Thrombomodulin promoter mutations, venous thrombosis, and varicose veins

We analyzed the distal promoter region of the thrombomodulin (TM) gene (nuc leotides -300 to -2052) in subjects from the Paris Thrombosis Study (PATHRO S), a French case-control study of venous thrombosis, to identify polymorph isms 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) migh t have functional consequences owing to its position. These 3 mutations wer e screened for in the entire study population of 327 patients and 398 contr ols. None of the 3 was significantly associated with thrombosis. Interestin gly, 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 Al a 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.