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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1311-1318.
Prepublished online as a Blood First Edition Paper on October 23, 2003; DOI 10.1182/blood-2003-07-2520.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis
Beatrice Saposnik,
Jean-Luc Reny,
Pascale Gaussem,
Joseph Emmerich,
Martine Aiach, and
Sophie Gandrille
From the Institut National de la Santé et de la Recherche Médicale (INSERM) U 428, Paris, France; Service d'Hématologie Biologique A; Service de Médecine Vasculaire-hypertension, Hôpital Européen Georges Pompidou, Paris France; and Laboratoire d'Hémostase, Université Paris V, Paris, France.
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 activated PC (aPC) activity and PC activation by competing for PC with membrane-associated EPCR. Elevated sEPCR levels are found in approximately 20% of healthy subjects, but the mechanisms underlying this interindividual variability are unknown. We measured sEPCR levels in 100 healthy male volunteers, and observed 2 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 3 haplotypes, 1 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 overrepresented in the patients. In multivariate analysis, subjects carrying the A3 haplotype had an increased risk of thrombosis (odds ratio [OR] = 1.8; P = .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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