P061 Epigenetic alterations at diagnosis predict susceptibility, prognosis and treatment escalation in inflammatory bowel disease – IBD Character

Abstract

Introduction: Biomarker discovery to predict disease outcomes is a key focus in Inflammatory Bowel Disease (IBD). We have characterized disease-associated methylation changes in newly diagnosed IBD, defined the relationship to genetic variation (meQTL) and assessed its prognostic utility in IBD. Methods: Genome-wide methylation and genotyping were performed in 641 peripheral blood DNA samples from new IBD cases across Europe (298 controls, 150 CD, 167 UC, 26 IBDU) using the Illumina 450k and HumanOmniExpressExome-8 BeadChips, respectively. Covariates included age, sex and cell counts, deconvoluted by the Houseman method. Treatment escalation in IBD was defined as the need for surgery and/or biologic therapies after initial induction of disease remission. Results: Totally, 1261 probes exhibited Holm significant IBDassociated methylation differences, including MIR21 (P=2.8×1020), RPS6KA2 (5.5×1026) and PHOSPHO1 (8.3×1015) and were consistent within the European cohort. Paired genetic and methylation data showed 4517 significant meQTLs on several key loci: RPS6KA2 (holm P=1.4×1020), ITGB2 (P=3.3×1038) and MIR21 (P=3.5×1019). Follow-up data were available for 296 patients with IBD and 68 patients required treatment escalation. Forty DMPs predicted treatment escalation (top probe holm P=7.49×106). Unsupervised linear discriminant consensus clustering were performed using three top probes, identifying two patient subgroups with significantly different disease courses (HR 6.95, 95% CI: 2.6-18.3; P=2.5×1018), outperforming conventional biomarkers such as Albumin (HR 2.6 (1.4-4.9); P=0.0001). Conclusion: These data show novel associations and important unequivocal replication of recent discoveries and provide insight into germline variation of epigenetic mechanisms in IBD. As biomarkers, themethylome shows promise in predicting disease course in IBD.