Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome.
DNA methylation
Mendelian randomization
epigenetic clock
gene expression
genetics
inflammatory bowel diseases [IBD]
methylation
prognosis
quantitative trait loci
Journal
Journal of Crohn's & colitis
ISSN: 1876-4479
Titre abrégé: J Crohns Colitis
Pays: England
ID NLM: 101318676
Informations de publication
Date de publication:
18 Mar 2023
18 Mar 2023
Historique:
pubmed:
28
8
2022
medline:
22
3
2023
entrez:
27
8
2022
Statut:
ppublish
Résumé
Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. 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. 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). 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.
Sections du résumé
BACKGROUND
BACKGROUND
Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD].
METHODS
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 36029471
pii: 6677995
doi: 10.1093/ecco-jcc/jjac127
pmc: PMC10024547
doi:
Substances chimiques
Biological Factors
0
VMP1 protein, human
0
Membrane Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
170-184Subventions
Organisme : European Commission FP7
ID : 2858546
Organisme : Wellcome Trust
ID : WT097943MA
Pays : United Kingdom
Investigateurs
Erik Andersson
(E)
Ian D Arnott
(ID)
Monica Bayes
(M)
Ferdinando Bonfiglio
(F)
Ray K Boyapati
(RK)
Adam Carstens
(A)
Christina Casén
(C)
Ewa Ciemniejewska
(E)
Mauro D'Amato
(M)
Fredrik A Dahl
(FA)
Trond Espen Detlie
(T)
Hazel E Drummond
(HE)
Gunn S Ekeland
(GS)
Daniel Ekman
(D)
Anna B Frengen
(AB)
Mats Gullberg
(M)
Ivo G Gut
(IG)
Marta Gut
(M)
Simon C Heath
(SC)
Fredrik Hjelm
(F)
Henrik Hjortswang
(H)
Gwo-Tzer Ho
(GT)
Daisy Jonkers
(D)
Nicholas A Kennedy
(NA)
Charles W Lees
(CW)
Torbjørn Lindahl
(T)
Mårten Lindqvist
(M)
Angelika Merkel
(A)
Eddie Modig
(E)
Aina E F Moen
(AEF)
Hilde Nilsen
(H)
Elaine R Nimmo
(ER)
Colin L Noble
(CL)
Niklas Nordberg
(N)
Kate R O'Leary
(KR)
Anette Ocklind
(A)
Christine Olbjørn
(C)
Erik Pettersson
(E)
Marieke Pierik
(M)
Dominique Poncelet
(D)
Dirk Repsilber
(D)
Céline Sabatel
(C)
Renaud Schoemans
(R)
Alan G Shand
(AG)
Johan D Söderholm
(JD)
Janne Sølvernes
(J)
Mikael Sundell
(M)
Tone M Tannæs
(TM)
Leif Törkvist
(L)
Anne-Clémence Veillard
(AC)
Nicholas T Ventham
(NT)
David C Wilson
(DC)
Panpan You
(P)
Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.
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