Differential placental gene expression in preeclampsia (original) (raw)
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Differential Placental Gene Expression in Severe Preeclampsia
Placenta, 2009
We investigated the global placental gene expression profile in severe preeclampsia. Twenty-one women were randomly selected from 50 participants with uncomplicated pregnancies to match 21 patients with severe preeclampsia. A 30 K Human Genome Survey Microarray v.2.0 (Applied Biosystems) was used to evaluate the gene expression profile. After RNA isolation, five preeclamptic placentas were excluded due to poor RNA quality. The series composed of 37 hybridizations in a one-channel detection system of chemiluminescence emitted by the microarrays. An empirical Bayes analysis was applied to find differentially expressed genes. In preeclamptic placentas 213 genes were significantly (fold-change ! 2 and p 0.01) up-regulated and 82 were down-regulated, compared with normal placentas. Leptin (40 fold), laeverin (10 fold), different isoforms of b-hCG (3-6 fold), endoglin (4 fold), FLT1 (3 fold) and FLT4 (2 fold) were up-regulated. PDGFD was down-regulated (2 fold). Several differentially expressed genes were associated with Alzheimer disease, angiogenesis, Notch-, TGFb-and VEGF-signalling pathways. Sixteen genes best discriminated preeclamptic from normal placentas. Comparison between early-(<34 weeks) and late-onset preeclampsia showed 168 differentially expressed genes with oxidative stress, inflammation, and endothelin signalling pathways mainly involved in early-onset disease. Validation of the microarray results was performed by RT-PCR, quantitative urine hCG measurement and placental histopathologic examination. In summary, placental gene expression is altered in preeclampsia and we provide a comprehensive list of the differentially expressed genes. Placental gene expression is different between early-and late-onset preeclampsia, suggesting differences in pathophysiology.
Creation of gene expression database on preeclampsia-affected human placenta
2017
Publication of gene expression raw data in public repositories made it possible to reuse these data for cross-experiment integrative analysis and make new insights into biological phenomena. However, data uploaded by independent contributors are not standardized, sometimes incomplete and need preprocessing before any further analysis. Hence, the aim of this study was to create a specialized database of gene expression profiles, particularly in preeclampsia-affected human placenta as a cause of high rate of morbidity and mortality all over the world with unknown etiology and pathogenesis. Methods. All experiment and sample metadata were automatically extracted from ArrayExpress database via Bioservices. NCBI database was used to supplement the missing data along with the corresponding scientific articles and authors personal data. The experimental sample attributes were standardized according to MeSH term dictionary and Experimental Factor Ontology. Results. A database of more than 1000 samples of normal and preeclampsia-affected human placenta was created and supplied with metadata containing information on biological specimen, diagnosis, gestational age, mode of delivery and other sample characteristics. Conclusion. The samples in our newly created database now contain metadata for them to be comparable. The biological samples may be arranged in different case-control groups of larger size than in individual datasets for statistically significant analysis.
Placenta, 2009
Background: Preeclampsia is a pregnancy-specific disorder that remains a leading cause of maternal, fetal and neonatal morbidity and mortality, and is associated with risk for future cardiovascular disease. There are no reliable predictors, specific preventative measures or treatments other than delivery. A widely held view is that the antecedents of preeclampsia lie with impaired placentation in early pregnancy. Accordingly, we hypothesized dysregulation of global gene expression in first trimester placentas of women who later manifested preeclampsia.
Hypertension, 2016
Preeclampsia (PE) is a complex, hypertensive disorder of pregnancy, demonstrating considerable variability in maternal symptoms and fetal outcomes. Unfortunately, prior research has not accounted for this variability, resulting in a lack of robust biomarkers and effective treatments for PE. Here, we created a large (N=330) clinically relevant human placental microarray data set, consisting of 7 previously published studies and 157 highly annotated new samples from a single BioBank. Applying unsupervised clustering to this combined data set identified 3 clinically significant probable etiologies of PE: "maternal", with healthy placentas and term deliveries; "canonical", exhibiting expected clinical, ontological, and histopathologic features of PE; and "immunologic" with severe fetal growth restriction and evidence of maternal antifetal rejection. Moreover, these groups could be distinguished using a small quantitative polymerase chain reaction panel and ...
Scientific reports, 2015
One in five pregnant women suffer from gestational complications, prevalently driven by placental malfunction. Using RNASeq, we analyzed differential placental gene expression in cases of normal gestation, late-onset preeclampsia (LO-PE), gestational diabetes (GD) and pregnancies ending with the birth of small-for-gestational-age (SGA) or large-for-gestational-age (LGA) newborns (n = 8/group). In all groups, the highest expression was detected for small noncoding RNAs and genes specifically implicated in placental function and hormonal regulation. The transcriptome of LO-PE placentas was clearly distinct, showing statistically significant (after FDR) expressional disturbances for hundreds of genes. Taqman RT-qPCR validation of 45 genes in an extended sample (n = 24/group) provided concordant results. A limited number of transcription factors including LRF, SP1 and AP2 were identified as possible drivers of these changes. Notable differences were detected in differential expression s...
Gene expression profiling of pre-eclamptic placentae by RNA sequencing
Scientific Reports, 2015
Pre-eclampsia is a common and complex pregnancy disorder that often involves impaired placental development. In order to identify altered gene expression in pre-eclamptic placenta, we sequenced placental transcriptomes of nine pre-eclamptic and nine healthy pregnant women in pools of three. The differential gene expression was tested both by including all the pools in the analysis and by excluding some of the pools based on phenotypic characteristics. From these analyses, we identified altogether 53 differently expressed genes, a subset of which was validated by qPCR in 20 cases and 19 controls. Furthermore, we conducted pathway and functional analyses which revealed disturbed vascular function and immunological balance in pre-eclamptic placenta. Some of the genes identified in our study have been reported by numerous microarray studies (BHLHE40, FSTL3, HK2, HTRA4, LEP, PVRL4, SASH1, SIGLEC6), but many have been implicated in only few studies or have not previously been linked to pr...
