Unidad de Bioquímica, Centro de Investigación, Hospital Universitario La Fe, Valencia, Spain.
Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1435-40. doi: 10.1161/ATVBAHA.113.301360. Epub 2013 Mar 21.
To investigate the association of the THBD c.1418C>T polymorphism, which encodes for the replacement of Ala455 by Val in thrombomodulin (TM), with venous thromboembolism (VTE), plasma soluble TM, and activated protein C levels. In addition, human umbilical vein endothelial cells (HUVEC) isolated from 100 umbilical cords were used to analyze the relation between this polymorphism and THBD mRNA and TM protein expression.
The THBD c.1418C>T polymorphism was genotyped in 1173 patients with VTE and 1262 control subjects. Levels of soluble TM and activated protein C were measured in 414 patients with VTE (not on oral anticoagulants) and 451 controls. HUVECs were genotyped for the polymorphism and analyzed for THBD mRNA and TM protein expression and for the ability to enhance protein C activation by thrombin. The 1418T allele frequency was lower in patients than in controls (P<0.001), and its presence was associated with a reduced VTE risk, reduced soluble TM levels, and increased circulating activated protein C levels (P<0.001). In cultured HUVEC, the 1418T allele did not influence THBD expression but was associated with increased TM in cell lysates, increased rate of protein C activation, and reduced soluble TM levels in conditioned medium.
The THBD 1418T allele is associated with lower soluble TM, both in plasma and in HUVEC-conditioned medium, and with an increase in functional membrane-bound TM in HUVEC, which could explain the increased activated protein C levels and the reduced VTE risk observed in individuals carrying this allele.
研究血栓调节蛋白（TM）中编码丙氨酸 455 被缬氨酸取代的 THBD c.1418C>T 多态性与静脉血栓栓塞症（VTE）、血浆可溶性 TM 和活化蛋白 C 水平的关系。此外，还分析了该多态性与 THBD mRNA 和 TM 蛋白表达之间的关系，使用从 100 根脐带中分离出的人脐静脉内皮细胞（HUVEC）进行分析。
在 1173 例 VTE 患者和 1262 例对照者中对 THBD c.1418C>T 多态性进行基因分型。在 414 例未服用口服抗凝剂的 VTE 患者和 451 例对照者中测量可溶性 TM 和活化蛋白 C 水平。对多态性进行基因分型，并分析 HUVEC 的 THBD mRNA 和 TM 蛋白表达以及对凝血酶增强蛋白 C 活化的能力。与对照组相比，患者的 1418T 等位基因频率较低（P<0.001），其存在与 VTE 风险降低、可溶性 TM 水平降低和循环活化蛋白 C 水平升高相关（P<0.001）。在培养的 HUVEC 中，1418T 等位基因不影响 THBD 表达，但与细胞裂解物中 TM 增加、蛋白 C 活化率增加和条件培养基中可溶性 TM 水平降低相关。
THBD 1418T 等位基因与血浆和 HUVEC 条件培养基中的可溶性 TM 降低以及 HUVEC 中功能性膜结合 TM 增加相关，这可以解释携带该等位基因的个体中观察到的活化蛋白 C 水平升高和 VTE 风险降低。
