Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial
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 PI...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Epigenetics |
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| Online Access: | http://dx.doi.org/10.1080/15592294.2022.2146966 |
| _version_ | 1797678805165277184 |
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| author | Grégoire Coppens Ilse Vanhorebeek Ines Verlinden Inge Derese Pieter J Wouters Koen F. Joosten Sascha C. Verbruggen Fabian Güiza Greet Van den Berghe |
| author_facet | Grégoire Coppens Ilse Vanhorebeek Ines Verlinden Inge Derese Pieter J Wouters Koen F. Joosten Sascha C. Verbruggen Fabian Güiza Greet Van den Berghe |
| author_sort | Grégoire Coppens |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:05:16Z |
| format | Article |
| id | doaj.art-2fce528f7e944d6183617d654d51006d |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:05:16Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-2fce528f7e944d6183617d654d51006d2023-09-21T13:23:12ZengTaylor & Francis GroupEpigenetics1559-22941559-23082023-12-0118110.1080/15592294.2022.21469662146966Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trialGrégoire Coppens0Ilse Vanhorebeek1Ines Verlinden2Inge Derese3Pieter J Wouters4Koen F. Joosten5Sascha C. Verbruggen6Fabian Güiza7Greet Van den Berghe8KU LeuvenKU LeuvenKU LeuvenKU LeuvenKU LeuvenErasmus Medical Centre, Sophia Children’s HospitalErasmus Medical Centre, Sophia Children’s HospitalKU LeuvenKU LeuvenCritically 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.http://dx.doi.org/10.1080/15592294.2022.2146966critical illnesschildrenpicudna methylationepigeneticneurocognitive developmentgrowthdevelopmentnutritionparenteral nutrition |
| spellingShingle | Grégoire Coppens Ilse Vanhorebeek Ines Verlinden Inge Derese Pieter J Wouters Koen F. Joosten Sascha C. Verbruggen Fabian Güiza Greet Van den Berghe Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial Epigenetics critical illness children picu dna methylation epigenetic neurocognitive development growth development nutrition parenteral nutrition |
| title | Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial |
| title_full | Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial |
| title_fullStr | Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial |
| title_full_unstemmed | Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial |
| title_short | Assessment of aberrant DNA methylation two years after paediatric critical illness: a pre-planned secondary analysis of the international PEPaNIC trial |
| title_sort | assessment of aberrant dna methylation two years after paediatric critical illness a pre planned secondary analysis of the international pepanic trial |
| topic | critical illness children picu dna methylation epigenetic neurocognitive development growth development nutrition parenteral nutrition |
| url | http://dx.doi.org/10.1080/15592294.2022.2146966 |
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