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.