Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
These exposures have been associated with coordinated alterations in stress-response regulation, circadian and sleep-related pathways, and metabolic processes.
“These exposures have been associated with coordinated alterations in stress-response regulation, circadian and sleep-related pathways, and metabolic processes (102–115).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [105]
The Background and Discussion (page unavailable in our copy) describe altered methylation in HPA-axis and glucocorticoid-signalling genes, including genes involved in cortisol metabolism, after stress or paediatric critical illness. They do not establish coordinated alterations in circadian or sleep-related pathways, or in metabolic processes beyond cortisol metabolism; searches for “sleep” and “circadian” found no supporting passage. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMaternal exposure to Canadian residential schools has been linked to higher cortisol, catecholamines, and inflammatory cytokine levels in offspring, including cases in which offspring were not raised by their biological parents.
“Similarly, maternal exposure to Canadian residential schools has been linked to higher cortisol, catecholamines, and inflammatory cytokine levels in offspring, including cases in which offspring were not raised by their biological parents (104, 105).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [105]
The Methods and Discussion describe DNA methylation in children after paediatric intensive care, not maternal exposure to residential schools. Searches for Canadian residential schools and the claimed offspring findings found no passage addressing cortisol, catecholamines, inflammatory cytokines, or whether offspring were raised by biological parents in that context. The indexed copy provides no page numbers. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
limma powers differential expression analyses for RNA-sequencing and microarray studies
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv007 · Cited by 40,458 · see citing works
Identifying differentially expressed genes using false discovery rate controlling procedures
Reiner, A., Yekutieli, D., & Benjamini, Y. (2003) · Bioinformatics · doi:10.1093/bioinformatics/btf877 · Cited by 1,765 · see citing works
Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., Pace, T. W. W., Mercer, K. B., Mayberg, H. S., Bradley, B., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3275 · Cited by 1,447 · see citing works
Dynamic DNA methylation programs persistent adverse effects of early-life stress
Murgatroyd, C., Patchev, A. V., Wu, Y., Micale, V., Bockmühl, Y., Fischer, D., Holsboer, F., Wotjak, C. T., Almeida, O. F. X., & Spengler, D. (2009) · Nature Neuroscience · doi:10.1038/nn.2436 · Cited by 1,162 · see citing works
Early Life Programming and Neurodevelopmental Disorders
Bale, T. L., Baram, T. Z., Brown, A. S., Goldstein, J. M., Insel, T. R., McCarthy, M. M., Nemeroff, C. B., Reyes, T. M., Simerly, R. B., Susser, E. S., et al. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.05.028 · Cited by 961 · see citing works
De novo identification of differentially methylated regions in the human genome
Peters, T. J., Buckley, M. J., Statham, A. L., Pidsley, R., Samaras, K., Lord, R. V., Clark, S. J., & Molloy, P. L. (2015) · Epigenetics & Chromatin · doi:10.1186/1756-8935-8-6 · Cited by 956 · see citing works
Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation
Yehuda, R., Daskalakis, N. P., Bierer, L. M., Bader, H. N., Klengel, T., Holsboer, F., & Binder, E. B. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.08.005 · Cited by 782 · cited 2× · see citing works
“…hormone ( CRH ) and its receptor CRHR1 , arginine vasopressin ( AVP ) and its receptor AVPR1b , pro-opiomelanocortin ( POMC ), corticotropin receptor ( MC2R ), glucocorticoid receptor GRα ( NR3C1 ) and for the GRα-regulated chaperone protein FK506 binding protein 51 ( FKBP5 ) [23, 25–31].”
