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

Authors :
Mishra, Neha
Aden, Konrad
Sørensen, Signe B
Overgaard, Silja H
Schulte, Berenice
Nikolaus, Susanna
Rey, Guillaume
Gasparoni, Gilles
Lyons, Paul A
Schultze, Joachim L
Walter, Jörn
Andersen, Vibeke
Blase, Johanna I
Consortium, SYSCID
Dermitzakis, Emmanouil T
Schreiber, Stefan
Rosenstiel, Philip
Banos, Aggelos
Bertsias, George
Beyer, Marc-Daniel
Boumpas, Dimitrios
Finckh, Axel
Franke, Andre
Baran, Nathan
Georges, Michel
Gu, Wei
Häsler, Robert
Jawhara, Mohamad
Kenyon, Amy
Kratsch, Christina
Krause, Roland
Lauc, Gordan
Mangino, Massimo
Natoli, Gioacchino
Bordoni, Dora
Ostaszewski, Marek
Pezer, Marija
Raes, Jeroen
Rahmouni, Souad
Ramos-Pamplona, Marilou
Reiz, Benedikt
Rosati, Elisa
Sanoudou, Despina
Satagopam, Venkata
Schneider, Reinhard
Tran, Florian
Schulte-Schrepping, Jonas
Sidiropoulos, Prodromos
Smith, Kenneth G C
Spector, Timothy
Vandeputte, Doris
Vieira-Silva, Sara
Vojta, Aleksandar
Warnat-Herresthal, Stefanie
Zoldoš, Vlatka
Conrad, Claudio
Avalos, Diana
Jaeckel, Charlot
Scherer, Michael
Source :
Genome medicine 14(1), 110 (2022). doi:10.1186/s13073-022-01112-z, Genome Medicine
Publication Year :
2022
Publisher :
BioMed Central, 2022.

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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Genome medicine 14(1), 110 (2022). doi:10.1186/s13073-022-01112-z, Genome Medicine
Accession number :
edsair.doi.dedup.....e222e3f5620b8a534c502c9275665baa