Thrombomodulin Promoter Mutations, Venous Thrombosis, and Varicose Veins

Abstract

Abstract-We analyzed the distal promoter region of the thrombomodulin (TM) gene (nucleotides Ϫ300 to Ϫ2052) in subjects from the Paris Thrombosis Study (PATHROS), a French case-control study of venous thrombosis, to identify polymorphisms that might modify TM gene expression. Eight novel mutations were found in the 40 DNA samples initially screened. Two of these mutations (Ϫ1748G/C and Ϫ1208/Ϫ1209 del TT) were frequent. One rare transition (Ϫ1166G/A) might have functional consequences owing to its position. These 3 mutations were screened for in the entire study population of 327 patients and 398 controls. None of the 3 was significantly associated with thrombosis. Interestingly, the Ϫ1208/Ϫ1209 TT deletion was associated with varicose veins in the patients. This mutation was in tight linkage disequilibrium with the ϩ1418 C/T change in the coding sequence, a known polymorphism that predicts an

Inherited Abnormalities in the protein C Activation Pathway

“…Le Flem at al (12) analyzed the distal promoter region of the TM gene (nucleotides -300 to -2052) in patients with VTE. Eight novel mutations were found, the more frequent being the G-1748C and the del-1208/-1209TT polimorphisms.…”

Thrombomodulin gene polymorphisms in brain infarction and mortality after stroke

“…Two TM promoter polymorphisms (-1748G/C, -1208/-1209del TT) have been investigated in patients with venous thrombosis included in the Paris Thrombosis Study (PATHROS) study [9]. The -1208/ -1209delTT polymorphism is in linkage disequilibrium with the +1418C/T polymorphism [9], which is responsible for Ala455Val substitution in the EGF6 domain of TM [5].…”

Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function

“…26 This polymorphism was found not to be associated with venous thrombophilia, 27 but has been suggested to be associated with varicose veins through linkage with promoter mutations. 28 Although much of the above data are suggestive of a causal effect of the TM mutation in thromboembolic disease, there is incomplete understanding of the function of most of the identified mutations. Clarification of the functional consequences is important because most of the mutations are rare events, or occur in small families, and the clinical effects of the mutations are difficult to ascertain in these settings.…”