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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:445.)
© 2001 American Heart Association, Inc.

Thrombosis

Thrombomodulin Promoter Mutations, Venous Thrombosis, and Varicose Veins

Léna Le Flem; Louise Mennen; Marie-Laurence Aubry; Martine Aiach; Pierre-Yves Scarabin; Joseph Emmerich; Martine Alhenc-Gelas

From the Service d’Hématologie Biologique A and Service des Maladies Vasculaires (L.L.F., M.L.A., J.E., M.A., M.A.G.), Hôpital Européen Georges Pompidou, AP-HP and Unité INSERM 428, Faculté de Pharmacie, Université René Descartes, and Unité INSERM 258 (M.M., P.Y.S.), Paris, France.

Correspondence to Dr Martine Alhenc-Gelas, Service d’Hématologie Biologique A, Hôpital Européen Georges Pompidou, 20 rue Leblanc, F-75908 Paris Cedex 15, France. E-mail martine.alhenc-gelas{at}egp.ap-hop-paris.fr

Abstract—We analyzed the distal promoter region of the thrombomodulin (TM) gene (nucleotides -300 to -2052) 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 (-1748G/C and -1208/-1209 del TT) were frequent. One rare transition (-1166G/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 -1208/-1209 TT deletion was associated with varicose veins in the patients. This mutation was in tight linkage disequilibrium with the +1418 C/T change in the coding sequence, a known polymorphism that predicts an Ala 455 Val substitution in the sixth epidermal growth factor–like TM module, a domain previously implicated in the proliferative functions of TM. This linkage suggests that the Ala 455 Val mutation may promote changes in these functions and thus be involved in varicose vein formation.

Key Words: thrombomodulin • thrombosis • coagulation • gene • angiogenesis

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