Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial

Grégoire Coppens, Ilse Vanhorebeek, Ines Verlinden, Inge Derese, Pieter J. Wouters, Koen F. Joosten, Sascha C. Verbruggen, Fabian Güiza, Greet Van den Berghe*

*Corresponding author for this work

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Abstract

Critically ill children requiring intensive care suffer from impaired physical/neurocognitive development 2 y later, partially preventable by omitting early use of parenteral nutrition (early-PN) in the paediatric intensive-care-unit (PICU). Altered methylation of DNA from peripheral blood during PICU-stay provided a molecular basis hereof. Whether DNA-methylation of former PICU patients, assessed 2 y after critical illness, is different from that of healthy children remained unknown. In a pre-planned secondary analysis of the PEPaNIC-RCT (clinicaltrials.gov-NCT01536275) 2-year follow-up, we assessed buccal-mucosal DNA-methylation (Infinium-HumanMethylation-EPIC-BeadChip) of former PICU-patients (N = 406 early-PN; N = 414 late-PN) and matched healthy children (N = 392). CpG-sites differentially methylated between groups were identified with multivariable linear regression and differentially methylated DNA-regions via clustering of differentially methylated CpG-sites using kernel-estimates. Analyses were adjusted for technical variation and baseline risk factors, and corrected for multiple testing (false-discovery-rate <0.05). Differentially methylated genes were functionally annotated (KEGG-pathway database), and allocated to three classes depending on involvement in physical/neurocognitive development, critical illness and intensive medical care, or pre-PICU-admission disorders. As compared with matched healthy children, former PICU-patients showed significantly different DNA-methylation at 4047 CpG-sites (2186 genes) and 494 DNA-regions (468 genes), with most CpG-sites being hypomethylated (90.3%) and with an average absolute 2% effect-size, irrespective of timing of PN initiation. Of the differentially methylated KEGG-pathways, 41.2% were related to physical/neurocognitive development, 32.8% to critical illness and intensive medical care and 26.0% to pre-PICU-admission disorders. Two years after critical illness in children, buccal-mucosal DNA showed abnormal methylation of CpG-sites and DNA-regions located in pathways known to be important for physical/neurocognitive development.

Original languageEnglish
Article number2146966
JournalEpigenetics
Volume18
Issue number1
DOIs
Publication statusPublished - 2023

Bibliographical note

Funding Information:
This work was supported by European Research Council Advanced Grants under Grant AdvG-2012-321670 and AdvG-2017-785809 to Greet Van den Berghe; and the Methusalem program of the Flemish government (through the University of Leuven to Greet Van den Berghe and Ilse Vanhorebeek) under Grant METH14/06; and by the Institute for Science and Technology, Flanders, Belgium (through the University of Leuven to Greet Van den Berghe) under Grant IWT/110685/TBM and IWT/150181/TBM); by the Sophia Research Foundation (SSWO) to Sascha Verbruggen; by the “Stichting Agis Zorginnovatie” to Sascha Verbruggen; by the Erasmus Trustfonds (to Sascha Verbruggen); and by a European Society for Clinical Nutrition and Metabolism (ESPEN) research grant to Sascha Verbruggen. The resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the Research Foundation–Flanders (FWO) and the Flemish Government. The authors acknowledge the research team members involved in the study for their help with the technical and administrative support. Furthermore, they thank the children and their parents for their willingness to participate in the study.

Funding Information:
The resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the Research Foundation – Flanders (FWO) and the Flemish Government. The authors acknowledge the research team members involved in the study for their help with the technical and administrative support. Furthermore, they thank the children and their parents for their willingness to participate in the study.

Publisher Copyright:
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

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