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Oral
IBD
OMO-1 Epigenetic alterations in IBD: defining geographical, genetic, and immune-inflammatory influences on the circulating methylome
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  1. Rahul Kalla1,
  2. Alex Adams2,
  3. Jan Nowak3,
  4. Daniel Bergemalm4,
  5. Simen Vatn5,
  6. Nicholas Ventham1,
  7. Nicholas Kennedy6,
  8. Petr Ricanek5,
  9. Jonas Lindstrom5,
  10. Marieke Pierik7,
  11. Mauro D’Amato8,13,
  12. Fernando Gomollon9,
  13. Christine Olbjorn5,
  14. Rebecca Richmond10,
  15. Caroline Relton10,
  16. Johan Soderholm11,
  17. Jorgen Jahnsen5,12,
  18. Morten Vatn5,
  19. Jonas Halfvarson4,
  20. Jack Satsangi2
  1. 1University Of Edinburgh, Edinburgh, UK
  2. 2University of Oxford, Oxford, UK
  3. 3Poznan University of Medical Sciences, Poznan, Poland
  4. 4Orebro University, Orebro, Sweden
  5. 5University of Oslo, Oslo, Norway
  6. 6University of Exeter, Exeter, UK
  7. 7Maastricht University Medical Centre, Maastricht, Netherlands
  8. 8BioCruces Health Research Institute and IKERBASQUE, Bilbao, Spain
  9. 9HCU ‘Lozano Blesa,’ IIS Aragón, Zaragosa, Spain
  10. 10University of Bristol, Bristol, UK
  11. 11University of Linkoping, Linkoping, Sweden
  12. 12Akershus University Hospital, Akershus, Norway
  13. 13Monash University, Melbourne, Australia

Abstract

Introduction DNA methylation may provide critical insights into gene-environment interactions in inflammatory bowel disease (IBD).

Methods Using the multi-centre IBD Character inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U), epigenome-wide methylation was profiled using Illumina HumanMethylation450 platform. Differentially methylated position analysis was performed using age, sex and cell proportions as covariates. Integration of paired genomic and transcriptomic layers was done with Multi-Omics Factor Analysis v2 (MOFA). Unsupervised principal component analyses were performed to examine correlates of treatment escalation and clinical predictors of disease severity.

Results We report 137 differentially methylated positions (DMP) in whole blood in IBD, including VMP1/MIR21 (p=9.11×10-15) and RPS6KA2 (6.43×10-13); with consistency seen across Scandinavia and UK. Cell of origin analysis preferentially implicated the monocyte lineage. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10-15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10-16). 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 methylome, genome and transcriptome also identified specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) 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 This study highlights the stability of the IBD-specific circulating methylome across regions with shared ancestry. Through integrative multi-omic analyses we identify key pro-inflammatory genes that are upregulated in IBD at inception. Furthermore, differential methylation within certain genes such as TAP1 associate with disease course over time.

https://doi.org/10.1136/gutjnl-2021-BSG.8

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