Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome

J Crohns Colitis. 2023 Mar 18;17(2):170-184. doi: 10.1093/ecco-jcc/jjac127.

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.

Keywords: DNA methylation; Mendelian randomization; epigenetic clock; gene expression; genetics; inflammatory bowel diseases [IBD]; methylation; prognosis; quantitative trait loci.

MeSH terms

  • Biological Factors
  • Case-Control Studies
  • Colitis, Ulcerative* / diagnosis
  • Colitis, Ulcerative* / genetics
  • Epigenesis, Genetic
  • Epigenome
  • Humans
  • Inflammatory Bowel Diseases* / genetics
  • Membrane Proteins / genetics

Substances

  • Biological Factors
  • VMP1 protein, human
  • Membrane Proteins