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Background & aimsPreclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.MethodsWe obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (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 biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (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 patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.ResultsSix proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.ConclusionsA set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.

Original publication

DOI

10.1053/j.gastro.2021.07.026

Type

Journal article

Journal

Gastroenterology

Publication Date

11/2021

Volume

161

Pages

1526 - 1539.e9

Addresses

Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. Electronic address: daniel.bergemalm@regionorebrolan.se.

Keywords

IBD Character Consortium, Humans, Colitis, Ulcerative, Blood Proteins, Proteome, Inflammation Mediators, Case-Control Studies, Reproducibility of Results, Predictive Value of Tests, Proteomics, Up-Regulation, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Chemokine CCL2, Matrix Metalloproteinase 10, Chemokine CXCL9, Chemokine CXCL11, Chemokine CCL11, Young Adult, Biomarkers, Signaling Lymphocytic Activation Molecule Family Member 1