BackgroundMethodGene–Stress–Epigenetic regulation of FKBP5: clinical and translational implications
Zannas, A. S., Wiechmann, T., Gassen, N. C., & Binder, E. B. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.235 · Cited by 622 · see citing works
Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure
van Bodegom, M., Homberg, J. R., & Henckens, M. J. A. G. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00087 · Cited by 562 · see citing works
Early versus late parenteral nutrition in critically ill children
Fivez, T., Kerklaan, D., Mesotten, D., Verbruggen, S., Wouters, P. J., Vanhorebeek, I., Debaveye, Y., Vlasselaers, D., Desmet, L., Casaer, M. P., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1514762 · Cited by 558 · see citing works
Self-citationVlasselaers, D., Milants, I., Desmet, L., Wouters, P. J., Vanhorebeek, I., van den Heuvel, I., Mesotten, D., Casaer, M. P., Meyfroidt, G., Ingels, C., et al. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60044-1 · Cited by 554 · see citing works
Self-citationReduced Cortisol Metabolism during Critical Illness
Boonen, E., Vervenne, H., Meersseman, P., Andrew, R., Mortier, L., Declercq, P. E., Vanwijngaerden, Y.-M., Spriet, I., Wouters, P. J., Vander Perre, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1214969 · Cited by 477 · see citing works
Self-citationLehne, B., Drong, A. W., Loh, M., Zhang, W., Scott, W. R., Tan, S.-T., Afzal, U., Scott, J., Jarvelin, M.-R., Elliott, P., et al. (2015) · Genome biology · doi:10.1186/s13059-015-0600-x · Cited by 380 · see citing works
Peña, C. J., Monk, C. E., & Champagne, F. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039791 · Cited by 377 · see citing works
Zannas, A. S., Jia, M., Hafner, K., Baumert, J. J., Wiechmann, T., Pape, J. C., Arloth, J., Ködel, M., Martinelli, S., Roitman, M., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1816847116 · Cited by 342 · see citing works
Lehne, B. C., Drong, A., Loh, M. C. S., Zhang, W., Scott, W. R., Tan, S.-T., Afzal, U., Schulz, R., Scott, J., Järvelin, M., et al. (2016) · Genome biology · doi:10.1186/s13059-016-0934-z · Cited by 284 · see citing works
Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis
Yehuda, R., & Seckl, J. (2011) · Endocrinology · doi:10.1210/en.2011-1218 · Cited by 276 · see citing works
Nelson, E. D., Kavalali, E. T., & Monteggia, L. M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3796-07.2008 · Cited by 254 · see citing works
Kertes, D. A., Kamin, H. S., Hughes, D. A., Rodney, N. C., Bhatt, S., & Mulligan, C. J. (2016) · Child Development · doi:10.1111/cdev.12487 · Cited by 219 · see citing works
Watson, R. S., Choong, K. L. M., Colville, G. A., Crow, S. S., Dervan, L. A., Hopkins, R. O., Knoester, H., Pollack, M. M., Rennick, J. E., & Curley, M. A. Q. (2018) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2017.12.084 · Cited by 217 · see citing works
Adrenal function and dysfunction in critically ill patients
Téblick, A., Peeters, B., Langouche, L., & den Berghe, G. V. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0185-7 · Cited by 156 · see citing works
Self-citationEarly-Life Stress Reduces DNA Methylation of the Pomc Gene in Male Mice
Wu, Y., Patchev, A. V., Daniel, G., Almeida, O. F. X., & Spengler, D. (2014) · Endocrinology · doi:10.1210/en.2013-1868 · Cited by 142 · see citing works
Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks
Kress, C., Thomassin, H., & Grange, T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601793103 · Cited by 121 · see citing works
Tyrka, A. R., Ridout, K. K., & Parade, S. H. (2016) · Development and Psychopathology · doi:10.1017/s0954579416000870 · Cited by 119 · see citing works
Verstraete, S., Verbruggen, S. C. A. T., Hordijk, J. A., Vanhorebeek, I., Dulfer, K., Güiza, F., van Puffelen, E., Jacobs, A., Leys, S., Durt, A., et al. (2018) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(18)30334-5 · Cited by 105 · see citing works
Self-citationThe poolr Package for Combining Independent and Dependent p Values
Cinar, O., & Viechtbauer, W. (2022) · Journal of Statistical Software · doi:10.18637/jss.v101.i01 · Cited by 101 · see citing works
Yang, X., Ewald, E. R., Huo, Y., Tamashiro, K. L., Salvatori, R., Sawa, A., Wand, G. S., & Lee, R. S. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.03.035 · Cited by 97 · see citing works
Annexin 1, Glucocorticoids, and the Neuroendocrine–Immune Interface
Buckingham, J. C., John, C., Solito, E., Tierney, T., Flower, R. J., Christian, H., & Morris, J. F. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1366.002 · Cited by 88 · see citing works
Cicchetti, D., & Handley, E. D. (2017) · Development and Psychopathology · doi:10.1017/s0954579417001407 · Cited by 87 · see citing works
Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus
Wiechmann, T., Röh, S., Sauer, S., Czamara, D., Arloth, J., Ködel, M., Beintner, M., Knop, L., Menke, A., Binder, E. B., et al. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0682-5 · Cited by 81 · see citing works
Toward nutrition improving outcome of critically ill patients: How to interpret recent feeding RCTs?
