Abstract
Background
Preeclampsia is a pregnancy-related condition that causes high blood pressure and proteinuria after 20 weeks of pregnancy. It is linked to increased maternal mortality, organ malfunction, and foetal development limitation. In this view, there is a need critical to identify biomarkers for the early detection of preeclampsia. The objective of this study is to discover critical genes and explore medications for preeclampsia treatment that may influence these genes.
Methods
Four datasets, including GSE10588, GSE25906, GSE48424 and GSE60438 were retrieved from the Gene Expression Omnibus database. The GSE10588, GSE25906, and GSE48424 datasets were then removed the batch effect using the “sva” R package and merged into a complete dataset. The differentially expressed genes (DEGs) were identified using the “limma” R package. The potential small-molecule agents for the treatment of PE was further screened using the Connective Map (CMAP) drug database based on the DEGs. Further, Weight gene Co-expression network (WGNCA) analysis was performed to identified gene module associated with preeclampsia, hub genes were then identified using the logistic regression analysis. Finally, the immune cell infiltration level of genes was evaluated through the single sample gene set enrichment analysis (ssGSEA).
Results
A total of 681 DEGs (376 down-regulated and 305 up-regulated genes) were identified between normal and preeclampsia samples. Then, Dexamethasone, Prednisone, Rimexolone, Piretanide, Trazodone, Buflomedil, Scoulerin, Irinotecan, and Camptothecin drugs were screened based on these DEGs through the CMAP database. Two modules including yellow and brown modules were the most associated with disease through the WGCNA analysis. KEGG analysis revealed that the chemokine signaling pathway, Th1 and Th2 cell differentiation, B cell receptor signalling pathway and oxytocin signalling pathway were significantly enriched in these modules. Moreover, two key genes, PLEK and LEP were evaluated using the univariate and multivariate logistic regression analysis from the hub modules. These two genes were further validated in the external validation cohort GSE60438 and qRT-PCR experiment. Finally, we evaluated the relationship between immune cell and two genes.
Conclusion
In conclusion, the present study investigated key genes associated with PE pathogenesis that may contribute to identifying potential biomarkers, therapeutic agents and develo** personalized treatment for PE.
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Introduction
Preeclampsia (PE) is a pregnancy disorder that causes high blood pressure and proteinuria [1] after 20 weeks of pregnancy [2].It affects 3%-10% of all pregnancies [3,4,5], and is associated with substantial maternal morbidity, mortality, organ dysfunction, iatrogenic premature delivery [6], and foetal development restriction [7]. Preeclampsia affects the brain development and function of the offspring, increasing the risk of intellectual disability [8], epilepsy [9], autism [10], and schizophrenia [11, 12]. Women with a history of PE are more likely to develop cardiovascular disease or hypertension,5 resulting in financial and psychological consequences on the family and society. There is no obvious therapeutic intervention for PE today; the only effective treatment is pregnancy, which might result in low birth weight and long-term detrimental health implications for infants [13, 14]. Early assessment of PE risk is critical for high-risk pregnant women because it allows for the implementation of preventive strategies to lower the incidence of PE and improve maternal and infant outcomes.
However, the etiology and pathogenesis of PE are yet unknown. Several hypotheses such as maternal-foetal (paternal) immune maladjustment [15] and inflammatory cytokine disorders [16], all suggest that PE is associated with a number of risk factors, including obesity, hypertension, diabetes, oxidative stress, foetal rejection, genetic polymorphism inheritance [17], and trophoblast insufficiency [18, 19]. The main causes are identified as immunological intolerance [20, 21] and angiogenesis imbalance, and numerous research has demonstrated the immune mechanism of PE development. The latter causes PE by generating an imbalance in immune tolerance at the mother-infant interaction [22, 23]. The pathophysiological basis of PE is shallow placental implantation. The mutual adaptation of villous trophoblast cells and the mother's immune system is required for effective placental development. The poor placental formation will result in acute-like graft rejection disease under the influence of specific immunological factors generating immune intolerance in the mother and child.
Immune system modifications have been widely recognized as the key determinants of PE [24], which is a systemic inflammatory response resulting in an imbalance between placental substances and the corresponding adaptation of the mother[25, 26]. Shah et al. [27] in their study compared the expression of CD66B, nuclear factor NF-κB, and cyclooxygenase-2 (COX-2) in the subcutaneous fat of women with PE (n = 7), normal pregnant women (n = 6), and normal non-pregnant women (n = 5). The percentages of CD66B, NF-κB, and COX-2 in PE patients were significantly higher than in normal non-pregnant or normal pregnant patients. Moreover, Xu et al. [52]. Leptin injection raised ICAM-1 and Eseltin circulation concentrations, resulting in hypertension and proteinuria in pregnant rats [53]. Our findings show that the expression level of this gene was higher in the placenta of the PE group than in the control group, which is consistent with earlier findings. PLEK, another hub gene, was found to be significantly expressed in the merged dataset. Its expression was higher in normal tissues than in PE tissues, although it was not significantly higher in the external validation set. Pleckstrin (PLEK), which is found on human chromosome 2, is a protein kinase C target [54] that is involved in signal transduction and hematopoietic cell differentiation [55]. PLEK play an important role in immune and inflammatory responses [56, 57]. Studies have been shown that PLEK is significantly over-expressed in periodontitis, cardiovascular disease, rheumatoid arthritis, and ulcerative colitis [58], and thought to be a crucial mediator in the secretion and activation pathways of pro-inflammatory cytokines TNF-α and IL-1β [59, 60]. While studies have suggested that LILRA2, EVI2A, and PLEK play a role in recurrent miscarriage [61], the underlying mechanism in placental function and regulation has yet to be fully investigated. This is the first study to examine PLEK expression in PE. An examination of its mechanisms would necessitate additional research.
