Systemic Inflammation in Preclinical Ulcerative Colitis.
Adolescent
Adult
Aged
Aged, 80 and over
Biomarkers
/ blood
Blood Proteins
/ analysis
Case-Control Studies
Chemokine CCL11
/ blood
Chemokine CCL2
/ blood
Chemokine CXCL11
/ blood
Chemokine CXCL9
/ blood
Colitis, Ulcerative
/ blood
Female
Humans
Inflammation Mediators
/ blood
Male
Matrix Metalloproteinase 10
/ blood
Middle Aged
Predictive Value of Tests
Proteome
Proteomics
Reproducibility of Results
Signaling Lymphocytic Activation Molecule Family Member 1
/ blood
Up-Regulation
Young Adult
CXCL9
Inflammatory Bowel Disease
MMP10
Preclinical Disease
Proximity Extension Assay
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
03
12
2020
revised:
12
07
2021
accepted:
12
07
2021
pubmed:
24
7
2021
medline:
18
1
2022
entrez:
23
7
2021
Statut:
ppublish
Résumé
Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. We 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. Six 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. A 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.
Sections du résumé
BACKGROUND & AIMS
Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.
METHODS
We 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.
RESULTS
Six 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.
CONCLUSIONS
A 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.
Identifiants
pubmed: 34298022
pii: S0016-5085(21)03277-7
doi: 10.1053/j.gastro.2021.07.026
pii:
doi:
Substances chimiques
Biomarkers
0
Blood Proteins
0
CCL11 protein, human
0
CCL2 protein, human
0
CXCL11 protein, human
0
CXCL9 protein, human
0
Chemokine CCL11
0
Chemokine CCL2
0
Chemokine CXCL11
0
Chemokine CXCL9
0
Inflammation Mediators
0
Proteome
0
SLAMF1 protein, human
0
Signaling Lymphocytic Activation Molecule Family Member 1
169535-43-7
MMP10 protein, human
EC 3.4.24.22
Matrix Metalloproteinase 10
EC 3.4.24.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Twin Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
1526-1539.e9Subventions
Organisme : Medical Research Council
ID : G0701898
Pays : United Kingdom
Investigateurs
Ian D Arnott
(ID)
Monica Bayes
(M)
Ferdinando Bonfiglio
(F)
Ray K Boyapati
(RK)
Adam Carstens
(A)
Christina Casén
(C)
Ewa Ciemniejewska
(E)
Fredrik A Dahl
(FA)
Trond Espen Detlie
(TE)
Hazel E Drummond
(HE)
Gunn S Ekeland
(GS)
Daniel Ekman
(D)
Anna B Frengen
(AB)
Mats Gullberg
(M)
Ivo G Gut
(IG)
Marta Gut
(M)
Simon C Heath
(SC)
Fredrik Hjelm
(F)
Henrik Hjortswang
(H)
Gwo-Tzer Ho
(GT)
Daisy Jonkers
(D)
Johan Söderholm
(J)
Nicholas A Kennedy
(NA)
Charles W Lees
(CW)
Torbjørn Lindahl
(T)
Mårten Lindqvist
(M)
Angelika Merkel
(A)
Eddie Modig
(E)
Aina E F Moen
(AEF)
Hilde Nilsen
(H)
Elaine R Nimmo
(ER)
Colin L Noble
(CL)
Niklas Nordberg
(N)
Kate R O'Leary
(KR)
Anette Ocklind
(A)
Christine Olbjørn
(C)
Erik Pettersson
(E)
Marieke Pierik
(M)
None Dominique
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.