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

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 &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).

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.