The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease.

BACKGROUND: The genetic contribution to inflammatory bowel disease (IBD), encompassing both Crohn's disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterize environmental and epigenetic influences. Recently, considerable progress has been made in characterizing the adult methylome in epigenome-wide association studies. METHODS: We report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD and UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform. RESULTS: We derived and validated a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI, and ARHGEF3), with specificity and high diagnostic accuracy for pediatric IBD in UK and North American cohorts (area under the curve: 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-methylation quantitative trait loci (meQTL) analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD, contrary to previous findings. CONCLUSIONS: These data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.