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Objective. To study the molecular mechanisms responsible for the development of diseases grouped within the great obstetrical syndromes (GOS) at the level of the transcriptome of human maternal placenta.Material and Methods. We gathered the results of genome-wide transcriptome studies of the human placental tissue using Gene Expression Omnibus (GEO) data repository for the following phenotypes: physiological pregnancy, preeclampsia (PE), premature birth, and intrauterine growth restriction (IUGR). Eleven data sets were selected and supplemented with our experimental data; a total of 481 samples of human placental tissue were included in the integrative analysis. Bioinformatic data processing and statistical analyses were performed in the R v3.6.1 software environment using the Bioconductor packages. The pooled dataset was used to search for common molecular targets for GOS via weighted gene co-expression network analysis (WGCNA). The functional annotation of genes and the resulting clusters was carried out with the DAVID database; protein-protein interaction network was built using the STRING software; and the hub genes for the network were identified using the MCC analysis with plugin cytoHubba in Cytoscape software 3.7.2.Results. We obtained a table of expression levels for 15,167 genes in 246 samples. Hierarchical clustering of this network allowed to find 55 modules of co-expressed genes in the group with PE, 109 modules in the group with PB, 75 modules in patients with IUGR, and 56 modules in the control group. The preservation analysis of co-expressed modules for the studied phenotypes suggested the presence of a common cluster comprising eight genes specific only for patients with PE and IUGR, as well as the module of 23 co-expressed genes typical only for patients with PB and IUGR. Protein-protein interaction network was built for these gene sets, and the SOD1, TXNRD1, and UBB genes were the central nodes in the network. Based on network topology evaluation with cytoHubba, six hub genes (rank ˂ 5) were identified as follows: SOD1, TKT, TXNRD1, GCLM, GOT1, and ACO1.Conclusion. The obtained results allowed to identify promising genetic markers for preeclampsia, intrauterine growth restriction, and miscarriage. Moreover, the study also made it possible to identify the most important overlapping molecular mechanisms of these diseases occurring in the placental tissue.

We describe the role of genomic and postgenomic technologies in the study of the preeclampsia genetic architecture in this review. Preeclampsia is a severe hypertensive disease of pregnancy that causes a significant level of maternal and perinatal morbidity and mortality. We emphasize the importance of integrative analysis of genomic, methylomic, transcriptomic, and proteomic data for characterizing the molecular mechanisms of preeclampsia, identifying new candidate genes and molecules for targeted therapy of this gestational complication.

The advent of high-throughput sequencing technologies has expanded our understanding of the biological significance of non-coding regions of the genome. In recent years, more and more studies have been devoted to studying the role of noncoding RNAs in the development of diseases, as well as their participation in various cellular processes. Until now, all transcriptome studies of native placental tissue with the description of the noncoding RNA region were carried out without isolating individual cell populations. This approach, due to the high cellular heterogeneity of the placental tissue, significantly complicates the ability to determine the molecular-biological functions of individual cells and their role in the molecular pathogenesis of reproductive disorders. In this work, we propose a technique for obtaining total RNA from single decidual cells of frozen placental tissue obtained by laser-capture microdissection technology for transcriptome sequencing, including a cluster of noncoding RNAs. This technique can be successfully used to study the full-genome expression profile of other placental cell populations. The high accuracy of results on the transcriptome profiling of decidual cells obtained using the developed technique was additionally confirmed by an integrative analysis with the results of a 10x Genomics experiment.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Regulatory single nucleotide polymorphisms (rSNPs) are the least-studied group of SNP; however, they play an essential role in the development of human pathology by altering the level of candidate genes expression. In this work, we analyzed 29 rSNPs in 17 new candidate genes associated with preeclampsia (PE) according to the analysis of the transcriptome in placental tissue. Three ethnic groups have been studied (Yakut, Russian, and Buryat). We have detected significant associations of PE with eight rSNPs in six differentially expressed genes, i.e., rs10423795 in the LHB gene; rs3771787 in the HK2 gene; rs72959687 in the INHA gene; rs12678229, rs2227262, and rs3802252 in the NDRG1 gene; rs34845949 in the SASH1 gene; and rs66707428 in the PPP1R12C gene. We used a new approach to detecting genetic markers of multifactorial diseases in the case of PE based on a combination of genomic, transcriptomic, and bioinformatic approaches. This approach proved its efficiency and may be applied to detecting new potential genetic markers in genes involved in disease pathogenesis, which reduces missing heritability in multifactorial diseases.

