Systemic Inflammation in Preclinical Ulcerative Colitis
Daniel Bergemalm, Erik Andersson, Johan Hultdin, Carl Eriksson, Stephen Rush, Rahul Kalla, Alex Adams, Åsa V. Keita, Mauro D’Amato, Fernando Gomollón, Jørgen Jahnsen, Ian Arnott, Mónica Bayés, Ferdinando Bonfiglio, Ray Boyapati, Adam Carstens, Christina Casèn, Ewa Ciemniejewska, Fredrik A. Dahl, Trond Espen Detlie, Hazel E. Drummond, Gunn S. Ekeland, Daniel Ekman, Anna B. Frengen, Mats Gullberg, Marta Gut, Marta Gut, Simon Heath, Fredrik Hjelm, Henrik Hjortswang, Gwo‐Tzer Ho, Daisy Jonkers, Johan D. Söderholm, Nicholas A. Kennedy, Charles W. Lees, Torbjørn Lindahl, C. Lindqvist, Angelika Merkel, Eddie Modig, Aina Elisabeth Fossum Moen, Hilde Nilsen, Elaine R. Nimmo, Colin Noble, Niklas Nordberg, Kate O'Leary, Anette Ocklind, Christine Olbjørn, Erik Pettersson, Marieke Pierik, Dominique, Petr Ricanek, Jack Satsangi, Dirk Repsilber, Pontus Karling, Jonas Halfvarson
Abstract
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.