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Network-Based Analysis Reveals Novel Biomarkers in Peripheral Blood of Patients With Preeclampsia

ABSTRACT: WGCNA is a potent systems biology approach that explains the connection of gene expression based on a microarray database, which facilitates the discovery of disease therapy targets or potential biomarkers. Preeclampsia is a kind of pregnancy-induced hypertension caused by complex factors. The disease’s pathophysiology, however, remains unknown. The focus of this research is to utilize WGCNA to identify susceptible modules and genes in the peripheral blood of preeclampsia patients. Obtain the whole gene expression data of GSE48424 preeclampsia patients and normal pregnant women from NCBI’s GEO database. WGCNA is used to construct a gene co-expression network by calculating correlation coefficients between modules and phenotypic traits, screening important modules, and filtering central genes. To identify hub genes, we performed functional enrichment analysis, pathway analysis, and protein-protein interaction (PPI) network construction on key genes in critical modules. Then, the genetic data file GSE149437 and clinical peripheral blood samples were used as a validation cohort to determine the diagnostic value of these key genes. Nine gene co-expression modules were constructed through WGCNA analysis. Among them, the blue module is significantly related to preeclampsia and is related to its clinical severity. Thirty genes have been discovered by using the intersection of the genes in the blue module and the DEGs genes as the hub genes. It was found that HDC, MS4A2, and SLC18A2 scored higher in the PPI network and were identified as hub genes. These three genes were also differentially expressed in peripheral blood validation samples. Based on the above three genes, we established the prediction model of peripheral blood markers of preeclampsia and drew the nomogram and calibration curve. The ROC curves were used in the training cohort GSE48424 and the validation cohort GSE149437 to verify the predictive value of the above model. Finally, it was confirmed in the collected clinical peripheral blood samples that MS4A2 was differentially expressed in the peripheral blood of early-onset and late-onset preeclampsia, which is of great significance. This study provides a new biomarker and prediction model for preeclampsia.

SUBMITTER: Lin J

PROVIDER: S-EPMC9243560 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPreeclampsia (PE), one of hypertension-related disorders of pregnancy, is a common cause of maternal death worldwide. This study aimed to identify a circRNA-miRNA-mRNA-associated ceRNA network and related pathways in PE.Material and methodsWe downloaded 3 microarray datasets from the Gene Expression Omnibus database, obtained 163 differentially expressed circRNAs (dif-circRNAs) (61 upregulated and 102 downregulated), 39 differentially expressed microRNAs (dif-miRNAs) (22 upregulated and 17 downregulated), and 271 differentially expressed mRNAs (dif-mRNAs) (168 upregulated and 103 downregulated) from placenta tissues of PE. Functional enrichment analysis and protein-protein interaction (PPI) network with module analysis of dif-mRNAs were performed. The regulatory relationship between dif-miRNAs and dif-mRNAs/circRNAs was predicted via related databases. A circRNA-miRNA-mRNA regulatory network was constructed.ResultsA total of 53 pairs were obtained, including 13 circRNAs (10 upregulated and 3 downregulated), 9 miRNAs (3 upregulated and 6 downregulated) and 31 mRNAs (22 upregulated and 9 downregulated). GNB5 and IL2RB were obtained. KEGG enrichment analysis showed that both of them were closely related with the PI3K-Akt signalling pathway. Therefore, ceRNAs might affect the PI3K-Akt signalling pathway via the upregulation of GNB5 by binding to miR-1248 in PE. Meanwhile, hsa_circ_0052661 might upregulate IL2RB by binding miR-4303 to play a role in PE in the same way.ConclusionGNB5 and IL2RB might be key genes involved in the PI3K-Akt signalling pathway in PE, and hsa_circ_0087208, hsa_circ_0035443, hsa_circ_0067557 and hsa_circ_0052661 might regulate these key genes in PE by binding miR-1248 or miR-4303.Key messagesThere is still a lack of predictive and diagnostic factors for preeclampsia, which is a common cause of maternal death worldwide.This study identified a novel circRNA-associated ceRNA network and related pathways in preeclampsia.GNB5 and IL2RB might be key genes in their related circRNA-associated ceRNA network, and probably take an important role in preeclampsia via PI3K-Akt signalling pathway, which made them to be potential markers of preeclampsia.

Project description:Background: Preeclampsia (PE) is a placental disease characterized by hypertension and proteinuria in pregnant women, which is associated with a high maternal and infantile morbidity. However, circulating biomarkers able to predict the prognosis of PE are lacking. Methods: Thirty-eight women were included in the study. They consisted of 19 patients with PE (13 with severe PE and 6 women with non-severe PE) and 19 gestational age-matched normal pregnancy controls. We measured coagulation pathway, endothelial responses and microparticle release and circulating gene expression in PE patient groups and normotensive controls. Results: The measurement of markers associated with coagulation pathway, endothelial activation and circulating microparticles enabled to discriminate PE from normal pregnancy but were not sufficient to distinguish severe from non-severe PE. PE patients also exhibited a specific transcriptional program distinct from that of control women and subtle differences were observed between severe and non-severe PE. Functional annotation of the up-modulated signature in PE highlighted two main functions related to ribosome and complement. Importantly, we found that 8 genes were specifically up-modulated in severe preeclampsia. Among these genes, the expression of VSIG4 was significantly increased in patients with severe preeclampsia in comparison with controls and patients with non-severe preeclampsia. Conclusion: Using transcriptional signatures of blood samples, we identified the gene encoding the estrogen receptor as a potential diagnostic marker of severe preeclampsia. In addition, the determination of this gene may improve the prognostic assessment of severe preeclampsia. Thirty-eight women were included in the study: 19 patients with PE, including 6 women with non-severe PE and 13 with severe PE, and 19 women with normal pregnancy (NP) selected according to age, weight, smoking status, race, gestational age at the inclusion, and blood pH (Table 1 of manuscript). Women with NP had no history of medical illness or medication, and received routing prenatal care. The diagnostic of PE was based on a blood pressure of M-bM-^IM-% 140/90 mmHg taken twice, uricemia above normal laboratory range (120-420 M-BM-5mol/L), and proteinuria higher than 300 mg in a 24 hour-collection, occurring after 20 gestational weeks in previously normotensive women (Table 2). The criteria used to define severe PE included one of the following conditions: a blood pressure higher than 160/110 mmHg, a proteinuria higher than 1500 mg/24h), a multisystem disorder, maternal cerebral symptoms (seizures, stroke) or intrauterine growth restriction below the 3M-BM-0 percentile. Women with multiple gestations, fetal congenital malformations/chromosomal abnormalities, recent infection, antiphospholipid antibodies, trauma, drug or alcohol abuse during pregnancy, preexisting hypertension, thrombophilia with PE history, or women receiving anticoagulant or antiaggregation therapy were excluded from the study. Two microarrays (one non-severe PE and one normal) were discarded from the analysis for technical reasons. Thus, only 36 microarrays are included here.

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Network-Based Analysis Reveals Novel Biomarkers in Peripheral Blood of Patients With Preeclampsia

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