Analysis of systemic epigenetic alterations in inflammatory bowel disease: defining geographical, genetic, and immune-inflammatory influences on the circulating methylomeDepartment of Gastroenterology, Akershus University Hospital, Lørenskog, Norway.
Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom.
Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom; Exeter IBD and Pharmacogenetics group, University of Exeter, United Kingdom .
Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway; Medical Research Council Integrative Epidemiology Unit (MRC IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK .
Medical Research Council Integrative Epidemiology Unit (MRC IEU), School of Social and Health Services Research Unit, Akershus University Hospital, Lørenskog, Norway; Community Medicine, University of Bristol, Bristol, UK.
Department of Surgery and Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. (IBD-Character Consortium)
Maastricht University Medical Centre (MUMC), Department of Gastroenterology and Hepatology, Maastricht, Netherlands.
CIC bioGUNE - BRTA, Derio, Spain and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
HCU "Lozano Blesa," IIS Aragón, CIBEREHD, Zaragoza, Spain.
Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, Campus Ahus, University of Oslo, Oslo, Norway .
Medical Research Council Integrative Epidemiology Unit (MRC IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
Medical Research Council Integrative Epidemiology Unit (MRC IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, Campus Ahus, University of Oslo, Oslo, Norway .
Institute of Clinical Medicine, Campus Ahus, University of Oslo, Oslo, Norway .
Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom; Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom .
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2023 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 17, no 2, p. 170-184Article in journal (Refereed) Published
Abstract [en]
BACKGROUND: Epigenetic alterations may provide valuable insights into gene-environment interactions play in the pathogenesis of Inflammatory Bowel Disease (IBD).
METHODS: Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) with covariates of age, sex, and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission.
RESULTS: A total of 137 differentially methylated positions (DMP) were identified in IBD, including VMP1/MIR21 (p=9.11×10 -15) and RPS6KA2 (6.43×10 -13); with consistency seen across Scandinavia and UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10 -15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10 -16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10 -7 vs. non-IBD r -0.14, p=0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14-12.56, logrank p=9.70×10 -4).
CONCLUSION: These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.
Place, publisher, year, edition, pages
Oxford University Press, 2023. Vol. 17, no 2, p. 170-184
Keywords [en]
DNA methylation, epigenetic clock, gene expression, genetics, inflammatory bowel diseases (IBD), mendelian randomisation, methylation quantitative trait loci, prognosis
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:oru:diva-100872DOI: 10.1093/ecco-jcc/jjac127ISI: 000893054800001PubMedID: 36029471Scopus ID: 2-s2.0-85150666844OAI: oai:DiVA.org:oru-100872DiVA, id: diva2:1690968
Funder
European Commission, 2858546Wellcome trust, WT097943MA2022-08-292022-08-292025-02-11Bibliographically approved