Department of Hematology, Oslo University Hospital, Kirkeveien 166, Oslo, Norway.
Biochem Biophys Res Commun. 2010 Jun 18;397(1):106-11. doi: 10.1016/j.bbrc.2010.05.078. Epub 2010 May 16.
Tissue factor pathway inhibitor (TFPI) is the primary physiological inhibitor of tissue factor (TF) induced coagulation. Low plasma TFPI levels have been shown to be associated with increased risk of arterial and venous thrombosis. Several clinical studies have reported that single nucleotide polymorphisms (SNPs) in the regulatory regions of the gene, such as the -287T/C, the -399C/T, and the -33T/C SNPs, may affect plasma TFPI levels. However, molecular studies investigating the functionality of the polymorphisms are lacking. In this study, we found that the -287C and -399T alleles affected the activity of the promoter using a reporter gene system. This was also the case for the -33T/C polymorphism. An association regarding the transcriptional activity of the reporter gene was detected between the -287C allele and the -33T/C polymorphism. Analysis of the polymorphic sites with electrophoretic mobility shift assay (EMSA) showed that all three polymorphisms potentially alter DNA-protein interactions. Based on these findings, we speculate that the -287C and the -33C alleles can be associated with lowered risk of thrombosis.
组织因子途径抑制剂（TFPI）是组织因子（TF）诱导的凝血的主要生理抑制剂。低血浆 TFPI 水平与动脉和静脉血栓形成的风险增加有关。几项临床研究报告称，基因调节区域的单核苷酸多态性（SNPs），如-287T/C、-399C/T 和-33T/C SNPs，可能会影响血浆 TFPI 水平。然而，缺乏对这些多态性的功能进行分子研究。在这项研究中，我们发现 -287C 和 -399T 等位基因通过报告基因系统影响启动子的活性。-33T/C 多态性也是如此。在报告基因的转录活性之间检测到 -287C 等位基因和-33T/C 多态性之间存在关联。通过电泳迁移率变动分析（EMSA）对多态性位点的分析表明，所有三种多态性都可能改变 DNA-蛋白质相互作用。基于这些发现，我们推测 -287C 和 -33C 等位基因可能与降低血栓形成的风险有关。