Bjog-an International Journal of Obstetrics and Gynaecology, 2010
Please cite this paper as: Sekizawa A, Purwosunu Y, Farina A, Shimizu H, Nakamura M, Wibowo N, Rizzo N, Okai T. Prediction of pre-eclampsia by an analysis of placenta-derived cellular mRNA in the blood of pregnant women at 15–20 weeks of gestation. BJOG 2010;117:557–564.Objective A panel of cellular mRNA markers was used to predict the occurrence of pre-eclampsia in pregnant women at 15–20 weeks of gestation.Design Prospective cohort study.Setting The Department of Obstetrics and Gynaecology, University of Indonesia, Cipto Mangunkusumo National Hospital, Indonesia.Sample Peripheral blood samples from asymptomatic pregnant women.Methods Among 660 women, 62 developed pre-eclampsia at later gestation (pre-eclampsia group) and each case was matched with five controls. Therefore, the RNA expression levels in the cellular component of maternal blood in 62 women with pre-eclampsia were compared with those in 310 controls.Main outcome measures The cellular RNA expression levels of genes related to angiogenesis and oxidative stress were compared between pre-eclampsia and control groups. A receiver operating characteristic (ROC) curve was used to analyse the sensitivity of each available marker. A logistic regression analysis was performed to calculate the odds for each woman to be classified as a case.Results The univariate ROC analysis identified soluble vascular endothelial growth factor receptor-1 (Flt-1) and endoglin (ENG) as the markers with the highest sensitivity. The best multivariate model was obtained by combining Flt-1, ENG, placental growth factor (PlGF) and parity. The relative ROC curve yielded a sensitivity of 66% at a 10% 1 − specificity rate with an area under the curve of 0.884 (P < 0.001).Conclusion A panel of cellular mRNA markers in maternal blood can predict the development of pre-eclampsia long before clinical onset.
Differentially Expressed Genes in the Pre-Eclamptic Placenta: A Systematic Review and Meta-Analysis
PLoS ONE, 2013
Objective: To systematically review the literature on human gene expression data of placental tissue in pre-eclampsia and to characterize a meta-signature of differentially expressed genes in order to identify novel putative diagnostic markers. Data Sources: Medline through 11 February 2011 using MeSH terms and keywords related to placenta, gene expression and gene expression arrays; GEO database using the term ''placent*''; and reference lists of eligible primary studies, without constraints. Methods: From 1068 studies retrieved from the search, we included original publications that had performed gene expression array analyses of placental tissue in the third trimester and that reported on differentially expressed genes in preeclampsia versus normotensive controls. Two reviewers independently identified eligible studies, extracted descriptive and gene expression data and assessed study quality. Using a vote-counting method based on a comparative meta-profiling algorithm, we determined a meta-signature that characterizes the significant intersection of differentially expressed genes from the collection of independent gene signatures. Results: We identified 33 eligible gene expression array studies of placental tissue in the 3 rd trimester comprising 30 datasets on mRNA expression and 4 datasets on microRNA expression. The pre-eclamptic placental meta-signature consisted of 40 annotated gene transcripts and 17 microRNAs. At least half of the mRNA transcripts encode a protein that is secreted from the cell and could potentially serve as a biomarker. Conclusions: In addition to well-known and validated genes, we identified 14 transcripts not reported previously in relation to pre-eclampsia of which the majority is also expressed in the 1 st trimester placenta, and three encode a secreted protein.
Preeclampsia leads to dysregulation of various signaling pathways in placenta
Journal of Hypertension, 2011
Objectives To compare gene expression profiles of placentas from preeclamptic and normal pregnancies. Study design We performed microarray experiments to analyze genome-wide expression profiling for 10 placentas from pregnant women with preeclampsia and 10 placentas from women who experienced noncomplicated pregnancies (CON), and to identify dysregulated signaling pathways as well as genes in preeclampsia. RT-PCR, realtime RT-PCR and/or immunofluorescence analyses were performed to validate the data obtained from microarray experiments. Results Unsupervised hierarchical clustering showed heterogeneity of preeclampsia at the molecular levels, whereas expression profiles of preeclampsia are distinctly different from those of CON. A list of genes which are differentially expressed between preeclampsia and CON included well known preeclampsia markers, such as Flt-1, leptin, HTRA1 and SIGLEC6. Gene Set Enrichment Analysis, a pathway-oriented analysis method for expression profiles, provided evidence that a number of biological activities including pathways that regulate actin cytoskeleton, TGFb signaling, oxidative phosphorylation, and proteasome activity were aberrantly either up-regulated or downregulated in preeclampsia. RT-PCR and real-time-RT-PCR for genes contributing these biological pathways (gene sets) enriched in either CON or preeclampsia reinforced that these biological processes were systemically dysregulated in preeclampsia. Conclusions Genome-wide expression profiles of preeclampsia showed heterogeneous characteristics of preeclampsia at the molecular levels. Dysregulation of genes and biological pathways could contribute to abnormal behavior of preeclmapsia. Our results will help further understand underlying mechanisms by which preeclampsia affects placental physiology. J Hypertens
Analysis of the Placental Tissue Transcriptome of Normal and Preeclampsia Complicated Pregnancies
Acta Naturae, 2014
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 ex...