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Systemic Inflammation in Preclinical Ulcerative Colitis
Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.ORCID iD: 0000-0002-1906-0746
Örebro University, School of Medical Sciences. Department of Gastroenterolog.ORCID iD: 0000-0002-6598-1984
Department of Medical Biosciences, Division of Clinical Chemistry, Umeå University, Umeå, Sweden.
Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.ORCID iD: 0000-0002-1046-383x
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2021 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 161, no 5, p. 1526-1539.e9Article in journal (Refereed) Published
Abstract [en]

BACKGROUND & AIMS: Pre-clinical ulcerative colitis is poorly defined. We aimed to characterize the pre-clinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.

METHODS: We obtained plasma samples, biobanked from individuals who later in life developed ulcerative colitis (n=72), and matched healthy controls (n=140), within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biological relevance of these findings were validated in an inception cohort of ulcerative colitis patients (n=101), and healthy controls (n=50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of ulcerative colitis patients (n=41) and matched healthy controls (n=37) were explored.

RESULTS: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP1) were upregulated (p<0.05) in pre-clinical ulcerative colitis compared to controls based on both univariate and mulativariable models. Ingenuity Pathway Analyses identified several potential key regulators, including IL-1b, TNF, IFN-gamma, OSM, NFĸB, IL-6 and IL-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve ulcerative colitis patients from controls with leave-one-out cross-validation (AUC=0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly upregulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.

CONCLUSIONS: A set of inflammatory proteins are upregulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be upregulated already at exposure to genetic and environmental risk factors.

Place, publisher, year, edition, pages
Elsevier, 2021. Vol. 161, no 5, p. 1526-1539.e9
Keywords [en]
CXCL9, Inflammatory Bowel Disease, MMP10, pre-clinical disease, proximity extension assay
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:oru:diva-93441DOI: 10.1053/j.gastro.2021.07.026ISI: 000750577700026PubMedID: 34298022Scopus ID: 2-s2.0-85117620429OAI: oai:DiVA.org:oru-93441DiVA, id: diva2:1585111
Funder
Västerbotten County CouncilSwedish Research Council, 2020-02021 2017-00650EU, FP7, Seventh Framework Programme, 2858546Swedish Foundation for Strategic Research , RB13-016
Note

Funding agencies:

Bengt Ihre research foundation

Orebro University Hospital Research Foundation OLL-709831 OLL-936004 

OLL-890291 OLL-790011 OLL-723021

Available from: 2021-08-16 Created: 2021-08-16 Last updated: 2022-02-15Bibliographically approved

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Bergemalm, DanielAndersson, ErikEriksson, CarlRepsilber, DirkHalfvarson, Jonas

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