The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease

Alexandra Noble; Richard Hansen; Alex  Adams; Jan  Nowak; Guo  Cheng; Komal  Nayak; Aisling  Quinn; Mark  Kristiansen; Rahul Kalla; Nicholas T.  Ventham; Federica  Giachero; Chamara  Jayamanne; Georgina Louise Hold; Emad M. El-Omar; Nicholas M. Croft; David Wilson; R Mark Beattie; James J Ashton; Matthias Zilbauer; Sarah Ennis; Holm Uhlig; Jack J. Satsangi

doi:10.1093/ecco-jcc/jjae157

The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease

Alexandra Noble (Lead / Corresponding author), Richard Hansen, Alex Adams, Jan Nowak, Guo Cheng, Komal Nayak, Aisling Quinn, Mark Kristiansen, Rahul Kalla, Nicholas T. Ventham, Federica Giachero, Chamara Jayamanne, Georgina Louise Hold, Emad M. El-Omar, Nicholas M. Croft, David Wilson, R Mark Beattie, James J Ashton, Matthias Zilbauer, Sarah EnnisHolm Uhlig, Jack J. Satsangi (Lead / Corresponding author)

Respiratory Medicine and Gastroenterology

Research output: Contribution to journal › Article › peer-review

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Abstract

Background
The genetic contribution to inflammatory bowel disease (IBD), encompassing both Crohn’s disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterize environmental and epigenetic influences. Recently, considerable progress has been made in characterizing the adult methylome in epigenome-wide association studies.

Methods
We report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD and UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform.

Results
We derived and validated a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI, and ARHGEF3), with specificity and high diagnostic accuracy for pediatric IBD in UK and North American cohorts (area under the curve: 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-methylation quantitative trait loci (meQTL) analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD, contrary to previous findings.

Conclusions
These data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.

Original language	English
Article number	jjae157
Number of pages	13
Journal	Journal of Crohn's and Colitis
Early online date	4 Oct 2024
DOIs	https://doi.org/10.1093/ecco-jcc/jjae157
Publication status	E-pub ahead of print - 4 Oct 2024

Keywords

DNA methylation
IBD
diagnostics
paediatrics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/ecco-jcc/jjae157Licence: CC BY

Final Published VersionFinal published version, 1.3 MBLicence: CC BY

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Noble, A., Hansen, R., Adams, A., Nowak, J., Cheng, G., Nayak, K., Quinn, A., Kristiansen, M., Kalla, R., Ventham, N. T., Giachero, F., Jayamanne, C., Hold, G. L., El-Omar, E. M., Croft, N. M., Wilson, D., Beattie, R. M., Ashton, J. J., Zilbauer, M., ... Satsangi, J. J. (2024). The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease. Journal of Crohn's and Colitis, Article jjae157. Advance online publication. https://doi.org/10.1093/ecco-jcc/jjae157

@article{5b2753b331ef42dbbf3c76497152e3ed,

title = "The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease",

abstract = "BackgroundThe genetic contribution to inflammatory bowel disease (IBD), encompassing both Crohn{\textquoteright}s disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterize environmental and epigenetic influences. Recently, considerable progress has been made in characterizing the adult methylome in epigenome-wide association studies.MethodsWe report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD and UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform.ResultsWe derived and validated a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI, and ARHGEF3), with specificity and high diagnostic accuracy for pediatric IBD in UK and North American cohorts (area under the curve: 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-methylation quantitative trait loci (meQTL) analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD, contrary to previous findings.ConclusionsThese data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.",

keywords = "DNA methylation, IBD, diagnostics, paediatrics",

author = "Alexandra Noble and Richard Hansen and Alex Adams and Jan Nowak and Guo Cheng and Komal Nayak and Aisling Quinn and Mark Kristiansen and Rahul Kalla and Ventham, {Nicholas T.} and Federica Giachero and Chamara Jayamanne and Hold, {Georgina Louise} and El-Omar, {Emad M.} and Croft, {Nicholas M.} and David Wilson and Beattie, {R Mark} and Ashton, {James J} and Matthias Zilbauer and Sarah Ennis and Holm Uhlig and Satsangi, {Jack J.}",

note = "{\textcopyright} The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn{\textquoteright}s and Colitis Organisation.",

year = "2024",

month = oct,

day = "4",

doi = "10.1093/ecco-jcc/jjae157",

language = "English",

journal = "Journal of Crohn's and Colitis",

issn = "1873-9946",

publisher = "Oxford University Press",

}

Noble, A, Hansen, R, Adams, A, Nowak, J, Cheng, G, Nayak, K, Quinn, A, Kristiansen, M, Kalla, R, Ventham, NT, Giachero, F, Jayamanne, C, Hold, GL, El-Omar, EM, Croft, NM, Wilson, D, Beattie, RM, Ashton, JJ, Zilbauer, M, Ennis, S, Uhlig, H & Satsangi, JJ 2024, 'The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease', Journal of Crohn's and Colitis. https://doi.org/10.1093/ecco-jcc/jjae157

TY - JOUR

T1 - The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease

AU - Noble, Alexandra

AU - Hansen, Richard

AU - Adams, Alex

AU - Nowak, Jan

AU - Cheng, Guo

AU - Nayak, Komal

AU - Quinn, Aisling

AU - Kristiansen, Mark

AU - Kalla, Rahul

AU - Ventham, Nicholas T.

AU - Giachero, Federica

AU - Jayamanne, Chamara

AU - Hold, Georgina Louise

AU - El-Omar, Emad M.

AU - Croft, Nicholas M.

AU - Wilson, David

AU - Beattie, R Mark

AU - Ashton, James J

AU - Zilbauer, Matthias

AU - Ennis, Sarah

AU - Uhlig, Holm

AU - Satsangi, Jack J.

PY - 2024/10/4

Y1 - 2024/10/4

N2 - BackgroundThe genetic contribution to inflammatory bowel disease (IBD), encompassing both Crohn’s disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterize environmental and epigenetic influences. Recently, considerable progress has been made in characterizing the adult methylome in epigenome-wide association studies.MethodsWe report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD and UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform.ResultsWe derived and validated a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI, and ARHGEF3), with specificity and high diagnostic accuracy for pediatric IBD in UK and North American cohorts (area under the curve: 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-methylation quantitative trait loci (meQTL) analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD, contrary to previous findings.ConclusionsThese data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.

AB - BackgroundThe genetic contribution to inflammatory bowel disease (IBD), encompassing both Crohn’s disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterize environmental and epigenetic influences. Recently, considerable progress has been made in characterizing the adult methylome in epigenome-wide association studies.MethodsWe report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD and UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform.ResultsWe derived and validated a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI, and ARHGEF3), with specificity and high diagnostic accuracy for pediatric IBD in UK and North American cohorts (area under the curve: 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-methylation quantitative trait loci (meQTL) analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD, contrary to previous findings.ConclusionsThese data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.

KW - DNA methylation

KW - IBD

KW - diagnostics

KW - paediatrics

U2 - 10.1093/ecco-jcc/jjae157

DO - 10.1093/ecco-jcc/jjae157

M3 - Article

SN - 1873-9946

JO - Journal of Crohn's and Colitis

JF - Journal of Crohn's and Colitis

M1 - jjae157

ER -

The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease

Abstract

Keywords

UN SDGs

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