title: 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.
  
  
  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.
authors.affiliation: Unidad de Bioquímica, Centro de Investigación, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Navarro
authors.forename: Pilar
authors.initials: P
authors.lastname: Medina
authors.forename: Elena
authors.initials: E
authors.lastname: Bonet
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: Vicenta
authors.initials: V
authors.lastname: Martínez-Sales
authors.forename: Laura
authors.initials: L
authors.lastname: Martos
authors.forename: Miguel
authors.initials: M
authors.lastname: Rivera
authors.forename: Esther
authors.initials: E
authors.lastname: Roselló-Lletí
authors.forename: Ignacio
authors.initials: I
authors.lastname: Alberca
authors.forename: Vanessa
authors.initials: V
authors.lastname: Roldán
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Mira
authors.forename: Fernando
authors.initials: F
authors.lastname: Ferrando
authors.forename: Amparo
authors.initials: A
authors.lastname: Estellés
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Bertina
authors.forename: Francisco
authors.initials: F
authors.lastname: España
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002478:Cells, Cultured; D042783:Endothelial Cells; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011486:Protein C / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D018570:Risk Assessment; D012995:Solubility; D018180:Thrombomodulin / Q000235:genetics* / Q000378:metabolism; D054556:Venous Thromboembolism / Q000453:epidemiology / Q000235:genetics*; D020246:Venous Thrombosis / Q000453:epidemiology / Q000235:genetics
chemical_list: D005819:Genetic Markers; D011486:Protein C; D012333:RNA, Messenger; D018180:Thrombomodulin
keywords: endothelial cells; gene expression; protein C; thrombomodulin; venous thrombosis