Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis

Abstract

Summary. Background: Binding of protein C (PC) to the endothelial cell PC receptor (EPCR) stimulates PC activation by increasing the affinity of PC for the thrombin‐thrombomodulin complex. A soluble form of this receptor (sEPCR) circulates in plasma and inhibits both PC activation and APC anticoagulant activity. Objectives: The aim of this study was to investigate whether variations in the EPCR gene or plasma sEPCR levels are risk factors for deep venous thrombosis (DVT). Patients/methods: In a large case‐control study, the Leiden Thrombophilia Study (LETS), sEPCR levels were measured by ELISA. All subjects were genotyped for three haplotype‐tagging SNPs, enabling us to detect all four common haplotypes of the EPCR gene. Results: The distribution of sEPCR levels in the control population was trimodal and was genetically controlled by haplotype 3 (H3). This haplotype explained 86.5% of the variation in sEPCR levels. Carriers of two H3 alleles had higher sEPCR levels (439 ng mL−1) than carriers of one H3 allele (258 ng mL−1), which had higher levels than non‐H3 carriers (94 ng mL−1). Haplotype 4 was associated with a slightly increased risk (OR = 1.4, 95%CI:1.0–2.2). The risk of subjects with sEPCR levels in the top quartile (≥ 137 ng mL−1) was increased compared to that of subjects in the first quartile (< 81 ng mL−1), but since there was no dose–response effect, it is most likely that low sEPCR levels reduce the risk of DVT. Conclusions: Our data do not suggest a strong association between EPCR haplotypes and thrombosis risk, but low sEPCR levels appear to reduce the risk of DVT.

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

“…There is no consensus as to whether the presence of the A3 haplotype per se increases the risk of VTE. Three reports indicated that the A3 haplotype is not associated with an increased VTE risk 15,16 and had no effect on the risk of VTE in factor V Leiden carriers, 19 whereas another report showed that the A3 haplotype was associated with a 2.5-fold increased risk of VTE in men but not in women.…”

“…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.…”

“…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. In addition, we measured the effect of prothrombin and sEPCR levels on VTE risk, since these parameters have been associated with the 20210A and 4600G alleles respectively.…”

Endothelial Cell Protein C Receptor Gene 6936a/G, 1651c/G, 4678g/C Polymorphisms and Soluble Endothelial Protein C Receptor Levels Impact on in Vitro Fertilization Outcomes

“…Four haplotypes involved in alteration of soluble EPCR levels were demonstrated, among which, the haplotype 3 (H3) is linked with increased soluble EPCR levels. This haplotype is identified by the G/C/A/G combination at positions 1651, 3610, 4216, and 6936, respectively [13]. Moreover, 4678G/C (rs 9574) is a singlenucleotide polymorphisms (SNP) representative of one of the four different haplotypes in the EPCR gene, haplotype 1 (H1) [13].…”

“…This haplotype is identified by the G/C/A/G combination at positions 1651, 3610, 4216, and 6936, respectively [13]. Moreover, 4678G/C (rs 9574) is a singlenucleotide polymorphisms (SNP) representative of one of the four different haplotypes in the EPCR gene, haplotype 1 (H1) [13]. Poor pregnancy outcome was associated with specific gene variants and altered soluble EPCR levels in some [14] but not all [15] studies.…”