Characterization of the circulating transcriptomic landscape in inflammatory bowel disease provides evidence for dysregulation of multiple transcription factors including NFE2, SPI1, CEBPB, and IRF2

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Characterization of the circulating transcriptomic landscape in inflammatory bowel disease provides evidence for dysregulation of multiple transcription factors including NFE2, SPI1, CEBPB, and IRF2

Nowak, Jan K. (författare): Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland,Univ Oxford, England; Poznan Univ Med Sci, Poland

Adams, Alex T. (författare): Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom,Univ Oxford, England

Kalla, Rahul (författare): MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom,Univ Edinburgh, Scotland

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Lindstrøm, Jonas C. (författare): Health Services Research Unit, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway,Akershus Univ Hosp, Norway; Univ Oslo, Norway

Vatn, Simen (författare): Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway,Univ Oslo, Norway; Akershus Univ Hosp, Norway

Bergemalm, Daniel, 1977- (författare): Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,Department of Gastroenterology,Orebro Univ, Sweden

Keita, Åsa (författare): Linköpings universitet,Avdelningen för kirurgi, ortopedi och onkologi,Medicinska fakulteten

Gomollón, Fernando (författare): HCU "Lozano Blesa," IIS Aragón, Zaragoza, Spain

Jahnsen, Jørgen (författare): Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway,Univ Oslo, Norway; Akershus Univ Hosp, Norway

Vatn, Morten H. (författare): Institute of Clinical Medicine, University of Oslo, Oslo, Norway; EpiGen Institute, Akershus University Hospital, University of Oslo, Oslo, Norway,Univ Oslo, Norway; Univ Oslo, Norway

Ricanek, Petr (författare): Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway,Akershus Univ Hosp, Norway

Ostrowski, Jerzy (författare): Department of Genetics, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland; Department of Gastroenterology, Hepatology and Clinical Oncology, Centre for Postgraduate Medical Education, Warsaw, Poland,Maria Sklodowska Curie Natl Res Inst Oncol, Poland; Ctr Postgrad Med Educ, Poland

Walkowiak, Jaroslaw (författare): Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland,Poznan Univ Med Sci, Poland

Halfvarson, Jonas, 1970- (författare): Örebro universitet,Institutionen för medicinska vetenskaper,IBD-Character consortium,Orebro Univ, Sweden

Satsangi, Jack (författare): Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom,Univ Oxford, England; Univ Edinburgh, Scotland

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(creator_code:org_t)

2022-02-25
2022
Engelska.
Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 16:8, s. 1255-1268

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://liu.diva-por... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; https://urn.kb.se/re...; visa färre...

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AIM: To assess the pathobiological and translational importance of whole blood transcriptomic analysis in inflammatory bowel disease (IBD).METHODS: We analyzed whole blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn's disease [CD, n = 156], ulcerative colitis [UC, n = 167], and controls [n = 267]), exploring differential expression (DESeq2), co-expression networks (WGCNA), and transcription factor involvement (EPEE, ChEA, DoRothEA). Findings were validated by analysis of an independent replication cohort (99 CD, 100 UC, and 95 controls). In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure.RESULTS: Disease-specific transcriptomes were defined in IBD (8697 transcripts), CD (7152), and UC (8521), with the most highly significant changes in single genes, including CD177 (log2-fold change [LFC] = 4.63, p = 4.05 × 10 -118), MCEMP1 (LFC = 2.45, p = 7.37 × 10 -109), and S100A12 (LFC = 2.31, p = 2.15 × 10 -93). Significantly over-represented pathways included IL-1 (p = 1.58 × 10 -11), IL-4, and IL-13 (p = 8.96 × 10 -9). Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 (PU.1), CEBPB, and IRF2, all regulators of cytokine signaling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% CI 5.3-102.0).CONCLUSION: Transcriptomic analysis has allowed for a detailed characterization of IBD pathobiology, with important potential translational implications.

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Av författaren/redakt...: Nowak, Jan K.; Adams, Alex T.; Kalla, Rahul; Lindstrøm, Jonas ...; Vatn, Simen; Bergemalm, Danie ...; visa fler...; Keita, Åsa; Gomollón, Fernan ...; Jahnsen, Jørgen; Vatn, Morten H.; Ricanek, Petr; Ostrowski, Jerzy; Walkowiak, Jaros ...; Halfvarson, Jona ...; Satsangi, Jack; visa färre...

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Av lärosätet: Örebro universitet; Linköpings universitet

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Characterization of the circulating transcriptomic landscape in inflammatory bowel disease provides evidence for dysregulation of multiple transcription factors including NFE2, SPI1, CEBPB, and IRF2

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