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Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 Years Before Diagnosis

      Background & Aims

      Biomarkers are needed to identify patients at risk for development of inflammatory bowel diseases. We aimed to identify serum biomarkers of Crohn’s disease and ulcerative colitis that can be detected and quantified before diagnosis.

      Methods

      We obtained serum samples from patients archived before a diagnosis of Crohn’s disease (n = 200) or ulcerative colitis (n = 199), as well as from 200 healthy individuals (controls), collected from 1998 through 2013 as part of the US Defense Medical Surveillance System. We measured levels of antibodies against microbes (anti–Saccharomyces cerevisiae IgA or IgG, anti–Escherichia coli outer membrane porin C, anti-CBir1, anti-flagellin 2, anti-flagellin X, and perinuclear anti-neutrophil cytoplasmic antibodies) and 1129 proteins in each sample. We then used functional principal component analysis to derive the time-varying trajectory for each marker, which then was used in a multivariate model to predict disease status. Predictive performances at different prediagnosis timepoints were evaluated using area under the receiver operating characteristic curves (AUROCs). Biological pathways that were up-regulated in serum from patients with Crohn’s disease were identified based on changes in protein abundance at different time periods preceding diagnosis.

      Results

      We identified a panel of 51 protein biomarkers that were predictive of Crohn’s disease within 5 years with an AUROC of 0.76 and a diagnosis within 1 year with an AUROC of 0.87. Based on the proteins included in the panel, imminent development of CD was associated with changes in the complement cascade, lysosomes, innate immune response, and glycosaminoglycan metabolism. Serum antibodies and proteins identified patients who received a diagnosis of ulcerative colitis within 5 years with an AUROC of only 0.56 and within 1 year with an AUROC of 0.72.

      Conclusions

      We identified a panel of serum antibodies and proteins that were predictive of patients who will receive a diagnosis of Crohn’s disease within 5 years with high accuracy. By contrast we did not identify biomarkers associated with future diagnosis of ulcerative colitis.

      Keywords

      Abbreviations used in this paper:

      APCS (serum amyloid P component), ASCA (anti–Saccharomyces cerevisiae antibodies), CD (Crohn’s disease), CRP (C-reactive protein), DMSS (Defense Medical Surveillance System), DoDSR (US Department of Defense Serum Repository), HC (healthy control), IBD (inflammatory bowel disease), ICD-9 (International Classification of Diseases, Ninth Revision), IL (interleukin), KEGG (Kyoto Encyclopedia of Genes and Genomes), LASSO (least absolute shrinkage and selection operatory), pANCA (perinuclear anti–neutrophil cytoplasmic antibodies), PREDICTS (Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects), UC (ulcerative colitis)
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