Analysis of the genome-specific linkage disequilibrium patterns in certain populations is a highly promising approach to the identification of functional variants that underlie susceptibility to complex diseases. In the present study, the linkage disequilibrium patterns of the methylenetetrahydrofolate reductase gene (MTHFR) were examined in a group of patients with coronary atherosclerosis (coronary artery disease, CAD) and in a control sample from the Russian population. It was demonstrated that in the samples from one population, which were differentiated by the presence or absence of CAD, the MTHFR linkage disequilibrium patterns had similar features. Association of the MTHFR rs7533315 and rs2066462 polymorphisms with CAD was demonstrated. In addition, the evolution of the haplotypes and their role in the formation of CAD in the Russian population was reconstructed. The data on the association between genetic variability in the MTHFR locus and pathogenetically important indices of lipid metabolism were obtained. The high informativeness of the haplotype approach in case-control tests for associations with CAD was demonstrated.

Analysis of pregnancy course, labor and early neonatal period at 294 women and their new-born children has been made for the estimation of the efficacy of different antibacterial therapy variants of urogenital clamidiosis during the second half of pregnancy period. The danger of abortion and chronic intrauterine fetal hypoxia are most often gestational process complications revealed against chronic urogenital clamidiosis. The use of sumamed is course dose of 3 g is an optimum pharmacotherapeutic regimen during the second half of pregnancy period.

It is proved that intrauterine infections influence negatively on the period of pregnancy, the condition of fetus and newborn on the example of isolated, chlamydeous and chlamydeous-virus infections. The schemes of treatment of pregnant women in these groups are determined. It is revealed that the percentage of the possibility and the degree of heaviness of intrauterine infection is lowing if the newborn were born by women who got the treatment in the period of pregnancy.

Preeclampsia is one of the most severe gestational complications which is one of the leading causes of maternal and perinatal morbidity and mortality. A growth in the incidence of severe and combined forms of the pathology has been observed in recent years. According to modern concepts, inadequate cytotrophoblast invasion into the spiral arteries of the uterus and development of the ischemia-reperfusion syndrome in the placental tissue play the leading role in the development of preeclampsia, which is characterized by multipleorgan failure. In this regard, our work was aimed at studying the patterns of placental tissue transcriptome that are specific to females with PE and with physiological pregnancy, as well as identifying the potential promising biomarkers and molecular mechanisms of this pathology. We have identified 63 genes whose expression proved to differ significantly in the placental tissue of females with PE and with physiological pregnancy. A cluster of differentially expressed genes (DEG) whose expression level is increased in patients with preeclampsia includes not only the known candidate genes that have been identified in many other genome-wide studies (e.g., LEP, BHLHB2, SIGLEC6, RDH13, BCL6), but also new genes (ANKRD37, SYDE1, CYBA, ITGB2, etc.), which can be considered as new biological markers of preeclampsia and are of further interest. The results of a functional annotation of DEG show that the development of preeclampsia may be related to a stress response, immune processes, the regulation of cell-cell interactions, intracellular signaling cascades, etc. In addition, the features of the differential gene expression depending on preeclampsia severity were revealed. We have found evidence of the important role of the molecular mechanisms responsible for the failure of immunological tolerance and initiation of the pro-inflammatory cascade in the development of severe preeclampsia. The results obtained elaborate the concept of the pathophysiology of preeclampsia and contain the information necessary to work out measures for targeted therapy of this disease.

Analysis of the genome-specific linkage disequilibrium patterns in certain populations is a highly promising approach to the identification of functional variants that underlie susceptibility to complex diseases. In the present study, the linkage disequilibrium patterns of the methylenetetrahydrofolate reductase gene (MTHFR) were examined in a group of patients with coronary atherosclerosis (coronary artery disease, CAD) and in a control sample from the Russian population. It was demonstrated that in the samples from one population, which were differentiated by the presence or absence of CAD, the MTHFR linkage disequilibrium patterns had similar features. Association of the MTHFR rs7533315 and rs2066462 polymorphisms with CAD was demonstrated. In addition, the evolution of the haplotypes and their role in the formation of CAD in the Russian population was reconstructed. The data on the association between genetic variability in the MTHFR locus and pathogenetically important indices of lipid metabolism were obtained. The high informativeness of the haplotype approach in case-control tests for associations with CAD was demonstrated.