Reliable pre-eclampsia pathways based on multiple independent microarray data sets

Abstract

Pre-eclampsia is a multifactorial disorder characterized by heterogeneous clinical manifestations. Gene expression profiling of preeclamptic placenta have provided different and even opposite results, partly due to data compromised by various experimental artefacts. Here we aimed to identify reliable pre-eclampsia-specific pathways using multiple independent microarray data sets. Gene expression data of control and preeclamptic placentas were obtained from Gene Expression Omnibus. Single-sample gene-set enrichment analysis was performed to generate gene-set activation scores of 9707 pathways obtained from the Molecular Signatures Database. Candidate pathways were identified by t-test-based screening using data sets, GSE10588, GSE14722 and GSE25906. Additionally, recursive feature elimination was applied to arrive at a further reduced set of pathways. To assess the validity of the pre-eclampsia pathways, a statistically-validated protocol was executed using five data sets including two independent other validation data sets, GSE30186, GSE44711. Quantitative real-time PCR was performed for genes in a panel of potential pre-eclampsia pathways using placentas of 20 women with normal or severe preeclamptic singleton pregnancies (n = 10, respectively). A panel of ten pathways were found to discriminate women with pre-eclampsia from controls with high accuracy. Among these were pathways not previously associated with pre-eclampsia, such as the GABA receptor pathway, as well as pathways that have already been linked to pre-eclampsia, such as the glutathione and CDKN1C pathways. mRNA expression of GABRA3 (GABA receptor pathway), GCLC and GCLM (glutathione metabolic pathway), and CDKN1C was significantly reduced in the preeclamptic placentas. In conclusion, ten accurate and reliable pre-eclampsia pathways were identified based on multiple independent microarray data sets. A pathway-based classification may be a worthwhile approach to elucidate the pathogenesis of pre-eclampsia.

IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer

“…A publicly accessible microarray data set of IFN-treated cells (GEO accession GSE3920) was downloaded ( Indraccolo et al , 2007 ). Single sample gene set enrichment analysis (ssGSEA) ( Barbie et al , 2009 ) for ‘IFN- γ signature' in GSE3920 and KOV-75 was performed using R, as reported previously ( Kawasaki et al , 2014 ). Briefly, R code for ssGSEA was downloaded from Genepattern ( http://www.broadinstitute.org/cancer/software/genepattern/ ), and gmt file for IFN- γ signature gene symbols and gct file for KOV75 were used as input files and ‘ssGSEA-Projection.Library.R' and ‘common R' were calculated using R.…”

Neurodevelopmental consequences in offspring of mothers with preeclampsia during pregnancy: underlying biological mechanism via imprinting genes

“…For example, the maternally expressed imprinted gene CYCLIN-DEPENDENT KINASE INHIBITOR 1C ( CDKN1C ) has variously been reported to be significantly decreased [97], increased [98, 99], or unaltered [100] in preeclamptic placentas. These conflicting results may be explained by a difference in mode of delivery, given recent evidence demonstrating significantly increased CDKN1C expression in laboring versus non-laboring placentas [101].…”

Simvastatin inhibits oxidative stress via the activation of nuclear factor erythroid 2‐related factor 2 signaling in trophoblast cells

“…Although several lines of evidence have suggested that statins exert antioxidant effects by enhancing Nrf2 activation, no study has examined the efficacy of simvastatin on Nrf2 signaling in trophoblast cells . Among the Nrf2 target genes, we focused on HO‐1, GCLC and GCLM, as we found that their mRNA expression levels were decreased in pre‐eclamptic placentas . Overexpression of HO‐1 in endothelial cells results in a significant decrease in the production of soluble fms‐like tyrosine kinase 1 (sFlt‐1), the most important antiangiogenic factor associated with pre‐eclampsia .…”

“…We have previously reported that Nrf2 activation was significantly reduced in pre‐eclamptic compared with normal placentas, and consequently, the messenger ribonucleic acid (mRNA) expression of the target gene HO‐1 was decreased in pre‐eclamptic placentas . In addition, we found that the expressions of other Nrf2 target genes, GCLC and GCLM , were also reduced in pre‐eclamptic placentas . Yet the underlying precise mechanism by which Nrf2 activation is disrupted in pre‐eclamptic placentas still requires elucidation.…”