TOPLINE

Disease-specific DNA methylation signatures in whole blood were detected in adults years before the diagnosis of ulcerative colitis, independent of blood cell composition. A predictive model built from these early methylation changes identified future ulcerative colitis with encouraging performance, while failing to predict irritable bowel syndrome or rheumatoid arthritis.

METHODOLOGY

• Although whole-blood DNA methylation signatures have been consistently linked to diagnosis and treatment response in inflammatory bowel disease (IBD), whether these epigenetic changes arise before clinical onset remains unclear.
• Using data from a nationwide prospective cohort study, researchers analyzed whole-blood DNA methylation signatures before the clinical onset of IBD. They identified 44 individuals who developed incident Crohn's disease (median age at diagnosis, 54.1 years; 52.2% women) and 62 who developed incident ulcerative colitis (median age at diagnosis, 54.1 years; 64.5% women) during follow-up; control individuals without any gastrointestinal illness served as comparators.
• Whole-blood DNA methylation was assessed at study entry, with median intervals between baseline sampling and diagnosis of 4 years for Crohn's disease and 8 years for ulcerative colitis.
• An epigenome-wide association study (EWAS) was performed to examine whole-blood DNA methylation changes present before IBD diagnosis.
• To determine whether DNA methylation signatures could distinguish individuals who would later develop ulcerative colitis, a prediction model was built using data from 70% of individuals and its performance then tested in the remaining 30%.

TAKEAWAY

• EWAS identified three significant DNA methylation changes present years before IBD diagnosis, one of them at a gene controlling production of TNF-alpha, a key inflammatory signal in IBD.
• When ulcerative colitis was evaluated separately, EWAS identified 16 DNA methylation changes present years before diagnosis. These changes showed no tendency to become more pronounced closer to diagnosis. Notably, the strongest signal was located in a genomic region previously linked to Crohn's disease susceptibility.
• A diagnostic model for preclinical ulcerative colitis predicted future ulcerative colitis with an area under the curve (AUC) of 0.85 and failed to identify preclinical irritable bowel syndrome (AUC, 0.39) or rheumatoid arthritis (AUC, 0.45), supporting the disease-specific nature of these early DNA methylation changes.
• Although no individual DNA methylation changes reached statistical significance in the Crohn's disease analysis overall, one specific change previously identified in other studies was also seen in this study, with alterations detectable up to a median of 4 years before diagnosis.

IN PRACTICE

"We anticipate that these findings, together with further studies in other cohorts, will shift the temporal framework of epigenetic involvement in both UC [ulcerative colitis] and CD [Crohn's disease] from established disease to the pre-clinical phase and provide a foundation for future disease interception approaches to prevention," the authors wrote.

SOURCE

The study was led by Alexandra Noble, University of Oxford, Oxford, England. It was published online as a research letter in Gastroenterology.

LIMITATIONS

The relatively small number of individuals who later developed Crohn's disease may have limited the ability to detect significant preclinical DNA methylation changes related to the condition.

DISCLOSURES

The nationwide prospective cohort study received core support from the Chief Scientist Office of the Scottish Government Health Directorates and the Scottish Funding Council and is currently supported by the Wellcome Trust. One author was supported by a Girdlers' Health Research Council of New Zealand Fellowship. The authors declared having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.