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Characterization of...
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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- Nowak, Jan K. (author)
- 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
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- Adams, Alex T. (author)
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom,Univ Oxford, England
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- Kalla, Rahul (author)
- 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. (author)
- 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
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- Vatn, Simen (author)
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway,Univ Oslo, Norway; Akershus Univ Hosp, Norway
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- Bergemalm, Daniel, 1977- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,Department of Gastroenterology,Orebro Univ, Sweden
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- Keita, Åsa (author)
- Linköpings universitet,Avdelningen för kirurgi, ortopedi och onkologi,Medicinska fakulteten
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- Gomollón, Fernando (author)
- HCU "Lozano Blesa," IIS Aragón, Zaragoza, Spain
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- Jahnsen, Jørgen (author)
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway,Univ Oslo, Norway; Akershus Univ Hosp, Norway
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- Vatn, Morten H. (author)
- 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
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- Ricanek, Petr (author)
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway,Akershus Univ Hosp, Norway
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- Ostrowski, Jerzy (author)
- 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
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- Walkowiak, Jaroslaw (author)
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland,Poznan Univ Med Sci, Poland
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- Halfvarson, Jonas, 1970- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,IBD-Character consortium,Orebro Univ, Sweden
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- Satsangi, Jack (author)
- 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
- English.
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In: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 16:8, s. 1255-1268
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Abstract
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Gastroenterologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)
Keyword
- Crohn’s disease
- inflammatory bowel disease
- transcription factor
- transcriptome
- ulcerative colitis
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Nowak, Jan K.
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Adams, Alex T.
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Kalla, Rahul
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Lindstrøm, Jonas ...
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Vatn, Simen
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Bergemalm, Danie ...
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Keita, Åsa
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Gomollón, Fernan ...
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Jahnsen, Jørgen
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Vatn, Morten H.
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Ricanek, Petr
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Ostrowski, Jerzy
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Walkowiak, Jaros ...
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Halfvarson, Jona ...
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Satsangi, Jack
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Gastroenterology ...
- Articles in the publication
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Journal of Crohn ...
- By the university
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Örebro University
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Linköping University