Abstract
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.
Highlights
Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD)
There was a significant overlap between differentially methylated positions (DMPs) seen in IBD, CD and UC compared with controls (Supplementary Fig. 2)
This study has demonstrated site-specific methylation changes in IBD compared with controls that were strongly significant following stringent correction for multiple testing
Summary
Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). 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. Inflammatory bowel disease (IBD) has a strong genetic contribution; a trans-ancestry meta-analysis of genome-wide associated studies (GWAS) has demonstrated 200 loci associated with IBD1. We use the Illumina 450 K platform to identify differentially methylated positions (DMPs) and regions (DMRs) in whole-blood DNA samples from 240 newly diagnosed IBD cases (121 CD and 119 UC) and 191 controls. In a subset of patients with separated cell data (n 1⁄4 68), we perform gene expression analysis using the Illumina HT12 microarray
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