A HAPLOTYPE OF THE EPCR GENE IS ASSOCIATED WITH INCREASED PLASMA LEVELS OF sEPCR AND IS A CANDIDATE RISK FACTOR FOR THROMBOSIS Short title : EPCR gene , sEPCR level and thrombotic

The endothelial cell protein C (PC) receptor EPCR facilitates PC activation by the thrombin-thrombomodulin complex. A soluble form of this receptor (sEPCR) found in plasma inhibits both aPC activity and PC activation by competing for PC with membrane-associated EPCR. Elevated sEPCR levels are found in ~20% of healthy subjects, but the mechanisms underlying this interindividual variability are unknown. We measured sEPCR levels in 100 healthy male volunteers, and observed two phenotypic groups of subjects. The temporal stability of sEPCR levels suggested genetic control. Extensive analysis of the EPCR gene in these subjects revealed 13 polymorphisms in complete linkage disequilibrium; these defined three haplotypes, one of which (A3) was strongly associated with high sEPCR levels. The high constitutive sEPCR levels observed in A3 haplotype carriers might reduce the efficiency of the PC system and predispose these subjects to venous thrombosis. By studying 338 patients with venous thrombosis and 338 age-and sex-matched healthy subjects, we found that the A3 haplotype was over-represented in the patients. In multivariate analysis, subjects carrying the A3 haplotype had an increased risk of thrombosis (OR=1.8, p=0.004). Thus, the A3 haplotype, which is associated with elevated plasma sEPCR levels, is a candidate risk factor for venous thrombosis.

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