, and Ϫ261GϾA 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 372TϾC polymorphism was more frequently found in female than in male controls (exact nominal Pϭ0.0012). However, this finding could not be validated by analysis of a second sample of 113 controls (exact nominal Pϭ1.0000). 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.

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

“…Matrix metalloproteinase-7 À181A4G was the only polymorphism differently distributed among gastric carcinoma patients compared with control subjects: AA 43.0%, AG 46.8%, and GG 10.1% in patients vs AA 27.2%, AG 62.7% and GG 10.1% in controls (Po0.04; Table 2). Comparison of the genotype distribution of our Caucasian control subjects with those published on other mainly Asiatic control groups (Wollmer et al, 2002;Ghilardi et al, 2003;Krex et al, 2003;Miao et al, 2003;Wang et al, 2004;Zhou et al, 2004;Matsumura et al, 2005;Zhang et al, 2005) showed significant differences for MMP-2 À1306C4T , MMP-7 À181A4G , TIMP-1 372C4T and TIMP-2 À418G4C (Table 3). All the SNPs were evaluated for association with the clinicopathological parameters.…”

Multiple-polymorphism associations of 7 matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease

“…Several have evaluated multiple MMP or TIMP SNPs. ( [18][19][20][21][22][23][24][25] ) Some of the studies failed to replicate prior findings ( 15,16,(18)(19)(20)(21)(22)(23)(24)(25), perhaps because of differences in study endpoints, small population sizes, differing study designs (e.g., cohort vs. matched controls), failure to account for epistasis (gene interactions: e.g., MMP-1 and MMP-3), and unmeasured intra-genic allelic heterogeneity.…”

“…Other cardiovascular studies have recently used an incarnation of this methodology but only investigated clinical phenotypes in afterthought. ( 29,30 ) Finally, prior studies of MMP and TIMP genes studied populations of around one hundred ( 10,17,25 ), multiple hundreds ( 11,12,13,16,18,19,21 ), between 1,000-1,700 participants. ( 14,15,20,(22)(23)(24)27 ) While the current study of >5,000 patients did not replicate all of those prior studies' findings, it improved on their sample sizes by 3-to 50-fold.…”

“…( [18][19][20][21][22][23][24][25] This study evaluated the association of SNPs in the genes encoding MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, and TIMP-3 with MI among patients undergoing coronary angiography.…”

No Association of Matrix Metalloproteinase [MMP]-2 (−735C > T) and Tissue Inhibitor of Metalloproteinase [TIMP]-2 (−418G > C) Gene Polymorphisms with Cervical Cancer Susceptibility

“…The genotype variants were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) methodology for all the SNPs. Primer sequences, PCR conditions and the restriction enzymes used have been described elsewhere for both MMP2 and TIMP2 [12][13][14][15]. Positive and negative controls were used in each genotyping assay, and 5 % of the samples were randomly selected and run in duplicates with 100 % concordance.…”