Dataset Information

Misbalance in type III collagen formation/degradation as a novel serological biomarker for penetrating (Montreal B3) Crohn's disease.

ABSTRACT:

Background

Misbalances in extracellular matrix turnover are key factors in the development of stricturing (Montreal B2) and penetrating (Montreal B3) Crohn's disease.

Aim

To determine whether serological markers for collagen formation and degradation could serve as biomarkers for complications of Crohn's disease.

Methods

Serum biomarkers for type I, III, V and VI collagen formation (P1NP, Pro-C3, Pro-C5, Pro-C6) and matrix metalloproteinase mediated degradation (C1M, C3M, C5M and C6M) were measured in a retrospective, single centre cohort of 112 patients with Crohn's disease in the terminal ileum (nonstricturing/nonpenetrating: n=40, stricturing: n=55, penetrating: n=17) and 24 healthy controls. Active inflammation was defined as CRP >5 mg/L.

Results

C3M and Pro-C5 levels were higher in penetrating vs nonpenetrating/nonstricturing and stricturing disease (33.6±5 vs 25.8±2.2 [P=.004] and 27.2±2.3 [P=.018] nmol/L C3M, 1262.7±259.4 vs 902.9±109.9 [P=.005] and 953.0±106.4 [P=.015] nmol/L Pro-C5). C1M (71.2±26.1 vs 46.2±6.2 nmol/L [P<.001]), C3M (31.6±3.9 vs 26.1±1.6 nmol/L [P=.002] and Pro-C5 levels (1171.7±171.5 vs 909.6±80.4 nmol/L [P=.002]) were higher in patients with active inflammation vs without active inflammation. Pro-C3/C3M-ratios were best to differentiate between penetrating vs nonstricturing/nonpenetrating and stricturing disease with area under the curves of 0.815±0.109 (P<.001) and 0.746±0.114 (P=.002) respectively.

Conclusions

Serological biomarkers show that penetrating Crohn's disease is characterised by increased matrix metalloproteinase-9 degraded type III collagen and formation of type V collagen. Active inflammation in Crohn's disease is characterised by increased formation of type V collagen and increased matrix metalloproteinase mediated breakdown of type I, III collagen. Pro-C3/C3M ratios are superior in differentiating between penetrating Crohn's disease vs inflammatory and stricturing Crohn's disease.

SUBMITTER: van Haaften WT

PROVIDER: S-EPMC6221070 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Misbalance in type III collagen formation/degradation as a novel serological biomarker for penetrating (Montreal B3) Crohn's disease.

van Haaften W T WT Mortensen J H JH Karsdal M A MA Bay-Jensen A C AC Dijkstra G G Olinga P P

Alimentary pharmacology & therapeutics 20170508 1

<h4>Background</h4>Misbalances in extracellular matrix turnover are key factors in the development of stricturing (Montreal B2) and penetrating (Montreal B3) Crohn's disease.<h4>Aim</h4>To determine whether serological markers for collagen formation and degradation could serve as biomarkers for complications of Crohn's disease.<h4>Methods</h4>Serum biomarkers for type I, III, V and VI collagen formation (P1NP, Pro-C3, Pro-C5, Pro-C6) and matrix metalloproteinase mediated degradation (C1M, C3M, C ...[more]