Gunst, J., Casaer, M. P., Preiser, J., Reignier, J., & den Berghe, G. V. (2023) · Critical Care · doi:10.1186/s13054-023-04317-9 · Cited by 77 · see citing works
Peeters, B., Meersseman, P., Perre, S. V., Wouters, P. J., Vanmarcke, D., Debaveye, Y. A., Billen, J., Vermeersch, P., Langouche, L., & den Berghe, G. V. (2018) · Intensive Care Medicine · doi:10.1007/s00134-018-5366-7 · Cited by 75 · see citing works
Self-citationVerstraete, S., Vanhorebeek, I., Covaci, A., Güiza, F., Malarvannan, G., Jorens, P. G., & den Berghe, G. V. (2015) · Intensive Care Medicine · doi:10.1007/s00134-015-4159-5 · Cited by 72 · see citing works
Self-citationGüiza, F., Vanhorebeek, I., Verstraete, S., Verlinden, I., Derese, I., Ingels, C., Dulfer, K., Verbruggen, S. C. A. T., Guerra, G. G., Joosten, K., et al. (2020) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(20)30046-1 · Cited by 62 · see citing works
Self-citationJacobs, A., Dulfer, K., Eveleens, R. D., Hordijk, J. A., Cleemput, H. V., Verlinden, I., Wouters, P. J., Mebis, L., Guerra, G. G., Joosten, K., et al. (2020) · The Lancet Child & Adolescent Health · doi:10.1016/s2352-4642(20)30104-8 · Cited by 61 · see citing works
Self-citationGreen, B. B., Armstrong, D. A., Lesseur, C., Paquette, A. G., Guerin, D. J., Kwan, L. E., & Marsit, C. J. (2015) · Biology of Reproduction · doi:10.1095/biolreprod.115.128066 · Cited by 52 · see citing works
Association of Acute Respiratory Failure in Early Childhood With Long-term Neurocognitive Outcomes
Watson, R. S., Beers, S. R., Asaro, L. A., Burns, C., Koh, M. J., Perry, M., Angus, D. C., Wypij, D., Curley, M. A. Q., RESTORE-Cognition Investigators, et al. (2022) · JAMA · doi:10.1001/jama.2022.1480 · Cited by 47 · see citing works
Glad, C. A. M., Andersson‐Assarsson, J. C., Berglund, P., Bergthorsdottir, R., Ragnarsson, Ó., & Johannsson, G. (2017) · Scientific Reports · doi:10.1038/srep44445 · Cited by 44 · see citing works
Lewis, C. R., Breitenstein, R. S., Henderson-Smith, A., Sowards, H., Piras, I. S., Huentelman, M. J., Doane, L. D., & Lemery‐Chalfant, K. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00885-4 · Cited by 44 · see citing works
Palma‐Gudiel, H., Prather, A. A., Lin, J., Oxendine, J. D., Guintivano, J., Xia, K., Rubinow, D. R., Wolkowitz, O. M., Epel, E. S., & Zannas, A. S. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.11.027 · Cited by 43 · see citing works
Langouche, L., Téblick, A., Gunst, J., & den Berghe, G. V. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad021 · Cited by 39 · see citing works
Self-citationGan, Y., Wang, C., He, R.-H., Hsu, P.-C., Yeh, H.-H., Hsieh, T.-H., Lin, H., Cheng, M.-Y., Jeng, C., Huang, M., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02517-8 · Cited by 38 · see citing works
Perinatal programming of metabolic diseases: The role of glucocorticoids
Facchi, J. C., de Lima, T. A. L., de Oliveira, L. R., Costermani, H. D. O., Miranda, G. D. S., & de Oliveira, J. C. (2019) · Metabolism · doi:10.1016/j.metabol.2019.154047 · Cited by 37 · see citing works
Mulder, R. H., Rijlaarsdam, J., Luijk, M. P. C. M., Verhulst, F. C., Felix, J. F., Tiemeier, H. W., Bakermans‐Kranenburg, M. J., & van IJzendoorn, M. H. (2017) · Development and Psychopathology · doi:10.1017/s095457941700013x · Cited by 35 · see citing works
