THU155 Aberrant DNA Methylation Within Genes Of The HPA-axis Two Years After Paediatric Critical Illness, Role Of Glucocorticoid Treatment And Association With Impaired Physical And Neurocognitive Development.

Abstract

Disclosure: G. Coppens: None. I. Vanhorebeek: None. F. Guïza: None. I. Derese: None. P.J. Wouters: None. J.F. Koen: None. S.C. Verbruggen: None. G. Van den Berghe: None.

Critically ill children requiring intensive care suffer from impaired physical, neurocognitive and behavioural development two years later. Other severe early-life adverse events, such as abuse or neglect occurring during sensitive neurodevelopmental windows, have been associated with similar developmental problems. Earlier work has demonstrated the risk of impaired development of brain regions crucial for cognition and behaviour through increased glucocorticoid-signalling that, when prolonged or excessive, can induce aberrant DNA methylation within the hypothalamus-pituitary-adrenal (HPA) axis. We hypothesised that paediatric critical illness induces long-term DNA methylation changes within the HPA-axis, possibly aggravated by treatment with glucocorticoids in the paediatric intensive care unit (PICU), which may contribute to the long-term physical, neurocognitive and behavioural impairments. We assessed buccal mucosal DNA methylation (Infinium-Human Methylation-EPIC-BeadChip) of former PICU patients two years after PICU discharge (N=608 No-glucocorticoid-treatment; N=210 glucocorticoid-treatment) and matched healthy children (N=392) among key genes of the different layers of the HPA-axis. CpG-sites differentially methylated between groups were identified with use of multivariable linear regression. Differentially methylated DNA-regions were detected via clustering of differentially methylated CpG-sites using kernel estimates. These analyses were adjusted for technical variation and baseline risk factors and corrected for multiple testing (FDR<0.05). Additionally, we investigated to what extent glucocorticoid treatment during PICU stay had played a direct role in bringing about any DNA methylation changes. Finally, we assessed whether an association with the long-term physical, neurocognitive and behavioural impairment was present, with use of multivariable linear models. Former PICU patients showed aberrant DNA methylation at 10 CpG-sites (located within NR3C1, FKBP5, TSC22D3, TNF and, HSD11B1) and one DNA-region (located within TNF). Additionally, we identified that the differential methylation of 2 CpG-sites within FKBP5 was at least partly attributable to the glucocorticoid treatment that was given during PICU stay. The aberrant DNA methylation in former PICU patients associated with impaired development. This was most pronounced for the hypomethylation within the promotor/5’UTR region of FKBP5, which associated with worse growth, intelligence, visual-motor integration, alertness and memory. Two years after critical illness in children, aberrant DNA methylation within different genes of the HPA axis was detected, some of which may partly be explained by the glucocorticoid treatment given during PICU admission. These changes associated with long-term physical and neurocognitive impairments of former PICU patients.

Presentation: Thursday, June 15, 2023