The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease.

Nicholas M Croft, Chamara Jayamanne, Aisling Quinn, Komal Nayak, Jan Nowak, Alexandra Noble, R Mark Beattie, Richard Hansen, Jack Satsangi, Georgina L Hold, James J Ashton, Federica Giachero, Rahul Kalla, Matthias Zilbauer, Holm H Uhlig, Emad El-Omar, David Wilson, Sarah Ennis, Nicholas T Ventham, Guo Cheng, Mark Kristiansen, Alex Adams

Journal: Journal of Crohn's & colitis 2025;19(3):

PMID: 39365013

Abstract

BACKGROUND

The genetic contribution to inflammatory bowel disease (IBD), encompassing both Crohn's disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterize environmental and epigenetic influences. Recently, considerable progress has been made in characterizing the adult methylome in epigenome-wide association studies.

METHODS

We report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD and UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform.

RESULTS

We derived and validated a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI, and ARHGEF3), with specificity and high diagnostic accuracy for pediatric IBD in UK and North American cohorts (area under the curve: 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-methylation quantitative trait loci (meQTL) analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD, contrary to previous findings.

CONCLUSIONS

These data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.

© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.

Address: Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK.; Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK.; Biomedical Research Centre, University of Oxford, Oxford, UK.; Department of Paediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland.; Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.; Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.; UCL Genomics, Great Ormond Street Institute of Child Health, University College London, London, UK.; Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.; Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's Hospital, Cambridge, UK.; Department of Paediatrics, John Radcliffe Hospital, Oxford University Hospital NHS Trust, Oxford, UK.; Department of Child Health, Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK.; Microbiome Research Centre, St George and Sutherland Clinical Campuses, University of New South Wales, Sydney, New South Wales, Australia.; Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.; Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Children and Young People, Edinburgh, UK.; Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.; Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK.; Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.; Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK.; Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK.; Biomedical Research Centre, University of Oxford, Oxford, UK.; Department of Paediatrics, University of Oxford, Oxford, UK.
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