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Title: Epigenetics of paediatric Crohn's disease
Author: Adams, Alexander Thomas
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2017
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Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a complex disease with multiple aetiological factors including genetics, environmental exposures and microbiota. Epigenetic alterations such as DNA methylation, histone modification, and microRNA activity may indicate or facilitate the interactions between genetic and non-genetic processes. This thesis describes a study of genome-wide changes in DNA methylation between children with Crohn’s disease and symptomatic controls performed with the Illumina HumanMethylation450 platform. At the time of publication [4] this work was the largest epigenome-wide study of IBD, and described 65 individual CpGs (Bonferroni corrected) and 19 differentially methylated regions where there were significant CD-associated methylation changes. A highly significant (p=1.97×10−15) hypomethylated differentially methylated region (DMR) in the penultimate exon of the critical autophagy gene VMP1, appearing to correspond to the microRNA mir21, has been replicated in 3 adult cohorts by pyrosequencing, and found in 2 subsequent Illumina 450k adult epigenome-wide studies. Hypomethylation of a highly significant CpG (p=4.47×10−15) in RPS6KA2 has also been replicated in 3 adult cohorts by pyrosequencing and 2 adult cohorts with the Illumina 450k platform. In line with our previously published work [458] methylation findings were demonstrated to be enriched in proximity to genetic risk loci, with an improved analytical technique correcting for Illumina 450k probe density and hidden confounding factors. Section 3.3.7 demonstrates enrichment of a DNA motif matching the binding sites for the IBD-associated transcription factors GLI1 and RUNX3 at significant methylation changes. Examining methylation at any combination of two significant CD-associated differentially methylated positions could distinguish between children with CD and paediatric symptomatic controls requiring colonoscopy to rule out IBD. These two probe biomarkers were tested in a separate paediatric cohort with AUCs of 0.79–0.98 (median 0.93) These data confirm the existence of significant DNA methylation differences between children with Crohn’s disease and symptomatic controls, offering potential insight into established genetic risk loci, and novel risk genes and processes. Characterisation of the observed DNA methylation changes and power calculations based on experimental results rather than simulated ones, will be of use to anyone planning a similar study in a complex disease in a heterogenous cellular population.
Supervisor: Satsangi, Jack ; Nimmo, Elaine Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: inflammatory bowel disease ; Crohn’s Disease ; ulcerative colitis ; epigenetic ; DNA methylation ; bisulfite conversion