The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease.
Noble A., Adams A., Nowak J., Cheng G., Nayak K., Quinn A., Kristiansen M., Kalla R., Ventham NT., Giachero F., Jayamanne C., Hansen R., Hold GL., El-Omar E., Croft NM., Wilson D., Beattie RM., Ashton JJ., Zilbauer M., Ennis S., Uhlig HH., Satsangi J.
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.