Jacobs, A., Derese, I., Perre, S. V., van Puffelen, E., Verstraete, S., Pauwels, L., Verbruggen, S. C. A. T., Wouters, P. J., Langouche, L., Guerra, G. G., et al. (2019) · Thyroid · doi:10.1089/thy.2018.0420 · Cited by 35 · see citing works
Self-citationActivity of the Growth Hormone/Insulin-like Growth Factor-I Axis in Critically Ill Children
Gardelis, J., Hatzis, T. D., Stamogiannou, L., Dona, A., Fotinou, A., Brestas, P. S., & Constantopoulos, A. G. (2005) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2005.18.4.363 · Cited by 35 · see citing works
Lebow, M., Schroeder, M., Tsoory, M., Holzman-Karniel, D., Mehta, D., Ben‐Dor, S., Gil, S., Bradley, B., Smith, A. K., Jovanović, T., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0509-3 · Cited by 34 · see citing works
Our Scientific Journey through the Ups and Downs of Blood Glucose Control in the ICU
den Berghe, G. V., Vanhorebeek, I., Langouche, L., & Gunst, J. (2023) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202309-1696so · Cited by 34 · see citing works
Self-citationMiura, R., Araki, A., Ishihara, T., Miyake, K., Miyashita, C., Nakajima, T., Kobayashi, S., Ishizuka, M., Kubota, T., & Kishi, R. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.147035 · Cited by 33 · see citing works
Serum free cortisol index, free cortisol, and total cortisol in critically ill children
Poomthavorn, P., Lertbunrian, R., Preutthipan, A., Sriphrapradang, A., Khlairit, P., & Mahachoklertwattana, P. (2009) · Intensive Care Medicine · doi:10.1007/s00134-009-1480-x · Cited by 30 · see citing works
Hordijk, J. A., Verbruggen, S. C. A. T., Buysse, C. M. P., Utens, E. M. W. J., Joosten, K. F. M., & Dulfer, K. (2022) · Quality of Life Research · doi:10.1007/s11136-022-03124-z · Cited by 30 · see citing works
Self-citationThe Role of Epigenetic Modifications in Late Complications in Type 1 Diabetes
Kern, B. Č., Podkrajšek, K. T., Kovač, J., Šket, R., Bizjan, B. J., Tesovnik, T., Debeljak, M., Battelino, T., & Bratina, N. (2022) · Genes · doi:10.3390/genes13040705 · Cited by 29 · see citing works
Developmental Neuroendocrinology of Early-Life Stress: Impact on Child Development and Behavior
Nicolaides, N. C., Kanaka‐Gantenbein, C., & Pervanidou, P. (2023) · Current Neuropharmacology · doi:10.2174/1570159x21666230810162344 · Cited by 28 · see citing works
Epigenetics of the Pathogenesis and Complications of Type 2 Diabetes Mellitus
Mannar, V., Boro, H., Patel, D., Agstam, S., Dalvi, M., & Bundela, V. (2023) · touchREVIEWS in Endocrinology · doi:10.17925/ee.2023.19.1.46 · Cited by 27 · see citing works
DNA methylation alterations in muscle of critically ill patients
Dyck, L. V., Güiza, F., Derese, I., Pauwels, L., Casaer, M. P., Hermans, G., Wouters, P. J., den Berghe, G. V., & Vanhorebeek, I. (2022) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12970 · Cited by 26 · see citing works
Self-citationMunetsuna, E., Yamada, H., Yamazaki, M., Ando, Y., Mizuno, G., Hattori, Y., Sadamoto, N., Ishikawa, H., Ohta, Y., Fujii, R., et al. (2019) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2019.01.016 · Cited by 25 · see citing works
Vanhorebeek, I., Malarvannan, G., Güiza, F., Poma, G., Derese, I., Wouters, P. J., Joosten, K., Verbruggen, S. C. A. T., Jorens, P. G., Covaci, A., et al. (2021) · Environment International · doi:10.1016/j.envint.2021.106962 · Cited by 23 · see citing works