PMID: 28481042

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Project description:Crohn's Disease (CD) is a relapsing inflammation of the gastrointestinal tract that affects a young working age population and is increasing in developing countries. Half of all sufferers will experience stricturing or fistulizing intestinal complications that require extensive surgical interventions and neither genes nor clinical risk factors can predict this debilitating natural history. We applied discovery and verification phase studies as part of an NCI-FDA modeled biomarker pipeline to identify differences in the low-mass (<25kDa) blood-serum proteome between CD behavioral phenotypes. A significant enrichment of epithelial component proteins was identified in CD patients with intestinal complications using quantitative proteomic profiling with label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). DAVID 6.7 (NIH) was used for functional annotation analysis of detected proteins and immunoblotting and multiple reaction monitoring (MRM) to verify a priori findings in a secondary independent cohort of complicated CD (CCD), uncomplicated inflammatory CD (ICD), Th1/17 pathway inflammation controls (rheumatoid arthritis), inflammatory bowel disease controls (ulcerative colitis), and healthy controls. Seventy-six high-confidence serum proteins were modulated in CCD versus ICD by LC-MS/MS (p < 0.05, FDR q<0.01), annotating to pathways of epithelial barrier homeostasis (p < 0.01). In verification phase, a putative serology panel developed from discovery proteomics data consisting of desmoglein-1, desmoplakin, and fatty acid-binding protein 5 (FABP5) distinguished CCD from all other groups (p = 0.041) and discriminated complication in CD (70% sensitivity and 72.5% specificity at score ?1.907, AUC = 0.777, p = 0.007). An MRM assay secondarily confirmed increased FABP5 levels in CCD (p < 0.001). In a longitudinal subanalysis-cohort, FABP5 levels were stable over a two-month period with no behavioral changes (p = 0.099). These studies along the biomarker development pipeline provide substantial proof-of-principle that a blood test can be developed specific to transmural intestinal injury. Data are available via the PRIDE proteomics data repository under identifier PXD001821 and PeptideAtlas with identifier PASS00661.

Project description:BACKGROUND & AIMS:There are few serum biomarkers to identify patients with Crohn's disease (CD) who are at risk for stricture development. The extracellular matrix components, collagen type III alpha 1 chain (COL3A1) and cartilage oligomeric matrix protein (COMP), could contribute to intestinal fibrosis. We investigated whether children with inflammatory CD (B1) who later develop strictures (B2) have increased plasma levels of COL3A1 or COMP at diagnosis, compared with children who remain B1. We compared results with previously studied biomarkers, including autoantibodies against colony-stimulating factor 2 (CSF2). METHODS:We selected 161 subjects (mean age, 12.2 y; 62% male) from the Risk Stratification and Identification of Immunogenic and Microbial Markers of Rapid Disease Progression in Children with Crohn's cohort, completed at 28 sites in the United States and Canada from 2008 through 2012. The children underwent colonoscopy and upper endoscopy at diagnosis and were followed up every 6 months for 36 months; plasma samples were collected at baseline. Based on CD phenotype, children were separated to group 1 (B1 phenotype at diagnosis and follow-up evaluation), group 2 (B2 phenotype at diagnosis), or group 3 (B1 phenotype at diagnosis who developed strictures during follow-up evaluation). Plasma samples were collected from patients and 40 children without inflammatory bowel disease (controls) at baseline and analyzed by enzyme-linked immunosorbent assay to measure COL3A1 and COMP. These results were compared with those from a previous biomarker study. The Kruskal-Wallis test and the pairwise Dunn test with Bonferroni correction were used to compare differences among groups. RESULTS:The median baseline concentration of COL3A1 was significantly higher in plasma from group 3 vs group 1 (P < .01) and controls (P = .01). Median baseline plasma concentrations of COMP did not differ significantly among groups. A model comprising baseline concentrations of COL3A1 and anti-CSF2 identified patients with B2 vs B1 CD with an area under the curve of 0.80 (95% CI, 0.71-0.89); the combined concentration identified patients with strictures with a sensitivity value of 0.70 (95% CI, 0.55-0.83) and a specificity value of 0.83 (95% CI, 0.67-0.93). CONCLUSIONS:We found median plasma concentrations of COL3A1, measured by enzyme-linked immunosorbent assay at diagnosis, to be significantly higher in patients with CD who later developed strictures than in patients without strictures. The combination of concentrations of COL3A1 and anti-CSF2 might be used to identify pediatric patients at CD diagnosis who are at risk for future strictures. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00790543.

Dataset Information

Misbalance in type III collagen formation/degradation as a novel serological biomarker for penetrating (Montreal B3) Crohn's disease.

Background

Aim

Methods

Results

Conclusions

Publications

Misbalance in type III collagen formation/degradation as a novel serological biomarker for penetrating (Montreal B3) Crohn's disease.

Similar Datasets

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