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

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• dc.contributor.author Mishra, Neha
• dc.contributor.author Scherer, Michael
• dc.contributor.author Rosenstiel, Philip
• dc.date.accessioned 2022-11-02T07:28:47Z
• dc.date.available 2022-11-02T07:28:47Z
• dc.date.issued 2022
• dc.description.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.
• dc.description.sponsorship Open Access funding enabled and organized by Projekt DEAL. This work was supported by the EU projects SYSCID (733100), IMI2 ImmUniverse (853995), the IMI2 Project 3TR (831434), the BMBF project iTREAT (01ZX1902A), and ExC 2167 Precision Medicine in Chronic Inflammation (RTF-VI).
• dc.format.mimetype application/pdf
• dc.identifier.citation Mishra N, Aden K, Blase JI, Baran N, Bordoni D, Tran F et al. Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease. Genome Med. 2022 Sep 24;14(1):110. DOI: 10.1186/s13073-022-01112-z
• dc.identifier.doi http://dx.doi.org/10.1186/s13073-022-01112-z
• dc.identifier.issn 1756-994X
• dc.identifier.uri http://hdl.handle.net/10230/54646
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Genome Med. 2022 Sep 24;14(1):110
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/733100
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/853995
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/831434
• dc.rights © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data ma
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Biologics
• dc.subject.keyword Biomarker
• dc.subject.keyword Intestinal inflammation
• dc.subject.keyword Personalized medicine
• dc.subject.keyword Therapy response
• dc.title Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion