Peripheral Blood DNA Methylation Signatures and Response to Tofacitinib in Moderate-to-severe Ulcerative Colitis.

IF 8.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Vincent Joustra, Andrew Y F Li Yim, Sara van Gennep, Ishtu Hageman, Tristan de Waard, Evgeni Levin, Peter Lauffer, Wouter de Jonge, Peter Henneman, Mark Löwenberg, Geert D'Haens
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Abstract

Introduction: Predictive biomarkers for treatment efficacy of ulcerative colitis [UC] treatments are lacking. Here, we performed a longitudinal study investigating the association and potential predictive power of genome-wide peripheral blood [PB] DNA methylation signatures and response to tofacitinib treatment in UC.

Methods: We recruited moderate-to-severe UC patients starting tofacitinib treatment, and measured PB DNA methylation profiles at baseline [T1], after 8 weeks [T2], and in a subset [n = 8] after a median of 20 weeks [T3] using the Illumina Infinium HumanMethylation EPIC BeadChip. After 8 weeks, we distinguished responders [R] from non-responders [NR] based on a centrally read endoscopic response [decrease in endoscopic Mayo score ≥1 or Ulcerative Colitis Endoscopic Index of Severity ≥2] combined with corticosteroid-free clinical and/or biochemical response. T1 PB samples were used for biomarker identification, and T2 and publicly available intraclass correlation [ICC] data were used for stability analyses. RNA-sequencing was performed to understand the downstream effects of the predictor CpG loci.

Results: In total, 16 R and 15 NR patients, with a median disease duration of 7 [4-12] years and overall comparable patient characteristics at baseline, were analysed. We identified a panel of 53 differentially methylated positions [DMPs] associated with response to tofacitinib [AUROC 0.74]. Most DMPs [77%] demonstrated both short- and long-term hyperstability [ICC ≥0.90], irrespective of inflammatory status. Gene expression analysis showed lower FGFR2 [pBH = 0.011] and LRPAP1 [pBH = 0.020], and higher OR2L13 [pBH = 0.016] expression at T1 in R compared with NR.

Conclusion: Our observations demonstrate the utility of genome-wide PB DNA methylation signatures to predict response to tofacitinib.

外周血 DNA 甲基化特征与中重度溃疡性结肠炎患者对法西替尼的反应
简介:目前尚缺乏预测溃疡性结肠炎(UC)疗效的生物标志物。在此,我们进行了一项纵向研究,调查全基因组外周血(PB)DNA甲基化特征与溃疡性结肠炎患者对法替尼治疗反应的相关性和潜在预测力:我们招募了开始接受托法替尼治疗的中重度 UC 患者,并使用 Illumina Infinium HumanMethylation EPIC BeadChip 在基线(T1)、8 周后(T2)和中位 20 周后(T3)测量了外周血 DNA 甲基化特征。8 周后,我们根据中心读取的内镜反应(内镜马约评分下降≥1 或 UCEIS ≥2)结合无皮质类固醇临床和/或生化反应,将反应者(R)与无反应者(NR)进行了分类。T1 PB样本用于生物标记物鉴定,而T2和公开的类内相关性(ICC)数据则用于稳定性分析。为了解预测CpG位点的下游效应,进行了RNA测序:共分析了 16 名 R 型和 15 名 NR 型患者,他们的中位病程为 7(4-12)年,基线时患者的总体特征相当。我们发现了53个与法西替尼应答相关的不同甲基化位点(DMPs)(AUROC 0.74)。大多数 DMPs(77%)显示出短期和长期的超稳定性(ICC ≥0.90),与炎症状态无关。基因表达分析显示,与NR相比,R患者在T1时FGFR2(pBH=0.011)和LRPAP1(pBH=0.020)表达较低,OR2L13(pBH=0.016)表达较高:我们的观察结果表明,全基因组 PB DNA 甲基化特征可用于预测对法替尼的反应。
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来源期刊
Journal of Crohns & Colitis
Journal of Crohns & Colitis 医学-胃肠肝病学
CiteScore
15.50
自引率
7.50%
发文量
1048
审稿时长
1 months
期刊介绍: Journal of Crohns and Colitis is concerned with the dissemination of knowledge on clinical, basic science and innovative methods related to inflammatory bowel diseases. The journal publishes original articles, review papers, editorials, leading articles, viewpoints, case reports, innovative methods and letters to the editor.
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