The circulating methylome in childhood-onset inflammatory bowel disease.

Alexandra Noble, Alex Adams, Jan Nowak, Guo Cheng, Komal Nayak, Aisling Quinn, Mark Kristiansen, Rahul Kalla, Nicholas T Ventham, Federica Giachero, Chamara Jayamanne, Richard Hansen, Georgina L Hold, Emad El-Omar, Nicholas M Croft, David Wilson, R Mark Beattie, James J Ashton, Matthias Zilbauer, Sarah Ennis, Holm H Uhlig, Jack Satsangi
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Abstract

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 characterise environmental and epigenetic influences. Recently considerable progress has been made in characterising the adult methylome, in epigenome-wide association studies. We report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD,UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform. We derive and validate a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI and ARHGEF3), with specificity and high diagnostic accuracy for paediatric IBD in UK and North American cohorts (AUC 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-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.

儿童期炎症性肠病的循环甲基组。
炎症性肠病(IBD)(包括克罗恩病(CD)和溃疡性结肠炎(UC))的遗传因素约占疾病变异的 20%,这凸显了研究环境和表观遗传影响的必要性。最近,全表观遗传关联研究在描述成人甲基组特征方面取得了重大进展。我们报告了利用 Illumina Infinium Human MethylationEPIC 平台对 86 名儿童期发病的 CD、UC 患者和 30 名对照者的循环甲基组进行的详细分析。我们得出并验证了 4 个探针甲基化生物标记物(RPS6KA2、VMP1、CFI 和 ARHGEF3),它们在英国和北美队列中对儿科 IBD 具有特异性和高诊断准确性(AUC 0.90-0.94)。诊断时存在明显的表观遗传年龄加速现象,在 CD 患者中观察到的加速度最大。顺式-MeQTL分析确定了HLA 6p22.1-p21.33区域内表观遗传改变的遗传决定因素。被动吸烟与 UC 而非 CD 的发病有关,这与之前的研究结果相反。这些数据为了解 IBD 的表观遗传学改变提供了新的视角,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。
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