PE is a complex systemic condition, and it has been shown that the immune system plays a significant role in its development [62]. As a result, we evaluated the landscape of 29 immune cell infiltration levels in PE and control samples. The results indicated that the infiltration level of neutrophils, T helper cells, Th2 cells, TIL, and Treg cells were significantly differed between PE and normal tissues. Immune cell infiltration is a new bioinformatics technique that has been used to investigate the diagnosis and prognosis of kidney cancer [63], malignant glioma [64], breast cancer [65], oral squamous cell carcinoma [66], ulcerative colitis[67], osteosarcoma [68], and variety of other diseases. Nonetheless, it has received little attention in the field of PE. The complicated connection between the maternal immune system and its semi-allogeneic foetus is critical in normal pregnancy. Moreover, establishing and maintaining the maternal and foetal immune balance is a prerequisite for normal pregnancy [69]. Abnormal maternal immunological and inflammatory responses to foetal antigens result in increased release of various toxic cytokines, which causes trophoblast cell invasion, vascular remodelling, and placental implantation disorders. Changes in the innate immune system primarily regulate this inflammatory response, with the adaptive immune system possibly playing a supporting role [70].
T cells are thought to be the most important cells in regulating immunological homeostasis [71, 72]. T lymphocytes account for 1%-3% of decidual immune cells [73]. In a normal pregnancy, the mother exhibits Th2 cell-type immunological tolerance, preventing embryo rejection [74]. However, in PE patients, the Th1/Th2 ratio increases. As a result, the Th1/Th2 balance changes towards Th1 [75]. Aside from the Th1/Th2 imbalance that contributes to the onset and progression of the disease, there is also an imbalance of Th17/ regulatory T cells. This imbalance, which was exacerbated by the Th17 immune bias, also contributed to the development of PE. Th17/ Treg cells are balanced at the maternal-foetal interface during normal pregnancy to preserve maternal immunological tolerance and inhibit the inflammatory response [76]. In our study, we identified most of T cells showed a significant difference between normal and PE samples, reveled that the T cells play an important role in PE.
Conclusion
PLEK and LEP were identified as two genes implicated in the development and progression of PE in this investigation. Although more in vivo and in vitro validations are needed, our findings help to understand the pathological process of PE and may serve as a theoretical foundation for future research. The functional annotation and pathway enrichment analysis results show that the immunological mechanism is important in the etiology of PE. Also, because of the maternal and infant complications of PE, it is critical to uncover the aetiology and molecular mechanism, develop molecular biomarkers and investigate effective drugs for the early detection, prevention, and personalized treatment of PE.
Limitations
This study not only points out several benefits of bioinformatics analysis but also highlights some limitations. The dependability of the original microarray dataset is critical to the validity of our conclusions, although the results are constrained due to the small sample size. Similarly, validation results are limited. Second, despite the identification of two hub genes as prospective biomarkers for PE immunoty**, no in vivo and in vitro studies have been conducted. More research on the functions and regulatory mechanisms of key genes in PE is still needed. As a result, this will be the focus of future efforts.
Availability of data and materials
The datasets that support the findings of this study are openly available in the Gene Expression Omnibus (GEO) database under accession ID GSE10588, GSE25906, GSE48424 and GSE60438, [http://www.ncbi.nlm.nih.gov/geo/].
Abbreviations
- PE:
-
Preeclampsia
- GEO:
-
Gene Expression Omnibus
- DEGs:
-
Differentially expressed genes
- WGCNA:
-
Weighted gene co-expression network analysis
- PPI:
-
Protein–protein interaction network
- CMAP:
-
Connectivity map
- TOM:
-
Topological overlap matrix
- GS:
-
Gene significance
- MEs:
-
Module eigengenes
- MM:
-
Module membership
- GO:
-
Gene ontology
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
- ssGSEA:
-
Single-sample Gene Set Enrichment Analysis
- MOA:
-
Mechanism of actions
- ROC:
-
Receiver operating characteristic
- AUC:
-
Area under the curve
- CCR:
-
Chemokine receptor
- TIL:
-
Tumor infiltrating lymphocyte
- MCC:
-
Maximal clique centrality
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The researchers thank the obstetrics and gynaecology department, surgery department, and laboratory department of Qilu Hospital and The First Affiliated Hospital of USTC for their support during the data collection process.
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YP wrote the proposal, participated in data collection, analyzed the data, and drafted the paper. NG,HH and AW approved the proposal with some revisions, participated in data analysis, and revised subsequent drafts of the paper. YM designed the entire study, provided administrative, technical, and material support, and gave a critical review of the intellectual content of the article. All authors read and approved the final manuscript.
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Peng, Y., Hong, H., Gao, N. et al. Bioinformatics methods in biomarkers of preeclampsia and associated potential drug applications. BMC Genomics 23, 711 (2022). https://doi.org/10.1186/s12864-022-08937-3
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DOI: https://doi.org/10.1186/s12864-022-08937-3