Self-citationAraki, R., Nishida, S., Hiraki, Y., Matsumoto, K., & Yabe, T. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.08.031 · Cited by 22 · see citing works
Cox, O., Song, H. Y., Garrison‐Desany, H. M., Gadiwalla, N., Carey, J. L., Menzies, J., & Lee, R. S. (2020) · Epigenetics · doi:10.1080/15592294.2020.1864169 · Cited by 22 · see citing works
Nagarajan, S., Seddighzadeh, B., Baccarelli, A., Wise, L. A., Williams, M. A., & Shields, A. E. (2016) · Epigenomics · doi:10.2217/epi.16.9 · Cited by 20 · see citing works
Jacobs, A., Derese, I., Perre, S. V., Wouters, P. J., Verbruggen, S. C. A. T., Billen, J., Vermeersch, P., Guerra, G. G., Joosten, K. F. M., Vanhorebeek, I., et al. (2019) · Intensive Care Medicine · doi:10.1007/s00134-019-05854-0 · Cited by 20 · see citing works
Self-citationVerlinden, I., Güiza, F., Derese, I., Wouters, P. J., Joosten, K. F. M., Verbruggen, S. C. A. T., den Berghe, G. V., & Vanhorebeek, I. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-00947-w · Cited by 20 · see citing works
Self-citationEffect of Intensive Insulin Therapy on the Somatotropic Axis of Critically Ill Children
Gielen, M., Mesotten, D., Brugts, M. P., Coopmans, W., Herck, E. V., Vanhorebeek, I., Baxter, R. C., Lamberts, S. W. J., Janssen, J. A. M. J. L., & den Berghe, G. V. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-3045 · Cited by 20 · see citing works
Self-citationImpact of Physical Activity and Doping on Epigenetic Gene Regulation
Schwarzenbach, H. (2011) · Drug Testing and Analysis · doi:10.1002/dta.294 · Cited by 19 · see citing works
Altered hypothalamic DNA methylation and stress-induced hyperactivity following early life stress
Fitzgerald, E., Sinton, M. C., Wernig-Zorc, S., Morton, N. M., Holmes, M. C., Boardman, J. P., & Drake, A. J. (2021) · Epigenetics & Chromatin · doi:10.1186/s13072-021-00405-8 · Cited by 19 · see citing works
Pediatric Critical Care Outcomes
Perry, M., Dervan, L. A., Manning, J. C., Watson, R. S., & Curley, M. A. Q. (2022) · Critical Care Clinics · doi:10.1016/j.ccc.2022.09.007 · Cited by 19 · see citing works
Featherstone, R. E., Gifford, R. L., Crown, L. M., Amirfathi, F., Alaniz, J. P., Yi, J., Tran, A., Adomian, D., Schwenk, A., Melnychenko, O., et al. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114099 · Cited by 13 · see citing works
Li, H., Liu, J., Sun, Y., Wang, W., Weng, S., Xiao, S., Huang, H., & Zhang, W. (2013) · Journal of Applied Toxicology · doi:10.1002/jat.2893 · Cited by 13 · see citing works
Martinez, M. E., Stohn, J. P., Mutina, E. M., Whitten, R. J., & Hernández, A. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1055116 · Cited by 12 · see citing works
Coppens, G., Vanhorebeek, I., Verlinden, I., Derese, I., Wouters, P. J., Joosten, K. F. M., Verbruggen, S. C. A. T., Güiza, F., & den Berghe, G. V. (2022) · Epigenetics · doi:10.1080/15592294.2022.2146966 · Cited by 12 · see citing works
Self-citationVerlinden, I., Coppens, G., Vanhorebeek, I., Güiza, F., Derese, I., Wouters, P. J., Joosten, K., Verbruggen, S. C. A. T., & den Berghe, G. V. (2023) · Clinical Epigenetics · doi:10.1186/s13148-023-01424-w · Cited by 12 · see citing works
Self-citationEvaluation of endocrine function in children admitted to pediatric intensive care unit
Aydın, B. K., Demirkol, D., Baş, F., Türkoğlu, Ü., Kumral, A., Karaböcüoğlu, M., Çıtak, A., & Darendelıler, F. (2013) · Pediatrics International · doi:10.1111/ped.12269 · Cited by 9 · see citing works
