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Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness
Grégoire Coppens1, Ilse Vanhorebeek1, Fabian Güiza1
1Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
Insights
Children treated in the pediatric intensive care unit (PICU) show long-term abnormal DNA methylation in hypothalamus-pituitary-adrenal (HPA) axis genes, linked to developmental impairments. Glucocorticoid treatment may exacerbate these epigenetic changes, impacting neurodevelopment.
Area of Science:
- Epigenetics
- Pediatric critical care
- Neurodevelopmental disorders
Background:
- Critically ill children experience long-term physical and neurocognitive deficits.
- Glucocorticoid therapy can alter DNA methylation in the hypothalamus-pituitary-adrenal (HPA) axis, potentially affecting brain development and behavior.
- The study investigates long-term epigenetic changes in former pediatric intensive care unit (PICU) patients.
Purpose of the Study:
- To determine if former PICU patients exhibit long-term abnormal DNA methylation within HPA-axis genes.
- To assess the influence of sex, age, and glucocorticoid treatment on these epigenetic alterations.
- To correlate HPA-axis DNA methylation changes with long-term developmental impairments.
Main Methods:
- Secondary analysis of the PEPaNIC-RCT and its 2-year follow-up data.
- Analysis of DNA methylation in buccal mucosa from 818 former PICU patients and 392 healthy children.
- Identification of differentially methylated positions and regions within HPA-axis genes, with adjustments for covariates and multiple testing.
Main Results:
- Former PICU patients displayed abnormal DNA methylation in 26 CpG sites and 3 DNA regions, primarily hypomethylation.
- These abnormalities were mostly sex-independent but partially age-dependent.
- Glucocorticoid treatment in the PICU was partly responsible for abnormal methylation in FKBP5, SRD5A1, and AKR1D1; FKBP5 and AKR1D1 methylation changes were most strongly associated with impaired development.
Conclusions:
- Two years post-critical illness, children exhibit HPA-axis gene methylation abnormalities, particularly in FKBP5 and AKR1D1.
- These epigenetic changes are partly linked to PICU glucocorticoid exposure and contribute to long-term developmental deficits.
- Findings suggest a need for caution regarding liberal glucocorticoid use in PICU settings.
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.
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