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

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...

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Veröffentlicht in:	Genome medicine Jg. 14; H. 1; S. 1 - 20
Hauptverfasser:	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, Dermitzakis, Emmanouil T., Schreiber, Stefan, Rosenstiel, Philip
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London BioMed Central 24.09.2022 BioMed Central Ltd Springer Nature B.V BMC
Schlagworte:	Adalimumab Analysis Antagonists Bioinformatics Biological analysis Biologics Biomarker Biomarkers Biomedical and Life Sciences Biomedicine Cancer Research Care and treatment Disease DNA methylation DNA sequencing Erythropoiesis Ethylenediaminetetraacetic acid Gastrointestinal diseases Gene expression Genes Genetics Genetics & genetic processes Genetics (clinical) Genomes Genomics Génétique & processus génétiques Human Genetics Humans Inflammatory bowel disease Inflammatory Bowel Diseases Inflammatory Bowel Diseases/drug therapy Inflammatory Bowel Diseases/genetics Infliximab Infliximab/therapeutic use Interferon Interferons Interferons/therapeutic use Intestinal inflammation Leukocytes (eosinophilic) Life sciences Lymphocytes T Machine learning Medical research Medicine, Experimental Medicine/Public Health Metabolomics Methylation Molecular Biology Molecular Medicine Monoclonal antibodies Olig2 protein Patients Personalized medicine Platelet aggregation Prospective Studies Remission Remission (Medicine) RNA Sciences du vivant Systems Biology Therapy response Transcriptomics Tumor necrosis factor Tumor Necrosis Factor Inhibitors Tumor Necrosis Factor-alpha Tumor necrosis factor-TNF Tumor necrosis factor-α Intestinal inflammation Biomarker Therapy response Personalized medicine Biologics
ISSN:	1756-994X, 1756-994X
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 scopus-id:2-s2.0-85138458387 info:eu-repo/grantAgreement/EC/H2020/733100
ISSN:	1756-994X 1756-994X
DOI:	10.1186/s13073-022-01112-z