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

Abstract

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-β1 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-β1 and TNFα polymorphisms and miscarriage.

Relationship between common interleukin 1-beta gene polymorphisms and the risk of gestational disorders: An updated meta-analysis

“…It has been well documented that polymorphisms could alter cytokine production levels and the strength of cytokine responses ( 43 ). The IL-1α and IL-1β, most-studied interleukins in pregnancy disorders, are proinflammatory cytokines that bind to the IL-1 receptor to rapidly initiate signal transduction and apply biological effects ( 44 ).…”

Overview of genetic causes of recurrent miscarriage and the diagnostic approach

“…Anti-inflammatory cytokines such as interleukin-10 (IL-10) and Toll-like receptors are important for embryonic implantation and development. SNPs of these genes may affect their expression and therefore may affect fetal implantation and development resulting in fetal loss (Zammiti et al, 2006;Razdaibiedina et al, 2018). Additionally, tumor necrosis factor-alpha (TNF-α) is an apoptosis-inducing factor in tumor cells.…”

New insights on the potential effect of progesterone in Covid‐19: Anti‐inflammatory and immunosuppressive effects

“…It has been shown that the anti‐inflammatory of P4 is mediated by GRs rather than by PRs. Moreover, P4 inhibits the expression of toll‐like receptors (TLRs) 3 and 4 and the release of IL‐6, tumor necrosis factor‐α (TNF‐α), and IL‐1β as well as the expression of CD86 and CD80 30 . Likewise, P4 inhibits T cell and macrophage activation in animal model studies by inhibiting the production of nitric oxide 30 .…”