Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD

Alison J. Dicker; Megan L. Crichton; Andrew J. Cassidy; Gill Brady; Adrian Hapca; Roger Tavendale; Gisli G. Einarsson; Elizabeth Furrie; J. Stuart Elborn; Stuart Schembri; Sara E. Marshall; Colin N. A. Palmer; James D. Chalmers

doi:10.1136/thoraxjnl-2016-209931

Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD

Alison J. Dicker, Megan L. Crichton, Andrew J. Cassidy, Gill Brady, Adrian Hapca, Roger Tavendale, Gisli G. Einarsson, Elizabeth Furrie, J. Stuart Elborn, Stuart Schembri, Sara E. Marshall, Colin N. A. Palmer, James D. Chalmers (Lead / Corresponding author)

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Abstract

Background: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggests MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD.

Methods: COPD patients (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested sub-cohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA sequencing, or airway inflammation during stable and exacerbated COPD.

Findings: MBL deficient COPD patients were significantly less likely to have severe exacerbations (Incidence Rate Ratio (I.R.R) 0.66, 95%CI 0.48-0.90, P=0.009), or to have a moderate or severe exacerbation (I.R.R 0.77, 95%CI 0.60-0.99, P=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the sub-cohort MBL deficient patients had a more diverse lung microbiota (P=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency.

Interpretation: MBL deficient genotype COPD patients have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.

Original language	English
Pages (from-to)	510-518
Number of pages	9
Journal	Thorax
Volume	73
Issue number	6
Early online date	3 Nov 2017
DOIs	https://doi.org/10.1136/thoraxjnl-2016-209931
Publication status	Published - Jun 2018

Keywords

Bacterial Infection
COPD Epidemiology
COPD Exacerbations
Innate Immunity
Macrophage Biology

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10.1136/thoraxjnl-2016-209931Licence: CC BY-NC

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© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Final published version, 2.97 MBLicence: CC BY-NC

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Mannose Binding Lectin Deficiency, Bacterial Infection and Disease Severity in Chronic Obstructive Pulmonary Disease: Towards Personalised Medicine for COPD
Chalmers, J., Marshall, S., Palmer, C. & Schembri, S.
1/07/13 → 30/06/15
Project: Research
The Tayside Bioresource: Leveraging Electronic Medical Records to Deliver Personalised Medicine (Biomedical Resource Grant)
Colhoun, H., Connell, J., Doney, A., Dow, E., Morris, A., Palmer, C., Pearson, E., Sullivan, F. & Treweek, S.
Wellcome Trust
1/02/13 → 31/10/15
Project: Research
The Role in ESX-1, a Novel Protein Secretion System, in Staphylococcus Aureus Virulence (Clinical Fellowship - James Chalmers)
Chalmers, J. & Palmer, T.
Wellcome Trust
1/01/13 → 31/12/15
Project: Research

Chalmers, James
- Molecular and Clinical Medicine - Clinical Professor (Teaching and Research) & Respiratory Research
Person: Academic

Tayside Clinical Trials Unit
Health and Clinical Services
Facility/equipment: Facility

Cite this

Dicker, A. J., Crichton, M. L., Cassidy, A. J., Brady, G., Hapca, A., Tavendale, R., Einarsson, G. G., Furrie, E., Elborn, J. S., Schembri, S., Marshall, S. E., Palmer, C. N. A., & Chalmers, J. D. (2018). Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD. Thorax, 73(6), 510-518. https://doi.org/10.1136/thoraxjnl-2016-209931

@article{3645c8e2e78a4a57bf89078bb3fcdda3,

title = "Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD",

abstract = "Background: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggests MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD.Methods: COPD patients (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested sub-cohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA sequencing, or airway inflammation during stable and exacerbated COPD. Findings: MBL deficient COPD patients were significantly less likely to have severe exacerbations (Incidence Rate Ratio (I.R.R) 0.66, 95%CI 0.48-0.90, P=0.009), or to have a moderate or severe exacerbation (I.R.R 0.77, 95%CI 0.60-0.99, P=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the sub-cohort MBL deficient patients had a more diverse lung microbiota (P=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency. Interpretation: MBL deficient genotype COPD patients have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.",

keywords = "Bacterial Infection, COPD Epidemiology, COPD Exacerbations, Innate Immunity, Macrophage Biology",

