Association of the Thrombomodulin Gene c.1418C>T Polymorphism With Thrombomodulin Levels and With Venous Thrombosis Risk

Abstract

Objective— 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. Approach and Results— 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. Conclusions— 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.

Functional Analysis of Two Haplotypes of the Human Endothelial Protein C Receptor Gene

“…Because the thrombomodulin gene (THBD) g.1418C>T polymorphism has been associated with the rate of PC activation in cultured HUVECs, 28 we selected passage 2 HUVECs which were homozygous wild type for the THBD g.1418C>T SNP (1418CC). The rate of PC activation increased with the number of H1 alleles, whereas it decreased in the presence of H3.…”

Soluble Thrombomodulin and Major Orthopedic Surgery

“…A similar association between sTM and age was found earlier. [16] Blood sTM level is determined by hereditary factors [9,13] and by pathological changes that lead to increased proteolytic cleavage of endothelial TM. [17] TM expression is depressed in the aged.…”

“…[5] Experimental and clinical studies have shown that a low level of sTM is associated with a prethrombotic state and venous thrombosis. [6][7][8][9] Application of recombinant human sTM is effective in prevention of the venous thrombosis in a rat model and after total hip replacement [10,11] for the treatment of disseminated intravenous coagulation. [12] On the other hand, the increased level of sTM causes severe bleeding after injuries and operations.…”

Association between genetic polymorphisms and deep vein thrombosis in a Chinese population

“…Consistent with previous studies [9,10], there was no statistical significant difference in this allelic variant between DVT patients and controls, which suggests that THBD c.1418C N T might be Recently, a large study assessing the genetic background of Chinese venous thrombosis patients [11] confirmed that the c.1456G N T and c.1418C N T variants had no obvious influence on the occurrence of DVT. A large sample study even suggested that the 1418 T allele might increase the stability of thrombomodulin, which would result in an increased protein C activation rate and a lower risk of venous thrombosis [12]. In addition, Tang et al [11] identified the novel variant THBD c. − 151G N T which was associated with DVT in China.…”