Noble Alexandra, Adams Alex, Nowak Jan, Cheng Guo, Nayak Komal, Quinn Aisling, Kristiansen Mark, Kalla Rahul, Ventham Nicholas T, Giachero Federica, Jayamanne Chamara, Hansen Richard, Hold Georgina L, El-Omar Emad, Croft Nicholas M, Wilson David, Beattie R Mark, Ashton James J, Zilbauer Matthias, Ennis Sarah, Uhlig Holm H, Satsangi Jack
Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK.
Biomedical Research Centre, University of Oxford, Oxford, UK.
J Crohns Colitis. 2025 Mar 5;19(3). doi: 10.1093/ecco-jcc/jjae157.
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.
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.
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.
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.
遗传因素对炎症性肠病（IBD，包括克罗恩病（CD）和溃疡性结肠炎（UC））的影响约占疾病变异的20%，这凸显了表征环境和表观遗传影响的必要性。最近，在全表观基因组关联研究中对成人甲基化组的表征取得了相当大的进展。
我们使用Illumina Infinium Human MethylationEPIC平台，报告了对86例儿童期发病的CD和UC患者以及30名对照者循环甲基化组的详细分析。
我们推导并验证了一种4探针甲基化生物标志物（RPS6KA2、VMP1、CFI和ARHGEF3），在英国和北美队列中对儿童IBD具有特异性和高诊断准确性（曲线下面积：0.90 - 0.94）。诊断时存在显著的表观遗传年龄加速，在CD患者中最为明显。顺式甲基化定量性状位点（meQTL）分析确定了表观遗传改变背后的遗传决定因素，特别是在HLA 6p22.1 - p21.33区域内。与先前的研究结果相反，被动吸烟暴露与UC而非CD的发生相关。
这些数据为IBD中的表观遗传改变提供了新的见解，并说明了全表观基因组关联研究在复杂疾病中的可重复性和转化潜力。