Dyck, L. V., Derese, I., Perre, S. V., Wouters, P. J., Casaer, M. P., Hermans, G., den Berghe, G. V., & Vanhorebeek, I. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2019-00842 · Cited by 8 · see citing works
Self-citationImpaired Pancreatic β-Cell Function in Critically Ill Children
Mohamed, S. A., Badawi, N. E., Rasol, H. A. A., AbdelAziz, H. M., Khalaf, N. A., & Yousef, R. M. (2021) · Frontiers in Pediatrics · doi:10.3389/fped.2021.603361 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Singer, M., Angus, D., Annane, D., Bauer, M. W., Kalil, A. C., Klompas, M., Machado, F. R., Martin, G. S., Randolph, A. G., Shankar‐Hari, M., et al. (2026) · The Lancet · doi:10.1016/s0140-6736(25)02422-5 · Cited by 55 · see citing works
The flux of energy in critical illness and the obesity paradox
Jaitovich, A., & Hall, J. B. (2025) · Physiological Reviews · doi:10.1152/physrev.00029.2024 · Cited by 33 · see citing works
Blood DNA methylation in post-acute sequelae of COVID-19 (PASC): a prospective cohort study
Balnis, J., Madrid, A., Drake, L. A., Vancavage, R., Tiwari, A., Patel, V., Ramos, R. B., Schwarz, J. J., Yucel, R. M., Singer, H. A., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105251 · Cited by 26 · see citing works
Environmental epigenetics: new horizons in redefining biological and health outcomes
Faraji, J., & Metz, G. A. S. (2026) · Environment International · doi:10.1016/j.envint.2026.110072 · Cited by 21 · see citing works
Epigenetic factors in posttraumatic stress disorder resilience and susceptibility
Addissouky, T. A., Sayed, I. E. T. E., & Wang, Y. (2025) · Egyptian Journal of Medical Human Genetics · doi:10.1186/s43042-025-00684-w · Cited by 18 · see citing works
On how to feed critically ill children in intensive care: A slowly shifting paradigm
Gunst, J., Vanhorebeek, I., Verbruggen, S. C. A. T., Dulfer, K., Joosten, K. F. M., & den Berghe, G. V. (2025) · Clinical Nutrition · doi:10.1016/j.clnu.2025.02.003 · Cited by 13 · see citing works
Self-citationNutrition and DNA Methylation: How Dietary Methyl Donors Affect Reproduction and Aging
Dusa, F. C., Vellai, T., & Sipos, M. (2025) · Dietetics · doi:10.3390/dietetics4030030 · Cited by 13 · see citing works
Incidence of New Comorbidities After Steroid Use in Patients With Sarcoidosis
Harper, L. J., Baughman, R. P., Lower, E. E., Bonella, F., Boyd, J., Hoover, E., James, W. E., Knoet, C., Martone, F., Obi, O. N., et al. (2025) · CHEST Journal · doi:10.1016/j.chest.2025.11.048 · Cited by 6 · see citing works
Delving Into the Interaction Between Exercise and Diabetes on Methylation of the FKBP5 Gene
Yang, T., Tsai, J., Hsu, H., Chen, Y., Liaw, Y.-C., Hsu, S. Y., Yang, H. J., & Liaw, Y. (2025) · Journal of Diabetes Research · doi:10.1155/jdr/1162708 · Cited by 3 · see citing works
Faraji, J., Schatz, N. A., King, S. E., Soltanpour, N., & Metz, G. A. S. (2025) · Current Zoology · doi:10.1093/eep/dvaf031 · Cited by 2 · see citing works
Kac, E., Qi, Q., & Ryznar, R. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1769422 · Cited by 1 · see citing works
“Similarly, maternal exposure to Canadian residential schools has been linked to higher cortisol, catecholamines, and in fl ammatory cytokine levels in offspring, including cases in which offspring were not raised by their biological parents (104, 105).”
