Hinterseher Irene, Krex Dietmar, Kuhlisch Eberhard, Schmidt Karl G, Pilarsky Christian, Schneiders Wolfgang, Saeger Hans D, Bergert Hendrik
Department of Visceral, Thoracic and Vascular Surgery, Medical School of the Technical University of Dresden, Fetscherstr, 74 D-01307 Dresden, Germany.
World J Surg. 2007 Nov;31(11):2248-54. doi: 10.1007/s00268-007-9209-x.
The formation of a sporadic abdominal aortic aneurysm (AAA) is explained by the remodeling of the extracellular matrix (ECM) and breakdown of structural components of the vascular wall. Matrix metalloproteinases are the principal matrix-degrading proteases and are known to play a major role in the remodeling of the extracellular matrix in arterial vessels. Their activity is controlled by tissue inhibitors of metalloproteinases (TIMPs). Decreased TIMP-1 and TIMP-2 expression in the extracellular matrix of the walls of AAAs has been shown in several studies. This case control study was designed to investigate the possible impact of genetic variants of the TIMP-1 gene in the etiology of AAA.
TIMP-1 single nucleotide polymorphisms (SNPs) were analyzed in a primary study sample of 50 patients with AAA and 44 controls. Differences in genotype and allele frequencies of identified polymorphisms were determined after sequencing the entire coding region and selected parts of the promoter using the automated laser fluorescence technique. A second sample (96 patients vs. 89 controls) was investigated by single-base sequencing to confirm significant results.
Three polymorphisms were identified, one of which, described for the first time in this article, is located in intron 4 (TIMP-1: 328 + 16C > T). A statistically significant difference in allele frequencies for SNP TIMP-1 372T>C was detected in the primary study group. The C allele was more frequent in male patients with AAA than in the control group [23 vs. 4, p = 0.029, OR (95% CI) 4.38 (1.13-20.47)]. However, this result could not be confirmed in a second sample of males [52 vs. 45, p = 0.624, OR (95% CI) 1.16 (0.65-2.06)]. There were no statistically significant differences in genotype or allele frequencies of the other detected SNPs between the two groups.
Our analysis of the entire coding region and selected parts of the promoter of the TIMP-1 gene failed to show an association between genetic polymorphisms and AAA, suggesting that variations in the TIMP-1 gene do not contribute to the development of AAA.
散发性腹主动脉瘤（AAA）的形成是由细胞外基质（ECM）重塑和血管壁结构成分破坏所导致。基质金属蛋白酶是主要的基质降解蛋白酶，在动脉血管细胞外基质重塑中起主要作用。其活性受金属蛋白酶组织抑制剂（TIMPs）控制。多项研究表明，AAA壁细胞外基质中TIMP - 1和TIMP - 2表达降低。本病例对照研究旨在探讨TIMP - 1基因遗传变异在AAA病因学中的可能影响。
在50例AAA患者和44例对照的主要研究样本中分析TIMP - 1单核苷酸多态性（SNP）。使用自动激光荧光技术对整个编码区和启动子的选定部分进行测序后，确定已识别多态性的基因型和等位基因频率差异。通过单碱基测序对第二个样本（96例患者与89例对照）进行研究以确认显著结果。
鉴定出三个多态性，其中一个在本文中首次描述，位于内含子4（TIMP - 1：328 + 16C>T）。在主要研究组中检测到SNP TIMP - 1 372T>C的等位基因频率存在统计学显著差异。AAA男性患者中C等位基因比对照组更常见[23比4，p = 0.029，OR（95%CI）4.38（1.13 - 20.47）]。然而，在男性的第二个样本中未能证实该结果[52比45，p = 0.624，OR（95%CI）1.16（0.65 - 2.06）]。两组之间其他检测到的SNP的基因型或等位基因频率无统计学显著差异。
我们对TIMP - 1基因整个编码区和启动子选定部分的分析未能显示遗传多态性与AAA之间存在关联，这表明TIMP - 1基因变异对AAA的发生发展没有影响。
