Association of Polymorphisms in Plasminogen Activator Inhibitor-1 (PAI-1), Tissue Plasminogen Activator (tPA), and Renin (REN) with Recurrent Pregnancy Loss in Korean Women

Hee Young Cho,Young Ran Kim,Eun Ju Ko,Woo Sik Lee,Nam Keun Kim,Hyeon Woo Park,Han Sung Park,Eun Hee Ahn,Ji Hyang Kim

doi:10.3390/jpm11121378

Abstract

Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses prior to 20 weeks of gestational age. Various factors, including immune dysfunction, endocrine disorders, coagulation abnormality, and genetic disorders influence RPL. In particular, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and renin (REN) have important roles in the thrombotic and thrombolytic systems, and abnormal expression of these genes have a reported negative correlation with pregnancy maintenance. Moreover, some polymorphisms of the three genes are related to expression levels and thrombotic disorder. Therefore, we investigated whether polymorphisms of PAI-1, tPA, and REN are linked to RPL. Genotyping of the six polymorphisms (PAI-1 rs11178, rs1050955, tPA rs4646972, rs2020918, REN rs1464816, and rs5707) was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and associations of the polymorphisms with RPL were evaluated by statistical analysis. The polymorphism PAI-1 rs1050955 GA+AA was associated with decreased RPL risk (AOR, 0.528; 95% CI 0.356–0.781; p = 0.001) as was the REN 10795 rs5707 GG genotype (AOR, 0.487; 95% CI 0.301–0.787; p = 0.003). In contrast, the tPA rs4646972 II genotype correlated with increased RPL risk (AOR, 1.606; 95% CI, 1.047–2.463; p = 0.030). This study provides evidence that tPA Alu rs4646972 may contribute to the risk of idiopathic RPL, but PAI-1 12068 rs1050955 and REN 10795 rs5707 are associated with a decreased risk of RPL. Therefore, these alleles may be useful as biomarkers to evaluate the risk of RPL.

Highlights

The genotype frequencies of the plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and REN genes in the recurrent pregnancy loss (RPL) and control groups indicated that the PAI-1 12068 rs1050955 GA (AOR, 0.529; 95% confidence intervals (CIs), 0.349–0.802; p = 0.003), AA (AOR, 0.527; 95% CI, 0.319–0.869; p = 0.012), and GA+AA
The tPA Alu rs4646972 II genotype was associated with an increased risk of RPL (AOR, 1.606; 95% CI, 1.047–2.463; p = 0.030; Table 2)
Overexpression of PAI-1 is associated with thrombus formation in various types of blood vessels [23] and adverse pregnancy complications including miscarriage, stillbirth, fetal growth restriction, and placental abruption [24]

Summary

Introduction

About 10–12% of pregnant women experience early miscarriages, and between 1%. 4% of all pregnant women experience recurrent pregnancy loss (RPL) [1]. Hypercoagulability, resulting from an increase in coagulation factors, a decrease in blood flow, and a decrease in the activity levels of natural anticoagulants, leads to an increased susceptibility to venous thromboembolism in pregnant women. Hypofibrinolysis and thrombophilia can be risk factors in RPL and infertility [3]. An imbalance in the dynamic equilibrium between fibrin formation and fibrinolysis will result in a prothrombotic state [4] and thrombophilia, with the formation of a microthrombosis at the embryonic implantation site, resulting in implantation failure and RPL [5]

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Conclusion