Abstract Background Consistent DNA methylation signatures in whole blood have been identified at diagnosis and in relation to treatment response in inflammatory bowel disease (IBD)(1-3), highlighting both the potential use of epigenetic biomarkers in clinical practice, and the relevance to disease pathogenesis. A critical issue is whether these epigenetic alterations precede clinical onset and may be used in disease prediction. We report the first analysis of DNA methylation signatures before disease development in Northern Europe, in the Generation Scotland nationwide prospective cohort. Methods Between 2006 and 2011 over 24,000 participants (18-98 years) were recruited into the Generation Scotland cohort and followed prospectively. Incident CD and UC cases were identified through linkage to primary care and hospital records based on SCIMP and ICD codes, J40 and K50 for CD, J41 and K51 for UC, J521 and K58 for irritable bowel syndrome (IBS) and N040 and M05 for rheumatoid arthritis (RA). In primary analysis, each case was matched with a healthy control based on sex and age (± 5 years). Individuals who later developed IBS or RA also served as disease controls in predictive modelling. Genome-wide DNA methylation profiles and genotyping data were available for all participants. Results We identified 44, 62, 252 and 108 incident CD, UC, IBS and RA cases with confirmed diagnoses during the follow-up, with a median interval of 4, 8,4 and 5 years between baseline sampling and diagnosis. In addition, 79, 93, 448, and 84 prevalent CD, UC, IBS and RA cases were identified. Baseline, blood-derived DNA methylation analysis in preclinical UC showed 16 CpG sites of genome-wide significance. These mapped to genes RBM47, RAC2, LINC01358, LPAR5, CEP72, TRAF3 and ITPR2. Elastic net regression analysis (70%/30% train/test) identified an expanded set of 769 CpG sites with accuracy in predicting subsequent diagnosis of UC (Testing AUC 0.83) and specificity compared with IBS (AUC 0.50) or RA (AUC 0.52). In CD, no markers achieved genome-wide significance; however, RPS6KA2 implicated in inception cohorts showed altered methylation before diagnosis (p = 0.008865), with dysregulation significant across the cohort with median time of 4 years before diagnosis. Conclusion Accurate and specific DNA methylation profiles are detectable in the circulation several years prior to the clinical onset of IBD. Specific alterations reported at diagnosis in CD are seen in pre-clinical disease. The UC-specific methylation signature has strong predictive potential and may allow strategies for risk stratification, early detection and targeted monitoring/prevention strategies as now underway in CD (4). Further validation in external cohorts is warranted to assess clinical applicability. References: 1.Noble A, Adams A, Nowak J, Cheng G, Nayak K, Quinn A, et al. The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease. Journal of Crohn’s and Colitis. 2024. 2.Ventham NT, Kennedy NA, Adams AT, Kalla R, Heath S, O’Leary KR, et al. Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease. Nature Communications. 2016;7(1):13507. 3.Joustra VW, Li Yim AYF, Henneman P, Hageman I, de Waard T, Levin E, et al. Development and validation of peripheral blood DNA methylation signatures to predict response to biological therapy in adults with Crohn’s disease (EPIC-CD): an epigenome-wide association study. The Lancet Gastroenterology 10(9):818-30. 4.Consortium TI. Intercept – Innovative Medicines Initiative – IBD biomarker project cited 2025 17 November. Conflict of interest: Noble, Alexandra: Grants from Girdlers’ New Zealand Health Research Council Fellowship (24/389). Li, Xue: No conflicts of interest Scotland, Generation: No conflict of interest Theodoratou, Evropi: No conflict of interest Satsangi, Jack: Grant: Grants to Oxford University from Helmsley Trust & European Community.
Noble et al. (Thu,) studied this question.