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Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort

View ORCID ProfileLouise A Organ, Anne-Marie R Duggan, Eunice Oballa, Sarah C Taggart, Juliet K Simpson, Arthur R Kang’ombe, Rebecca Braybrooke, Philip L Molyneaux, Diana J Leeming, Morten A Karsdal, Carmel B Nanthakumar, William A Fahy, Richard P Marshall, R Gisli Jenkins, Toby M Maher
doi: https://doi.org/10.1101/497156
Louise A Organ
1University of Nottingham, Division of Respiratory Medicine, Nottingham, UK.
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Anne-Marie R Duggan
2Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
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Eunice Oballa
2Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
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Sarah C Taggart
2Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
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Juliet K Simpson
2Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
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Arthur R Kang’ombe
2Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
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Rebecca Braybrooke
1University of Nottingham, Division of Respiratory Medicine, Nottingham, UK.
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Philip L Molyneaux
3NIHR Respiratory Clinical Research Facility, Royal Brompton Hospital, London, UK.
4Fibrosis Research Group, National Heart and Lung Institute, Imperial College, London, UK.
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Diana J Leeming
5Nordic Bioscience A/S, Biomarkers and Research, Herlev Hovedgade 205207, DK-2730, Herlev, Denmark.
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Morten A Karsdal
5Nordic Bioscience A/S, Biomarkers and Research, Herlev Hovedgade 205207, DK-2730, Herlev, Denmark.
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Carmel B Nanthakumar
2Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
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William A Fahy
2Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
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Richard P Marshall
2Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
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R Gisli Jenkins
1University of Nottingham, Division of Respiratory Medicine, Nottingham, UK.
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Toby M Maher
3NIHR Respiratory Clinical Research Facility, Royal Brompton Hospital, London, UK.
4Fibrosis Research Group, National Heart and Lung Institute, Imperial College, London, UK.
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Abstract

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was assessed in 145 newly-diagnosed individuals with IPF.

Serum levels of collagen synthesis neoepitopes, PRO-C3 and PRO-C6 (collagen type 3 and 6), were elevated in IPF compared with controls at baseline, and progressive disease versus stable disease during follow up, (PRO-C3 p<0.001; PRO-C6 p=0.029). Assessment of rate of change in neoepitope levels from baseline to 3 months (defined as ‘slope to month 3’: HIGH slope, slope > 0 vs. LOW slope, slope <=0) demonstrated no relationship with mortality for these markers (PRO-C3 (HR 1.62, p=0.080); PINP (HR 0.76, p=0.309); PRO-C6 (HR 1.14, p=0.628)). As previously reported, rising concentrations of collagen degradation markers C1M, C3M, C6M and CRPM were associated with an increased risk of overall mortality (HR=1.84, CI 1.03 – 3.27, p=0.038, HR=2.44, CI 1.39–4.31, p=0.002; HR= 2.19, CI 1.25–3.82, p=0.006; HR= 2.13 CI 1.21–3.75, p=0.009 respectively).

Elevated levels of PRO-C3 and PRO-C6 associate with IPF disease progression. Collagen synthesis and degradation biomarkers have the potential to enhance clinical trials in IPF and may inform prognostic assessment and therapeutic decision making in the clinic.

Footnotes

  • Take home message: This study demonstrates that synthesis neoepitopes for collagen type 3 and 6, but not the N-terminal pro-peptide of collagen type 1, distinguish individuals with IPF who have progressive disease from those with more stable disease.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 21, 2018.
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Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort
Louise A Organ, Anne-Marie R Duggan, Eunice Oballa, Sarah C Taggart, Juliet K Simpson, Arthur R Kang’ombe, Rebecca Braybrooke, Philip L Molyneaux, Diana J Leeming, Morten A Karsdal, Carmel B Nanthakumar, William A Fahy, Richard P Marshall, R Gisli Jenkins, Toby M Maher
bioRxiv 497156; doi: https://doi.org/10.1101/497156
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Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort
Louise A Organ, Anne-Marie R Duggan, Eunice Oballa, Sarah C Taggart, Juliet K Simpson, Arthur R Kang’ombe, Rebecca Braybrooke, Philip L Molyneaux, Diana J Leeming, Morten A Karsdal, Carmel B Nanthakumar, William A Fahy, Richard P Marshall, R Gisli Jenkins, Toby M Maher
bioRxiv 497156; doi: https://doi.org/10.1101/497156

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