Endothelial protein C receptor 1651C/G polymorphism and soluble endothelial protein C receptor levels in women with idiopathic recurrent miscarriage

Abstract

High levels of soluble endothelial protein C receptor (EPCR) induce coagulation dysfunction by inhibiting protein C activation, and activated protein C (APC) activity. We tested whether EPCR 1651C/G promoter variant and changes in plasma soluble EPCR levels are risk factors for idiopathic recurrent spontaneous miscarriage (RSM). A case-control study involving 283 RSM cases and 380 age and BMI-matched control women. EPCR 1651C/G genotyping was performed by PCR-RFLP method. Plasma-soluble EPCR levels were measured with ELISA. The 1651G allele frequency and C/G genotype were significantly higher in RSM cases than controls; none of the cases or control participants was a 1651G/G homozygote. Lower soluble EPCR levels were seen in RSM cases compared to controls, and higher soluble EPCR levels were seen in 1651C/G compared to 1651C/C carriers in cases and controls. Lower soluble EPCR levels were seen in cases, both in 1651C/C (P = 0.0046) and 1651C/G (P = 0.0032) genotype carriers. Multivariate analysis demonstrated strong association of EPCR 1651C/G [P = 0.011; adjusted odds ratio (aOR) (95% confidence interval [CI] = 3.13 (1.31-7.60)], but not soluble EPCR plasma levels [P = 0.067; aOR (95% CI) = 1.01 (1.00-1.10)], with increased RSM risk. In addition, smoking was independently associated with increased RSM risk [P = 0.002; aOR (95% CI) = 2.86 (1.48-5.52)]. EPCR 1651C/G polymorphism and elevated soluble EPCR levels but low soluble EPCR levels increase the risk of idiopathic RSM. Replication studies on other racial groups, and other EPCR gene variants, are warranted.

Down‐regulation of endothelial protein C receptor promotes preeclampsia by affecting actin polymerization

“…This may be due to excessive placental ECPR shedding or to other pathways leading to maternal vascular endothelial cell stimulation. Studies have also shown that the expression level of sEPCR is related to gene polymorphisms and specific site mutations . In addition, we did not perform in vivo experiments in this study, and we should further validate our findings in vivo using animal models such as mice.…”

“…Studies have also shown that the expression level of sEPCR is related to gene polymorphisms and specific site mutations. 53,54 In addition, we did not perform in vivo experiments in this study, and we should further validate our findings in vivo using animal models such as mice.…”

Genetic and epigenetic variations associated with idiopathic recurrent pregnancy loss

“…Variants of inhibitors of the coagulation process may have an association with iRPL. APC activator polymorphisms, such as thrombomodulin gene (THBD) rs1042579 (C1418T) and endothelial protein C receptor gene (EPCR) rs867186 (1652C/G) have been proposed to be risk factors for iRPL due to the association of these variants with lower levels of soluble proteins impeding the adequate regulation of coagulation processes [47,48]. Similarly, the rs2227589 (786G > A) polymorphism in the antithrombin (AT or SERPINC1) gene has been associated with an increased risk of iRPL, as these proteins inhibit the transition of prothrombin to thrombin and avoid the coagulation process [49].…”

The endothelial protein C receptor plays an essential role in the maintenance of pregnancy

“…Activated PC (aPC) inhibits excessive thrombin generation by limited proteolytic cleavage and inactivation of coagulation factors Va and VIIIa. EPCR gene polymorphisms are associated with recurrent miscarriages and unexplained pregnancy loss ( 12 – 14 ). Notably, functional deficiency of EPCR is created by its shedding from the membrane surface by the action of metalloproteases ( 15 , 16 ).…”