15 LONGITUDINAL EVALUATION OF MUCOSAL DNA METHYLATION IN ULCERATIVE COLITIS SHOWS DISEASE-SPECIFIC CHANGES

Abstract

Abstract Background Although inflammatory bowel disease (IBD) is heritable, the heritability is still largely unexplained despite substantial progress through GWAS and WGS. However, recent advances in epigenetics (gene environmental interactions), including DNA methylation (DNAm) analysis, has identified new disease-specific mechanisms controlling gene expression. We recently showed that IBD-associated blood DNAm patterns strongly correlated with inflammation (CRP as surrogate marker) and reverted to patterns seen in healthy controls following treatment, regardless of whether or not the underlying IBD was in remission, suggesting blood DNAm is more representative of the systemic inflammatory status rather than disease status (Gastroenterology, 2019, 156 (8): 2254–2265). Thus, we aimed to study DNAm patterns in rectal biopsies hypothesizing that DNAm in rectal biopsies will reflect disease status rather than systemic inflammatory status alone. Method Genome-wide DNA methylation was measured using the Illumina MethylationEPIC array on rectal biopsy DNA samples of 85 non-inflammatory, non-IBD controls and 215 newly diagnosed ulcerative colitis (UC) patients prior to therapy, along with 49 one-year follow-up UC cases (PROTECT cohort) to identify disease specific methylation patterns. Epigenome wide association studies (EWAS) were performed with UC and CRP as the outcomes in linear models adjusted for age, gender, race and five genotype-based principal components. Results At diagnosis, 2446 disease-specific CpG sites in rectal tissue (FDR<0.05) were identified. At baseline, the disease-associated DNAm signature in rectal tissue is distinct from our previous study from blood as only 15 CpGs were common between rectal tissue DNAm and blood DNAm. In contrast to what was observed in blood DNAm where the initial DNAm signature reverted back to control levels upon treatment, rectal tissue DNAm signatures remained persistent during follow-up (Figure 1). The majority of the disease-specific CpG sites identified in rectal biopsies showed a strong positive correlation with CRP. This evidence suggests that the treatment affects systemic measures of inflammation more strongly than disease tissues. Conclusion When studied longitudinally, the UC-specific DNA methylation patterns in rectal tissue are distinct from blood samples. In contrast to blood DNAm which normalizes after therapy during follow-up, rectal tissue DNAm changes persist after treatment in UC. This suggests the currently available therapies control the systemic inflammation effectively, but have less direct effect on the disease itself. Future therapies targeting disease-specific DNAm may be more effective in disease management and long-term remission.