Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome
Authors: Kalla Rahul , Adams Alex T , Nowak Jan K , Bergemalm Daniel , Vatn Simen , Ventham Nicholas T , Kennedy Nicholas A , Ricanek Petr , Lindstrom Jonas ,   IBD-Character Consortium, 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 Johan , Pierik Marie , D’Amato Mauro , Gomollón Fernando , Olbjørn Christine , Richmond Rebecca , Relton Caroline , Jahnsen Jørgen , Vatn Morten H , Halfvarson Jonas , Satsangi Jack 
Published: August 2022

AbstractBackgroundEpigenetic alterations may provide valuable insights into gene–environment interactions in the pathogenesis of inflammatory bowel disease [IBD].MethodsGenome-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.ResultsA 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 &lt; 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).ConclusionThese 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.