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; +11 more... Söderholm, Johan; Pierik, Marie; D'Amato, Mauro; Gomollón, Fernando; Olbjørn, Christine; Richmond, Rebecca; Relton, Caroline; Jahnsen, Jørgen; Vatn, Morten H; Halfvarson, Jonas; Satsangi, Jack; (2023) Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome. Journal of Crohn's & colitis, 17 (2). pp. 170-184. ISSN 1873-9946 DOI: https://doi.org/10.1093/ecco-jcc/jjac127
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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.
Item Type | Article |
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Faculty and Department | Academic Services & Administration > Directorate |
PubMed ID | 36029471 |
Elements ID | 202255 |
Official URL | http://dx.doi.org/10.1093/ecco-jcc/jjac127 |
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