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.
Related Articles in Blood Online :
- Thrombosis down to the vessel wall.
Frits R. Rosendaal Blood 2004 103: 1179-1180.[Full Text]
Common Sodium Channel Promoter Haplotype in Asian Subjects Underlies Variability in Cardiac Conduction
Associations of PPARGC1A Haplotypes With Plaque Score but Not With Intima-Media Thickness of Carotid Arteries in Middle-Aged Subjects
Genotype and Haplotype Association Study of the STRK1 Region on 5q12 Among Japanese
Association of Apolipoprotein E4 and Haplotypes of the Apolipoprotein E Gene With Lobar Intracerebral Hemorrhage
A Case-Control Study to Examine HLA Haplotype Associations in Patients with Posttreatment Chronic Lyme Disease
Polymorphisms and Haplotypes of the Regulator of G Protein Signaling-2 Gene in Normotensives and Hypertensives
A Population Association Study of Angiotensinogen Polymorphisms and Haplotypes With Left Ventricular Phenotypes
Interactive Effects of Common 2-Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function
Haplotype Analysis of the Human Renin Gene and Essential Hypertension
Angiotensinogen Gene Haplotype and HypertensionInteraction With ACE Gene I Allele