Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome
Author:
Kalla Rahul12ORCID, Adams Alex T13, Nowak Jan K4, Bergemalm Daniel5, Vatn Simen6, Ventham Nicholas T1, Kennedy Nicholas A17, Ricanek Petr68, Lindstrom Jonas98, Andersson Erik, Arnott Ian D, Bayes Monica, Bonfiglio Ferdinando, Boyapati Ray K, Carstens Adam, Casén Christina, Ciemniejewska Ewa, D’Amato Mauro, Dahl Fredrik A, Espen Detlie Trond, Drummond Hazel E, Ekeland Gunn S, Ekman Daniel, Frengen Anna B, Gullberg Mats, Gut Ivo G, Gut Marta, Heath Simon C, Hjelm Fredrik, Hjortswang Henrik, Ho Gwo-Tzer, Jonkers Daisy, Kennedy Nicholas A, Lees Charles W, Lindahl Torbjørn, Lindqvist Mårten, Merkel Angelika, Modig Eddie, Moen Aina E F, Nilsen Hilde, Nimmo Elaine R, Noble Colin L, Nordberg Niklas, O’Leary Kate R, Ocklind Anette, Olbjørn Christine, Pettersson Erik, Pierik Marieke, Poncelet Dominique, Repsilber Dirk, Sabatel Céline, Schoemans Renaud, Shand Alan G, Söderholm Johan D, Sølvernes Janne, Sundell Mikael, Tannæs Tone M, Törkvist Leif, Veillard Anne-Clémence, Ventham Nicholas T, Wilson David C, You Panpan, Söderholm Johan10, Pierik Marie11ORCID, D’Amato Mauro1213, Gomollón Fernando14ORCID, Olbjørn Christine68, Richmond Rebecca15ORCID, Relton Caroline15, Jahnsen Jørgen68, Vatn Morten H8, Halfvarson Jonas5ORCID, Satsangi Jack13,
Affiliation:
1. Institute of Genetics and Molecular Medicine, University of Edinburgh , Edinburgh , UK 2. MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh , Edinburgh , UK 3. Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital , Oxford , UK 4. Department of Paediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences , Poznan , Poland 5. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University , Örebro , Sweden 6. Department of Gastroenterology, Akershus University Hospital , Lørenskog , Norway 7. Exeter IBD and Pharmacogenetics group, University of Exeter , Exeter , UK 8. Institute of Clinical Medicine, Campus Ahus, University of Oslo , Oslo , Norway 9. Health Services Research Unit, Akershus University Hospital , Lørenskog , Norway 10. Department of Surgery and Clinical and Experimental Medicine, Linköping University , Linköping , Sweden 11. Maastricht University Medical Centre (MUMC), Department of Gastroenterology and Hepatology , Maastricht , Netherlands 12. CIC bioGUNE – BRTA , Derio , Spain , Bilbao , Spain 13. IKERBASQUE, Basque Foundation for Science , Derio , Spain , Bilbao , Spain 14. HCU ‘Lozano Blesa’, IIS Aragón, CIBEREHD , Zaragoza , Spain 15. Medical Research Council Integrative Epidemiology Unit (MRC IEU), School of Social and Community Medicine, University of Bristol , Bristol , UK
Abstract
Abstract
Background
Epigenetic alterations may provide valuable insights into gene–environment interactions 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 Crohn’s disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [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 the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission.
Results
A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 × 10−15] and RPS6KA2 [6.43 × 10−13], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 × 10−15]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 × 10−16]. 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 the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were 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.
Funder
European Commission FP7 Wellcome Trust
Publisher
Oxford University Press (OUP)
Subject
Gastroenterology,General Medicine
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