Risk of Recurrent Pregnancy Loss in the Ukrainian Population Using a Combined Effect of Genetic Variants: A Case-Control Study.

Eleni M Loizidou,Pavlo Tatarskyy,Sergey Chernushyn,Ganna Livshyts,Yurii Antipkin,Iryna Vorobiova,Anastasia Kucherenko,Ludmila Livshits,Marika A Kaakinen,Inga Prokopenko,Roman Gulkovskyi,Oleksandra Gorodna

doi:10.3390/genes12010064

Abstract

We assessed the predictive ability of a combined genetic variant panel for the risk of recurrent pregnancy loss (RPL) through a case-control study. Our study sample was from Ukraine and included 114 cases with idiopathic RPL and 106 controls without any pregnancy losses/complications and with at least one healthy child. We genotyped variants within 12 genetic loci reflecting the main biological pathways involved in pregnancy maintenance: blood coagulation (F2, F5, F7, GP1A), hormonal regulation (ESR1, ADRB2), endometrium and placental function (ENOS, ACE), folate metabolism (MTHFR) and inflammatory response (IL6, IL8, IL10). We showed that a genetic risk score (GRS) calculated from the 12 variants was associated with an increased risk of RPL (odds ratio 1.56, 95% CI: 1.21, 2.04, p = 8.7 × 10−4). The receiver operator characteristic (ROC) analysis resulted in an area under the curve (AUC) of 0.64 (95% CI: 0.57, 0.72), indicating an improved ability of the GRS to classify women with and without RPL. Ιmplementation of the GRS approach can help define women at higher risk of complex multifactorial conditions such as RPL. Future well-powered genome-wide association studies will help in dissecting biological pathways previously unknown for RPL and further improve the identification of women with RPL susceptibility.

Highlights

The loss of two or more sequential pregnancies in the first trimester of gestation is defined as recurrent pregnancy loss (RPL) [1]
The sample sizes varied greatly for the genotyped SNPs, whereas the genetic risk score (GRS) accounted for the variable number of genotyped SNPs per individual
The sensitivity analysis using the GRS with weights from our study effect estimates resulted in an odds ratios (ORs) of 1.83 (95% confidence intervals (CIs) (1.34, 2.57), p = 3.0 × 10−4 )

Summary

Introduction

RPL etiology, endocrine, immunological, anatomical and other factors are proposed to play a leading role, with most of the remaining RPL cases being idiopathic [5,6] Conditions such as chronic endometritis (CE) have been associated with RPL, and there are reliable diagnostic techniques, including hysteroscopy and CD138 immunohistochemical stain to identify CE in RPL cases [7,8]. Several infections, such as toxoplasma gondii, may lead to RPL [9,10].

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Discussion

Conclusion