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)

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)510-518
Number of pages9
JournalThorax
Volume73
Issue number6
Early online date3 Nov 2017
DOIs
Publication statusPublished - Jun 2018

Fingerprint

Microbiota
Chronic Obstructive Pulmonary Disease
Mannose-Binding Lectin
Lung
Mortality
Inflammation
Haemophilus
Bronchiectasis
Mannose-Binding Protein Deficiency
Incidence
Haemophilus influenzae
Sputum
Phagocytosis
Cystic Fibrosis
Genotype
Health

Keywords

  • Bacterial Infection
  • COPD Epidemiology
  • COPD Exacerbations
  • Innate Immunity
  • Macrophage Biology

Cite this

Dicker, Alison J. ; Crichton, Megan L. ; Cassidy, Andrew J. ; Brady, Gill ; Hapca, Adrian ; Tavendale, Roger ; Einarsson, Gisli G. ; Furrie, Elizabeth ; Elborn, J. Stuart ; Schembri, Stuart ; Marshall, Sara E. ; Palmer, Colin N. A. ; Chalmers, James D. / Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD. In: Thorax. 2018 ; Vol. 73, No. 6. pp. 510-518.
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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).",
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Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD. / Dicker, Alison J.; Crichton, Megan L.; Cassidy, Andrew J.; Brady, Gill; Hapca, Adrian; Tavendale, Roger; Einarsson, Gisli G.; Furrie, Elizabeth; Elborn, J. Stuart; Schembri, Stuart; Marshall, Sara E.; Palmer, Colin N. A.; Chalmers, James D. (Lead / Corresponding author).

In: Thorax, Vol. 73, No. 6, 06.2018, p. 510-518.

Research output: Contribution to journalArticle

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

VL - 73

SP - 510

EP - 518

JO - Thorax

JF - Thorax

SN - 0040-6376

IS - 6

ER -