Two-stage Genome-wide Methylation Profiling in Childhood-onset Crohnʼs Disease Implicates Epigenetic Alterations at the VMP1/MIR21 and HLA Loci

Adams, Alexander T.; Kennedy, Nicholas A; Hansen, Richard; Ventham, NT; O'Leary, Kate; Drummond, Hazel E.; Noble, Colin; El-Omar, Emad; Russell, Richard K.; Wilson, David C.; Nimmo, Elaine R.; Hold, Georgina L.; Satsangi, Jack

doi:10.1097/mib.0000000000000179

Cited by 84 publications

(90 citation statements)

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“…Our previously published early-onset CD whole-blood methylation data provided an additional independent validation cohort (36 paediatric CD, 36 controls)16. There was a highly significant correlation between the difference in beta values for the top 5,000 DMPs between CD cases and controls in the present adult data set and the paediatric data set (Pearson's correlation=0.77, 95% confidence interval 0.76–0.78, P value <2.2 × 10 16 , Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The paired methylation probe biomarkers described in Adams et al 16. in paediatric CD and controls were prospectively validated in the present adult data set using linear discriminant analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The SEPT09 blood-based DNA methylation biomarker has been used in diagnosis and screening for colorectal cancer49. We have previously demonstrated two methylation probes can accurately differentiate CD and controls and have prospectively validated the same two probe markers using the present data set16. Here we have used lasso27, an established machine learning technique that can help avoid over-fitting in large data sets where the number of variables vastly exceed the number of samples.…”

Section: Discussionmentioning

confidence: 99%

“…A previously described16 reimplementation of the Lasso function from the CHaMP pipeline63 was used for this analysis (Please note that the Lasso function described here is distinct from the lasso function described below in the biomarker discovery section).…”

Section: Methodsmentioning

confidence: 99%

“…In our own study in treatment-naive children with CD, highly significant differences in DNA methylation were noted to occur in genes implicated in disease pathogenesis16. The findings were replicable in a modest number of samples and a two DNA methylation probe biomarker was found to accurately discriminate IBD cases and controls, indicating a strong translational potential16.…”

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confidence: 85%

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Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

Ventham¹,

Kennedy²,

Adams³

et al. 2016

Nat Commun

199

158

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Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 85%

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Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

Ventham¹,

Kennedy²,

Adams³

et al. 2016

Nat Commun

199

158

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MiRNAs and inflammatory bowel disease: An interesting new story

Moein

Vaghari‐Tabari

Qujeq

et al. 2018

Journal Cellular Physiology

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Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory disorder, is caused by a dysregulated and aberrant immune response to exposed environmental factors in genetically susceptible individuals. Despite huge efforts in determining the molecular pathogenesis of IBD, an increasing worldwide incidence of IBD has been reported. MicroRNAs (miRNAs) are a set of noncoding RNA molecules that are about 22 nucleotides long, and these molecules are involved in the regulation of the gene expression. By clarifying the important role of miRNAs in a number of diseases, their role was also considered in IBD; numerous studies have been performed on this topic.In this review, we attempt to summarize a number of studies and discuss some of the recent developments in the roles of miRNAs in the pathophysiology, diagnosis, and treatment of IBD.

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Genetic Epidemiology of Inflammatory Bowel Disease, Early Twin and Family Studies

Halfvarson¹

2019

Molecular Genetics of Inflammatory Bowel Disease

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Two-stage Genome-wide Methylation Profiling in Childhood-onset Crohnʼs Disease Implicates Epigenetic Alterations at the VMP1/MIR21 and HLA Loci

Abstract: Article first published online 20 August 2014.Supplemental Digital Content is Available in the Text.

Cited by 84 publications

References 71 publications

Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

MiRNAs and inflammatory bowel disease: An interesting new story

Genetic Epidemiology of Inflammatory Bowel Disease, Early Twin and Family Studies

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