10 EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIED SHARED METHYLOMIC CONTRIBUTIONS TO SUSCEPTIBILITY AND PROGRESSION IN PEDIATRIC CROHN'S DISEASE

Abstract

Most Crohn’s Disease (CD) patients present with an inflammatory phenotype (B1), however, a subgroup rapidly progress to complicated disease behaviours such as stricturing (B2). Recent evidence suggests the involvement of gene-environmental interactions in CD. Epigenetic processes play a key role in mediating environmental influences. Therefore, we set out to examine the role of DNA methylation as a contributor to CD susceptibility and progression. We utilized a subset of pediatric subjects recruited under the RISK study. We generated genome-wide DNA methylation data using the Illumina HumanMethylationEPIC 850K array in whole blood DNA samples of 74 controls and 164 newly diagnosed CD cases (B1), of which 54 progressed to B2 at a later time point within 36 months from the day of diagnosis. β-values for each CpG site were modeled as a linear function of disease status with age, gender, and cell-type proportions as covariates. 1,043 CpGs exhibited significant association with CD susceptibility (FDR<0.05). Of these, 849 CpGs were hypermethylated and 194 were hypomethylated in cases compared to controls. CpGs in a long non-coding RNA, LOC100996291, showed the strongest association with CD. The 1,043 CpGs mapped to 627 unique genes, which were enriched for immune function-related TNF-alpha, Jak-STAT, Rap1 and PI3K-Akt signaling pathways. 142 of the 1,043 CD-susceptibility CpGs also exhibited association with disease progression (B1 vs B2), suggesting common epigenetic processes underlying both susceptibility and progression of CD. Using genetic association and the concept of Mendelian randomization, we identified CpGs that are potentially causal to CD rather than the consequence of the disease. Our findings suggest that dysregulated DNA methylation is associated with CD susceptibility and progression, and it may offer new pathophysiological insights and therapeutic targets to prevent the onset of CD and delay its progression.