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

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.

Effects of Single-Nucleotide Polymorphisms in Cytokine, Toll-Like Receptor, and Progesterone Receptor Genes on Risk of Miscarriage.

Spontaneous abortion is a complex, multifactorial pathology, where various genetic, neural, endocrine, and immunological factors are involved. Cytokines, Toll-like receptors, and progesterone receptors play critical roles in embryonic implantation and development. A delicate, stage-specific equilibrium of these proteins is required for successful pregnancy outcome. However, genetic variation from one individual to another results in variation in levels of Th1/Th2 cytokines, strength of identification of infectious agents by Toll-like receptors, and quality of progesterone recognition. Thus, a complex study encompassing effects of major SNPs of cytokine, TLR, and PGR genes on the risk of miscarriage is needed. In this study, we investigated SNPs of 9 genes (TLR2 G753A, TLR4 C399T, TLR9 G2848A, TGF-ß1 C509T, PGR PROGINS, IL-6 G174C, IL-8 C781T, IL-10 C592A, and TNFα G308A) in 106 women, whose pregnancy ended in miscarriage, and 74 women, who delivered in term without any pregnancy complication. All participants are from Ukrainian population. As a result, TLR9 and IL-10 SNPs have been found to play critical roles in the development of spontaneous abortion. TLR2, TLR4, IL-6, IL-8, and PGR SNPs were identified as secondary factors that can also affect the risk of miscarriage. There was no association found between TGF-ß1 and TNFα polymorphisms and miscarriage.