The interaction effect of angiogenesis and endothelial dysfunction-related gene variants increases the susceptibility of recurrent pregnancy loss

  • E. A. Trifonova
  • M. G. SwarovskayaEmail author
  • O. A. Ganzha
  • O. V. Voronkova
  • T. V. Gabidulina
  • V. A. Stepanov



The role of genetic polymorphisms in the pathogenesis of recurrent pregnancy loss (RPL) has been studied intensively. Complex diseases, including miscarriage, are believed to have a polygenic basis, and gene–gene interactions can play a significant role in the etiology of the disease. This study was conducted to investigate the association of gene–gene interactions with angiogenesis, endothelial dysfunction-related gene polymorphisms, and RPL.


A case–control study was conducted with 253 unrelated RPL patients with 2 or more spontaneous pregnancy losses and 339 healthy women with no history of pregnancy complications. Genotyping of single-nucleotide polymorphisms (SNPs) was performed using real-time polymerase chain reaction (real-time PCR), restriction fragment length polymorphism (RFLP), or allele-specific polymerase chain reaction methods.


The genotypes 677TT of the MTHFR gene, 936TT, 936CT, and 634CC, 634GC of the VEGF gene, and allele 894T of the NOS3 gene were associated with a predisposition to RPL in the Russian population. A significant role of additive and epistatic effects in the gene–gene interactions of the SNPs of SERPINE-1, ACE, NOS3, MTHFR, and VEGF genes in RPL was demonstrated.


The results showed that gene–gene interactions are important for RPL susceptibility. Additionally, analysis of the genotype combinations of several allelic variants provides more information on RPL risk than analysis of independent polymorphic markers.


Recurrent miscarriage Single-nucleotide polymorphism Gene–gene interactions Endothelial dysfunction 


Funding information

The work received financial support from the Russian Foundation for Basic Research (grant no. 18-44-700007).

Compliance with ethical standards

This study was approved by the Research Ethics Committee of the Institute for Medical Genetics of Tomsk city. Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have no competing interests.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Research Institute of Medical Genetics, Tomsk National Research Medical CenterRussian Academy of SciencesTomskRussia
  2. 2.Siberian State Medical UniversityTomskRussia

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