RGD Reference Report - Two-stage genome-wide methylation profiling in childhood-onset Crohn's Disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci. - Rat Genome Database

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Two-stage genome-wide methylation profiling in childhood-onset Crohn's Disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci.

Authors: Adams, Alex T  Kennedy, Nicholas A  Hansen, Richard  Ventham, Nicholas T  OʼLeary, Kate R  Drummond, Hazel E  Noble, Colin L  El-Omar, Emad  Russell, Richard K  Wilson, David C  Nimmo, Elaine R  Hold, Georgina L  Satsangi, Jack 
Citation: Adams AT, etal., Inflamm Bowel Dis. 2014 Oct;20(10):1784-93. doi: 10.1097/MIB.0000000000000179.
RGD ID: 41404530
Pubmed: PMID:25144570   (View Abstract at PubMed)
PMCID: PMC4736293   (View Article at PubMed Central)
DOI: DOI:10.1097/MIB.0000000000000179   (Journal Full-text)


BACKGROUND: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease.
METHODS: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa.
RESULTS: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10(-7)), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10(-7)), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10(-15)) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10(-5), n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10(-6), n = 99).
CONCLUSIONS: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Crohn's disease  IEP 41404530RNA:increased expression:leukocyteRGD 
Crohn's disease  ISOMIR21 (Homo sapiens)41404530; 41404530RNA:increased expression:leukocyteRGD 

Objects Annotated

Genes (Rattus norvegicus)
Mir21  (microRNA 21)

Genes (Mus musculus)
Mir21a  (microRNA 21a)

Genes (Homo sapiens)
MIR21  (microRNA 21)


Additional Information