author = "Dicker, {Alison J.} and Crichton, {Megan L.} and Cassidy, {Andrew J.} and Gill Brady and Adrian Hapca and Roger Tavendale and Einarsson, {Gisli G.} and Elizabeth Furrie and Elborn, {J. Stuart} and Stuart Schembri and Marshall, {Sara E.} and Palmer, {Colin N. A.} and Chalmers, {James D.}",

note = "Funding: Chief Scientist Office, Scotland (ETM/262). JDC is supported by the GSK/British Lung Foundation Chair of Respiratory Research and a fellowship from the Wellcome Trust (099084/Z/12/Z) . GoSHARE was supported by the Wellcome Trust (099177/Z/12/Z).",

year = "2018",

month = jun,

doi = "10.1136/thoraxjnl-2016-209931",

language = "English",

volume = "73",

pages = "510--518",

journal = "Thorax",

issn = "0040-6376",

publisher = "BMJ Publishing Group",

number = "6",

}

Dicker, AJ, Crichton, ML, Cassidy, AJ, Brady, G, Hapca, A, Tavendale, R, Einarsson, GG, Furrie, E, Elborn, JS, Schembri, S, Marshall, SE, Palmer, CNA & Chalmers, JD 2018, 'Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD', Thorax, vol. 73, no. 6, pp. 510-518. https://doi.org/10.1136/thoraxjnl-2016-209931

TY - JOUR

T1 - Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD

AU - Dicker, Alison J.

AU - Crichton, Megan L.

AU - Cassidy, Andrew J.

AU - Brady, Gill

AU - Hapca, Adrian

AU - Tavendale, Roger

AU - Einarsson, Gisli G.

AU - Furrie, Elizabeth

AU - Elborn, J. Stuart

AU - Schembri, Stuart

AU - Marshall, Sara E.

AU - Palmer, Colin N. A.

AU - Chalmers, James D.

N1 - Funding: Chief Scientist Office, Scotland (ETM/262). JDC is supported by the GSK/British Lung Foundation Chair of Respiratory Research and a fellowship from the Wellcome Trust (099084/Z/12/Z) . GoSHARE was supported by the Wellcome Trust (099177/Z/12/Z).

PY - 2018/6

Y1 - 2018/6

N2 - Background: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggests MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD.Methods: COPD patients (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested sub-cohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA sequencing, or airway inflammation during stable and exacerbated COPD. Findings: MBL deficient COPD patients were significantly less likely to have severe exacerbations (Incidence Rate Ratio (I.R.R) 0.66, 95%CI 0.48-0.90, P=0.009), or to have a moderate or severe exacerbation (I.R.R 0.77, 95%CI 0.60-0.99, P=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the sub-cohort MBL deficient patients had a more diverse lung microbiota (P=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency. Interpretation: MBL deficient genotype COPD patients have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.

AB - Background: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggests MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD.Methods: COPD patients (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested sub-cohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA sequencing, or airway inflammation during stable and exacerbated COPD. Findings: MBL deficient COPD patients were significantly less likely to have severe exacerbations (Incidence Rate Ratio (I.R.R) 0.66, 95%CI 0.48-0.90, P=0.009), or to have a moderate or severe exacerbation (I.R.R 0.77, 95%CI 0.60-0.99, P=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the sub-cohort MBL deficient patients had a more diverse lung microbiota (P=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency. Interpretation: MBL deficient genotype COPD patients have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.

KW - Bacterial Infection

KW - COPD Epidemiology

KW - COPD Exacerbations

KW - Innate Immunity

KW - Macrophage Biology

U2 - 10.1136/thoraxjnl-2016-209931

DO - 10.1136/thoraxjnl-2016-209931

M3 - Article

C2 - 29101284

VL - 73

SP - 510

EP - 518

JO - Thorax

JF - Thorax

SN - 0040-6376

IS - 6

ER -

Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD

Abstract

Keywords

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Projects

Mannose Binding Lectin Deficiency, Bacterial Infection and Disease Severity in Chronic Obstructive Pulmonary Disease: Towards Personalised Medicine for COPD

The Tayside Bioresource: Leveraging Electronic Medical Records to Deliver Personalised Medicine (Biomedical Resource Grant)

The Role in ESX-1, a Novel Protein Secretion System, in Staphylococcus Aureus Virulence (Clinical Fellowship - James Chalmers)

Profiles

Chalmers, James

Equipment

Tayside Clinical Trials Unit

Cite this