Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness
Abstract Background Critically ill children suffer from impaired physical/neurocognitive development 2 years later. Glucocorticoid treatment alters DNA methylation within the hypothalamus–pituitary–adrenal (HPA) axis which may impair normal brain development, cognition and behaviour. We tested the h...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13148-024-01640-y |
| _version_ | 1797274226637406208 |
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| author | Grégoire Coppens Ilse Vanhorebeek Fabian Güiza Inge Derese Pieter J. Wouters Arno Téblick Karolijn Dulfer Koen F. Joosten Sascha C. Verbruggen Greet Van den Berghe |
| author_facet | Grégoire Coppens Ilse Vanhorebeek Fabian Güiza Inge Derese Pieter J. Wouters Arno Téblick Karolijn Dulfer Koen F. Joosten Sascha C. Verbruggen Greet Van den Berghe |
| author_sort | Grégoire Coppens |
| collection | DOAJ |
| description | Abstract Background Critically ill children suffer from impaired physical/neurocognitive development 2 years later. Glucocorticoid treatment alters DNA methylation within the hypothalamus–pituitary–adrenal (HPA) axis which may impair normal brain development, cognition and behaviour. We tested the hypothesis that paediatric-intensive-care-unit (PICU) patients, sex- and age-dependently, show long-term abnormal DNA methylation within the HPA-axis layers, possibly aggravated by glucocorticoid treatment in the PICU, which may contribute to the long-term developmental impairments. Results In a pre-planned secondary analysis of the multicentre PEPaNIC-RCT and its 2-year follow-up, we identified differentially methylated positions and differentially methylated regions within HPA-axis genes in buccal mucosa DNA from 818 former PICU patients 2 years after PICU admission (n = 608 no glucocorticoid treatment; n = 210 glucocorticoid treatment) versus 392 healthy children and assessed interaction with sex and age, role of glucocorticoid treatment in the PICU and associations with long-term developmental impairments. Adjusting for technical variation and baseline risk factors and correcting for multiple testing (false discovery rate < 0.05), former PICU patients showed abnormal DNA methylation of 26 CpG sites (within CRHR1, POMC, MC2R, NR3C1, FKBP5, HSD11B1, SRD5A1, AKR1D1, DUSP1, TSC22D3 and TNF) and three DNA regions (within AVP, TSC22D3 and TNF) that were mostly hypomethylated. These abnormalities were sex-independent and only partially age-dependent. Abnormal methylation of three CpG sites within FKBP5 and one CpG site within SRD5A1 and AKR1D1 was partly attributable to glucocorticoid treatment during PICU stay. Finally, abnormal methylation within FKBP5 and AKR1D1 was most robustly associated with long-term impaired development. Conclusions Two years after critical illness in children, abnormal methylation within HPA-axis genes was present, predominantly within FKBP5 and AKR1D1, partly attributable to glucocorticoid treatment in the PICU, and explaining part of the long-term developmental impairments. These data call for caution regarding liberal glucocorticoid use in the PICU. |
| first_indexed | 2024-03-07T14:55:20Z |
| format | Article |
| id | doaj.art-47a59c8d1c894d999974022239e0fc52 |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-03-07T14:55:20Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-47a59c8d1c894d999974022239e0fc522024-03-05T19:27:32ZengBMCClinical Epigenetics1868-70832024-02-0116111510.1186/s13148-024-01640-yAbnormal DNA methylation within HPA-axis genes years after paediatric critical illnessGrégoire Coppens0Ilse Vanhorebeek1Fabian Güiza2Inge Derese3Pieter J. Wouters4Arno Téblick5Karolijn Dulfer6Koen F. Joosten7Sascha C. Verbruggen8Greet Van den Berghe9Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenDivision of Paediatric Intensive Care Unit, Department of Neonatal and Paediatric ICU, Erasmus Medical Centre, Sophia Children’s HospitalDivision of Paediatric Intensive Care Unit, Department of Neonatal and Paediatric ICU, Erasmus Medical Centre, Sophia Children’s HospitalDivision of Paediatric Intensive Care Unit, Department of Neonatal and Paediatric ICU, Erasmus Medical Centre, Sophia Children’s HospitalClinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU LeuvenAbstract Background Critically ill children suffer from impaired physical/neurocognitive development 2 years later. Glucocorticoid treatment alters DNA methylation within the hypothalamus–pituitary–adrenal (HPA) axis which may impair normal brain development, cognition and behaviour. We tested the hypothesis that paediatric-intensive-care-unit (PICU) patients, sex- and age-dependently, show long-term abnormal DNA methylation within the HPA-axis layers, possibly aggravated by glucocorticoid treatment in the PICU, which may contribute to the long-term developmental impairments. Results In a pre-planned secondary analysis of the multicentre PEPaNIC-RCT and its 2-year follow-up, we identified differentially methylated positions and differentially methylated regions within HPA-axis genes in buccal mucosa DNA from 818 former PICU patients 2 years after PICU admission (n = 608 no glucocorticoid treatment; n = 210 glucocorticoid treatment) versus 392 healthy children and assessed interaction with sex and age, role of glucocorticoid treatment in the PICU and associations with long-term developmental impairments. Adjusting for technical variation and baseline risk factors and correcting for multiple testing (false discovery rate < 0.05), former PICU patients showed abnormal DNA methylation of 26 CpG sites (within CRHR1, POMC, MC2R, NR3C1, FKBP5, HSD11B1, SRD5A1, AKR1D1, DUSP1, TSC22D3 and TNF) and three DNA regions (within AVP, TSC22D3 and TNF) that were mostly hypomethylated. These abnormalities were sex-independent and only partially age-dependent. Abnormal methylation of three CpG sites within FKBP5 and one CpG site within SRD5A1 and AKR1D1 was partly attributable to glucocorticoid treatment during PICU stay. Finally, abnormal methylation within FKBP5 and AKR1D1 was most robustly associated with long-term impaired development. Conclusions Two years after critical illness in children, abnormal methylation within HPA-axis genes was present, predominantly within FKBP5 and AKR1D1, partly attributable to glucocorticoid treatment in the PICU, and explaining part of the long-term developmental impairments. These data call for caution regarding liberal glucocorticoid use in the PICU.https://doi.org/10.1186/s13148-024-01640-yCritical illnessChildrenDNA methylationHPA axisGlucocorticoidLong-term outcome |
| spellingShingle | Grégoire Coppens Ilse Vanhorebeek Fabian Güiza Inge Derese Pieter J. Wouters Arno Téblick Karolijn Dulfer Koen F. Joosten Sascha C. Verbruggen Greet Van den Berghe Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness Clinical Epigenetics Critical illness Children DNA methylation HPA axis Glucocorticoid Long-term outcome |
| title | Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness |
| title_full | Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness |
| title_fullStr | Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness |
| title_full_unstemmed | Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness |
| title_short | Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness |
| title_sort | abnormal dna methylation within hpa axis genes years after paediatric critical illness |
| topic | Critical illness Children DNA methylation HPA axis Glucocorticoid Long-term outcome |
| url | https://doi.org/10.1186/s13148-024-01640-y |
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