Analysis of a T-287C polymorphism in the tissue factor pathway inhibitor gene and identification of a repressor element in the promoter
Analysis of a T-287C polymorphism in the tissue factor pathway inhibitor gene and identification of a repressor element in the promoter
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DOI：
10.1016/j.thromres.2007.08.012
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发表时间：
2008-01-01
影响因子：
7.5
通讯作者：
Hes, David
中科院分区：
文献类型：
--
作者：
Nekoo, Ali Amini;Hes, David
组织因子途径抑制物（TFPI）是组织因子诱导的凝血的主要调节因子。本研究的目的是调查的T-287 C多态性的TFPI基因，我们以前描述的启动子的潜在关联，与深静脉血栓形成（DVT），并分析其对启动子功能的影响。低TFPI水平与DVT风险升高相关，我们提供了DVT和T-287 C之间可能相关的证据。T-287 C和血浆TFP 1水平之间的任何关联都被环境影响所掩盖。我们研究了TFPI启动子区域之间的碱基-1999和+229周围的转录起始位点和T-287 C多态性在人内皮细胞系中使用双荧光素酶报告基因测定的生物学效应。由2.2kb TFPI启动子序列驱动的荧光素酶活性对于两种等位基因变体都是低的，但是来自-287C等位基因的表达水平显著低于-287T。来自两个等位基因的截短的TFPI启动子片段产生高得多的转录活性，但等位基因变体之间的报告基因表达差异不显著。我们的研究结果表明，在TFPI启动子-1999和-345之间存在有效的阻遏序列，并建议TFPI T-287 C启动子多态性可能是DVT的危险因素。(c)2007爱思唯尔有限公司保留所有权利。
Tissue factor pathway inhibitor (TFPI) is the principle regulator of tissue factor induced blood coagulation. The aim of this study was to investigate the potential association of a T-287C polymorphism in the promoter of the TFPI gene, which we described previously, with deep vein thrombosis (DVT) and to analyse its effect on promoter function. Low TFPI levels were shown to be associated with elevated risk of DVT and we present evidence for a possible association between DVT and T-287C. Any association between T-287C and plasma TFP1 levels was masked by environmental effects. We studied the TFPI promoter region between bases -1999 and +229 around the transcription start site and the biological effects of the T-287C polymorphism in a human endothelial cell line using a Dual Luciferase-Reporter Gene Assay. Luciferase activity driven by the 2.2 kb TFPI promoter sequence was low for both allelic variants, but levels of expression from the -287C allele were significantly lower than -287T. Truncated TFPI promoter fragments from both alleles generated much higher transcriptional activity, but differences in reporter gene expression between allelic variants were not significant. Our results indicate the presence of potent repressor sequences between - 1999 and - 345 in the TFPI promoter and suggest that the TFPI T-287C promoter polymorphism might be a risk factor for DVT. (c) 2007 Elsevier Ltd. All rights reserved.