Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk

Abstract

Endothelial cell protein C receptor (EPCR) enhances the generation of activated protein C (APC) by the thrombin-thrombomodulin complex. A soluble form of EPCR (sEPCR), which is generated by metalloprotease activity, is present in plasma. The distribution of sEPCR levels in healthy populations is bimodal. Previously, we described two polymorphisms in exon 4 of the EPCR gene, 4600A/G that encodes the substitution of Ser219 by Gly in the transmembrane region of EPCR and 4678G/C in the 3'-UT region. The aim of this study was to investigate the relationship between these two polymorphisms and plasma sEPCR and APC levels and risk of venous thrombosis. We genotyped 401 healthy controls from the Spanish population and measured their plasma sEPCR and APC levels. Carriers of the 4600AG genotype had significantly higher sEPCR levels than those with the AA genotype, while the 4678CC genotype was associated, to a lesser extent, with elevated APC levels. To assess the effect of these polymorphisms on the risk of thrombosis, we genotyped 405 patients with venous thromboembolism. The frequency of the 4600AG genotype was very similar in patients and controls (p=0.975), whereas the 4678CC genotype was significantly more frequent in controls than in patients (p=0.008). In multivariate analysis, carriers of the 4678CC genotype had a decreased risk of thrombosis (OR=0.61, p=0.009). These data indicate that individuals carrying the 4600AG genotype have high sEPCR levels but do not have an increased risk of thrombosis, whereas individuals carrying the 4678CC genotype have higher APC levels and lower risk of venous thromboembolism.

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

“…Among the 84 propositi, the frequency of the 4600G allele (A3 haplotype) was 0.167 (Table 2), which is clearly higher than that observed in previous studies of unselected VTE patients (0.094), 15 VTE patients with FV Leiden 19 (0.100) and healthy subjects (0.092). 15 The frequency of the 4678C allele (A1 haplotype) was 0.369, slightly lower than that observed in unselected VTE patients 15 (0.409) and VTE patients with FV Leiden 19 (0.395), and significantly lower than the 0.470 observed in healthy subjects. 15 The frequency of the 4600G allele was higher in the 84 propositi (0.167) than in their 149 asymptomatic relatives (0.070) (p<0.001), whereas that of the 4678C allele tended to be lower in the propositi (0.369) than in their asymptomatic relatives (0.456) (p=0.078) ( Table 2).…”

“…15 The frequency of the 4678C allele (A1 haplotype) was 0.369, slightly lower than that observed in unselected VTE patients 15 (0.409) and VTE patients with FV Leiden 19 (0.395), and significantly lower than the 0.470 observed in healthy subjects. 15 The frequency of the 4600G allele was higher in the 84 propositi (0.167) than in their 149 asymptomatic relatives (0.070) (p<0.001), whereas that of the 4678C allele tended to be lower in the propositi (0.369) than in their asymptomatic relatives (0.456) (p=0.078) ( Table 2). In addition, the frequency of the 4600G allele was higher in the 13 symptomatic than in the 149 asymptomatic relatives with the 20210A allele (OR 3.0, 1.0-8.9).…”

“…15 A study of the families of these symptomatic 20210A carriers revealed that the 4600G allele (A3 haplotype) of EPCR was associated with an increased risk of VTE in carriers of the 20210A allele. Furthermore, carriers of the 4600G allele experienced the first VTE episode at a younger age and were free of thrombosis at 40 years of age in a lower proportion than those carrying the 4600A allele.…”

“…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.…”

“…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. 15,19 Finally, haplotype 4 (A4), tagged by the rare allele of 3811 G/A, was reported to be associated with a slight increase in the risk of VTE. 16 The aim of this study was to investigate whether the A1 and A3 haplotypes of EPCR modify the risk of VTE in carriers of the 20210A variant.…”