Overweight and POMC methylation: epigenetic associations with adolescent depression
Ye, Y., Hu, J., Xiao, X.-Y., Ji, T., Wang, F. “., Jia, F., & Hou, C. (2025) · BMC Psychiatry · doi:10.1186/s12888-025-07162-y · Cited by 1 · see citing works
Coppens, G., Cramer, A. B. G., Vanhorebeek, I., Güiza, F., Wouters, P. J., Chaves, I., de Hoog, M., Dulfer, K., Joosten, K. F. M., den Berghe, G. V., et al. (2025) · Clinical Epigenetics · doi:10.1186/s13148-025-02027-3
Self-citationMiller, M. A., Brown, R. D., Krautkramer, C., Gogia, R., Fritz, H., Wylie, D., Kinney, K. L., & Champagne, F. A. (2026) · PLoS ONE · doi:10.1371/journal.pone.0346517
Factors associated with constipation in critically ill children: A retrospective study
Marino, L. V., Rothman, B., O’Connor, G., Sheppard, J., Kinoshita, M., Kidd, C., Latten, L., & Shine, A. M. (2026) · Nutrition in Clinical Practice · doi:10.1002/ncp.70155
- Authors
- Coppens, G., Vanhorebeek, I., Güiza, F., Derese, I., Wouters, P. J., Téblick, A., Dulfer, K., Joosten, K. F., Verbruggen, S. C., & Van den Berghe, G.
- Affiliations
- KU Leuven (BE)
- Erasmus MC - Sophia Children’s Hospital (NL)
- ORCID
- Venue
- Clinical Epigenetics
- Published
- 2024-02-23
- Volume
- 16
- Issue
- 1
- Pages
- 31-31
- ISSN
- 1868-7075 (ISSN-L)
- 1868-7083
- PMC
- PMC10893716
- OpenAlex
- W4392111446
- Cited by
- 15
- References
- 74
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 1
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Clinical Epigenetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- Lirias (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Methusalem program of the Flemish government (METH14/06)
- Sophia Research Foundation
- Stichting Agis Zorginnovatie
- European Society for Clinical Nutrition and Metabolism (Research grant)
- FP7 Ideas: European Research Council (AdvG-2012-321670)
- H2020 European Research Council (AdvG-2017-785809)
- Institute for Science and Technology, Flanders, Belgium (IWT/110685/TBM)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- DNA methylation, hypothalamic-pituitary-adrenal axis, critically ill children, intensive care unit, glucocorticoid therapy, FKBP5, AKR1D1, brain development, sex differences, age differences, CRHR1, proopiomelanocortin, melanocortin 2 receptor, NR3C1, SRD5A1, TSC22D3, TNF-α
- MeSH terms
- Child, DNA, Glucocorticoids, Humans, Receptors, Glucocorticoid, Critical Illness, DNA Methylation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
