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Meta-Analysis of Placental Transcriptome Data Identifies a Novel Molecular Pathway Related to Preeclampsia

Author

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  • Miranda van Uitert
  • Perry D Moerland
  • Daniel A Enquobahrie
  • Hannele Laivuori
  • Joris A M van der Post
  • Carrie Ris-Stalpers
  • Gijs B Afink

Abstract

Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings challenging. To generate a more robust preeclampsia gene expression signature, we performed a meta-analysis on the original data of 11 placenta RNA microarray experiments, representing 139 normotensive and 116 preeclamptic pregnancies. Microarray data were pre-processed and analyzed using standardized bioinformatics and statistical procedures and the effect sizes were combined using an inverse-variance random-effects model. Interactions between genes in the resulting gene expression signature were identified by pathway analysis (Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, Graphite) and protein-protein associations (STRING). This approach has resulted in a comprehensive list of differentially expressed genes that led to a 388-gene meta-signature of preeclamptic placenta. Pathway analysis highlights the involvement of the previously identified hypoxia/HIF1A pathway in the establishment of the preeclamptic gene expression profile, while analysis of protein interaction networks indicates CREBBP/EP300 as a novel element central to the preeclamptic placental transcriptome. In addition, there is an apparent high incidence of preeclampsia in women carrying a child with a mutation in CREBBP/EP300 (Rubinstein-Taybi Syndrome). The 388-gene preeclampsia meta-signature offers a vital starting point for further studies into the relevance of these genes (in particular CREBBP/EP300) and their concomitant pathways as biomarkers or functional molecules in preeclampsia. This will result in a better understanding of the molecular basis of this disease and opens up the opportunity to develop rational therapies targeting the placental dysfunction causal to preeclampsia.

Suggested Citation

  • Miranda van Uitert & Perry D Moerland & Daniel A Enquobahrie & Hannele Laivuori & Joris A M van der Post & Carrie Ris-Stalpers & Gijs B Afink, 2015. "Meta-Analysis of Placental Transcriptome Data Identifies a Novel Molecular Pathway Related to Preeclampsia," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-15, July.
  • Handle: RePEc:plo:pone00:0132468
    DOI: 10.1371/journal.pone.0132468
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    References listed on IDEAS

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    1. C Emily Kleinrouweler & Miranda van Uitert & Perry D Moerland & Carrie Ris-Stalpers & Joris A M van der Post & Gijs B Afink, 2013. "Differentially Expressed Genes in the Pre-Eclamptic Placenta: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-9, July.
    2. Adaikalavan Ramasamy & Adrian Mondry & Chris C Holmes & Douglas G Altman, 2008. "Key Issues in Conducting a Meta-Analysis of Gene Expression Microarray Datasets," PLOS Medicine, Public Library of Science, vol. 5(9), pages 1-13, September.
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