Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease

Author:

Mishra Neha,Aden Konrad,Blase Johanna I.,Baran Nathan,Bordoni Dora,Tran Florian,Conrad Claudio,Avalos Diana,Jaeckel Charlot,Scherer Michael,Sørensen Signe B.,Overgaard Silja H.,Schulte Berenice,Nikolaus Susanna,Rey Guillaume,Gasparoni Gilles,Lyons Paul A.,Schultze Joachim L.,Walter Jörn,Andersen Vibeke,Banos Aggelos,Bertsias George,Beyer Marc,Boumpas Dimitrios,Finckh Axel,Franke Andre,Georges Michel,Gu Wei,Häsler Robert,Jawhara Mohamad,Kenyon Amy,Kratsch Christina,Krause Roland,Lauc Gordan,Mangino Massimo,Natoli Gioacchino,Ostaszewski Marek,Pezer Marija,Raes Jeroen,Rahmouni Souad,Ramos-Pamplona Marilou,Reiz Benedikt,Rosati Elisa,Sanoudou Despina,Satagopam Venkata,Schneider Reinhard,Schulte-Schrepping Jonas,Sidiropoulos Prodromos,Smith Kenneth G. C.,Spector Timothy,Vandeputte Doris,Vieira-Silva Sara,Vojta Aleksandar,Warnat-Herresthal Stefanie,Zoldoš Vlatka,Dermitzakis Emmanouil T.,Schreiber Stefan,Rosenstiel PhilipORCID,

Abstract

Abstract Background and aims Treatment with tumor necrosis factor α (TNFα) antagonists in IBD patients suffers from primary non-response rates of up to 40%. Biomarkers for early prediction of therapy success are missing. We investigated the dynamics of gene expression and DNA methylation in blood samples of IBD patients treated with the TNF antagonist infliximab and analyzed the predictive potential regarding therapy outcome. Methods We performed a longitudinal, blood-based multi-omics study in two prospective IBD patient cohorts receiving first-time infliximab therapy (discovery: 14 patients, replication: 23 patients). Samples were collected at up to 7 time points (from baseline to 14 weeks after therapy induction). RNA-sequencing and genome-wide DNA methylation data were analyzed and correlated with clinical remission at week 14 as a primary endpoint. Results We found no consistent ex ante predictive signature across the two cohorts. Longitudinally upregulated transcripts in the non-remitter group comprised TH2- and eosinophil-related genes including ALOX15, FCER1A, and OLIG2. Network construction identified transcript modules that were coherently expressed at baseline and in non-remitting patients but were disrupted at early time points in remitting patients. These modules reflected processes such as interferon signaling, erythropoiesis, and platelet aggregation. DNA methylation analysis identified remission-specific temporal changes, which partially overlapped with transcriptomic signals. Machine learning approaches identified features from differentially expressed genes cis-linked to DNA methylation changes at week 2 as a robust predictor of therapy outcome at week 14, which was validated in a publicly available dataset of 20 infliximab-treated CD patients. Conclusions Integrative multi-omics analysis reveals early shifts of gene expression and DNA methylation as predictors for efficient response to anti-TNF treatment. Lack of such signatures might be used to identify patients with IBD unlikely to benefit from TNF antagonists at an early time point.

Funder

Horizon 2020

Innovative Medicines Initiative

Deutsche Forschungsgemeinschaft

Universitätsklinikum Schleswig-Holstein - Campus Kiel

Publisher

Springer Science and Business Media LLC

Subject

Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine

Cited by 24 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3