A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis

Abstract

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.

Haplotypes of the EPCR gene, prothrombin levels, and the risk of venous thrombosis in carriers of the prothrombin G20210A mutation

“…[14][15][16] Given that sEPCR binds both protein C and APC, it has been hypothesized that elevated sEPCR levels may result in decreased APC generation and in APC inhibition, 14 inducing decreased plasma APC levels and increased risk of VTE. 22 Our finding that the presence of the 4600G allele is associated with higher sEPCR levels and lower APC levels, and that increased sEPCR levels are associated with VTE in carriers of the 20210A allele, independently of the 4600A/G polymorphism, would support this hypothesis.…”

“…There is some evidence that prothrombin levels affect the APC-resistance phenotype, but the precise mechanism is not known. As to the EPCR 4600G allele, this allele has been associated in vivo and in vitro with increased sEPCR levels, [14][15][16] which might be due in part to increased sensitivity to ADAM17. 13 However, a recent report also attributes this to increased production of a soluble alternative splice product of EPCR.…”

“…13 However, its association with risk of VTE is controversial. [14][15][16] sEPCR retains its ability to bind both protein C and activated protein C (APC), and blocks APC anticoagulant activity. 17,18 Haplotype 1 (A1), tagged by the rare allele of 4678G/C, was reported to be associated with increased levels of APC and a reduced risk of VTE.…”

The functional properties of a truncated form of endothelial cell protein C receptor generated by alternative splicing

“…5 These higher levels of sEPCR are associated with one of the four EPCR haplotypes, A3, defined by a variation in the coding sequence of EPCR and resulting in the substitution of a serine with a glycine at position 219 in the transmembrane domain. 6 This haplotype promotes cellular shedding by tumor necrosis factor-α converting enzyme/ADAM17 (TACE). 7 High levels of sEPCR have been postulated to be associated with an increased risk of venous thrombosis, 6 but the data are controversial and two big studies failed to find an association.…”

“…6 This haplotype promotes cellular shedding by tumor necrosis factor-α converting enzyme/ADAM17 (TACE). 7 High levels of sEPCR have been postulated to be associated with an increased risk of venous thrombosis, 6 but the data are controversial and two big studies failed to find an association. 8,9 sEPCR blocks protein C activation by preventing protein C from binding to membrane EPCR.…”