Ishikawa Junko, Okada Hiromi, Kato Hisao, Takeshita Satoshi, Honda Shigenori, Kawasaki Tomio, Suehisa Etsuji, Tsuji Hajime, Madoiwa Seiji, Sakata Yoichi, Kojima Tetsuhito, Murata Mitsuru, Ikeda Yasuo, Kokubo Yoshihiro, Okamura Tomonori, Tomoike Hitonobu, Miyata Toshiyuki
National Cardiovascular Center Research Institute, Osaka, Japan.
Blood Coagul Fibrinolysis. 2009 Jan;20(1):22-6. doi: 10.1097/MBC.0b013e328304e0b9.
Tissue factor pathway inhibitor (TFPI) is an anticoagulant protease inhibitor that inhibits the tissue factor-initiated blood coagulation cascade reactions. Based on these anticoagulant functions of TFPI, we hypothesized that genetic variations in TFPI may alter the TFPI expression or impair the anticoagulant function and could predispose persons to deep vein thrombosis (DVT). This study was undertaken to examine whether the genetic polymorphisms in TFPI are associated with the plasma TFPI levels and risk for DVT. We sequenced the entire coding regions of TFPI in 175 Japanese DVT patients and identified 12 genetic variants, including one missense mutation, Asn221Ser. The missense mutation occurred at the site presumably attached to the glycosylphosphatidylinositol anchor in the TFPI-beta form. The allele frequency of the mutant Ser-coding allele of the Asn221Ser mutation was 8% in the Japanese general population consisting of 1684 individuals. The Asn221Ser mutation was significantly associated with the total TFPI levels (Asn/Asn, n = 108, total TFPI = 56.57 +/- 0.88 ng/ml (mean +/- SD) vs. Asn/Ser + Ser/Ser, n = 16, total TFPI = 63.44 +/- 2.28 ng/ml, P = 0.0058). The genotype was not associated with the free TFPI level. This Asn221Ser mutation was not associated with DVT. Thus, the Asn221Ser mutation occurring in the TFPI-beta form was associated with the total TFPI level, but not a risk for DVT. The absence of the putative glycosylphosphatidylinositol anchor in TFPI-beta under pathological conditions remains to be studied.
组织因子途径抑制物（TFPI）是一种抗凝蛋白酶抑制剂，可抑制组织因子启动的血液凝固级联反应。基于TFPI的这些抗凝功能，我们推测TFPI的基因变异可能会改变TFPI的表达或损害其抗凝功能，并可能使个体易患深静脉血栓形成（DVT）。本研究旨在探讨TFPI基因多态性是否与血浆TFPI水平及DVT风险相关。我们对175例日本DVT患者的TFPI整个编码区进行了测序，共鉴定出12个基因变异，其中包括一个错义突变Asn221Ser。该错义突变发生在TFPI-β形式中可能与糖基磷脂酰肌醇锚定相连的位点。在由1684名个体组成的日本普通人群中，Asn221Ser突变的Ser编码突变等位基因频率为8%。Asn221Ser突变与总TFPI水平显著相关（Asn/Asn，n = 108，总TFPI = 56.57 +/- 0.88 ng/ml（平均值 +/- 标准差） vs. Asn/Ser + Ser/Ser，n = 16，总TFPI = 63.44 +/- 2.28 ng/ml，P = 0.0058）。该基因型与游离TFPI水平无关。此Asn221Ser突变与DVT无关。因此，TFPI-β形式中发生的Asn221Ser突变与总TFPI水平相关，但与DVT风险无关。病理条件下TFPI-β中假定的糖基磷脂酰肌醇锚定缺失仍有待研究。
