The Interplay between Pathophysiological Pathways in Early-Onset Severe Preeclampsia Unveiled by Metabolomics

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Abstract
Introduction: Preeclampsia is a multi-system disorder unique to pregnancy responsible for a great part of maternal and perinatal morbidity and mortality. The precise pathogenesis of this complex disorder is still unrevealed. Methods: We examined the pathophysiological pathways involved in early-onset preeclampsia, a specific subgroup representing its most severe presentation, using LC-MS/MS metabolomic analysis based on multi-level extraction of lipids and small metabolites from maternal blood samples, collected at the time of diagnosis from 14 preeclamptic and six matched healthy pregnancies. Statistical analysis comprised multivariate and univariate approaches with the application of over representation analysis to identify differential pathways. Results: A clear difference between preeclamptic and control pregnancies was observed in principal component analysis. Supervised multivariate analysis using orthogonal partial least square discriminant analysis provided a robust model with goodness of fit (R2X = 0.91, p = 0.002) and predictive ability (Q2Y = 0.72, p < 0.001). Finally, univariate analysis followed by 5% false discovery rate correction indicated 82 metabolites significantly altered, corresponding to six overrepresented pathways: (1) aminoacyl-tRNA biosynthesis; (2) arginine biosynthesis; (3) alanine, aspartate and glutamate metabolism; (4) D-glutamine and D-glutamate metabolism; (5) arginine and proline metabolism; and (6) histidine metabolism. Conclusion: Metabolomic analysis focusing specifically on the early-onset severe form of preeclampsia reveals the interplay between pathophysiological pathways involved in this form. Future studies are required to explore new therapeutic approaches targeting these altered metabolic pathways in early-onset preeclampsia.
Funding Information
  • Erasmus+ Programme of the European Union (2013-0040)
  • 'la Caixa' Foundation (LCF/PR/GN14/10270005 and LCF/PR/GN18/10310003)
  • AGAUR 2017 SGR (1531)
  • Miguel Servet grant from the Instituto de Salud Carlos III (CP17/00114)
  • Fundació la Marató de TV3 (202026-10)
  • Instituto de Salud Carlos III (PI14/00226, PI15/00130, PIE15/00027, PI17/00675, PI18/00073, PI18/00960, PI19/00888, PI20/00569)
  • Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK), Ministerio de Economía y Competitividad (SAF PID2019-105/48RB-100)
  • European Reference Network (ERN) RARE-Liver (hepatic diseases) (1531)
  • AGAUR 2017 SGR grant (517)
  • Instituto Juan Carlos III (JR19/00006)

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