DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease

the COPDGene and ECLIPSE Investigators

Research output: Contribution to journalArticle

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.Methods: We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) 1 <80% predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLCCT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLCCT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis.Results: Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10-8).Conclusions: In COPD, TLCCT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.

Original languageEnglish (US)
Article number97
JournalRespiratory Research
Volume15
Issue number1
DOIs
StatePublished - Aug 20 2014
Externally publishedYes

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Total Lung Capacity
Dyneins
Chronic Obstructive Pulmonary Disease
Linear Models
Kartagener Syndrome
Cone-Beam Computed Tomography
Exercise Tolerance
Genome-Wide Association Study
Bronchodilator Agents
Spirometry
Vital Capacity
Forced Expiratory Volume
Norway
Single Nucleotide Polymorphism
Meta-Analysis
Cohort Studies
Chromosomes
Biomarkers
Smoking
Air

Keywords

  • Chronic obstructive
  • DNAH5
  • Genome-wide association analysis
  • Hyperinflation
  • Pulmonary disease
  • Total lung capacity

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease. / the COPDGene and ECLIPSE Investigators.

In: Respiratory Research, Vol. 15, No. 1, 97, 20.08.2014.

Research output: Contribution to journalArticle

the COPDGene and ECLIPSE Investigators. / DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease. In: Respiratory Research. 2014 ; Vol. 15, No. 1.
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abstract = "Background: Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.Methods: We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) 1 <80{\%} predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLCCT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLCCT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis.Results: Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10-8).Conclusions: In COPD, TLCCT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.",
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author = "{the COPDGene and ECLIPSE Investigators} and Lee, {Jin H.} and McDonald, {Merry Lynn N} and Cho, {Michael H.} and Wan, {Emily S.} and Castaldi, {Peter J.} and Hunninghake, {Gary M.} and Nathaniel Marchetti and Lynch, {David A.} and Crapo, {James D.} and Lomas, {David A.} and Coxson, {Harvey O.} and Bakke, {Per S.} and Silverman, {Edwin K.} and Hersh, {Craig P.} and Stephanie Bratschie and Rochelle Lantz and Sandra Melanson and Lori Stepp and Bowler, {Russell P.} and Curtis, {Jeffrey L.} and Han, {MeiLan K.} and Hokanson, {John E.} and Make, {Barry J.} and Sutherland, {E. Rand} and Bleecker, {Eugene R.} and Crystal, {Ronald G.} and Hogg, {James C.} and Province, {Michael A.} and Rennard, {Stephen I.} and Thomas, {Duncan C.} and Thomas Croxton and Weiniu Gan and Lisa Postow and Walsh, {John W.} and Randel Plant and Delia Prieto and Daniel Cossette and Kelly, {Roxanne K.} and Douglas Everett and Andre Williams and Ruthie Knowles and Carla Wilson and John Hokanson and Nadia Hansel and Beaty, {Terri L} and Homayoon Farzadegan and Wise, {Robert A} and Brown, {Robert Howard} and Diette, {Gregory B} and Horton, {Karen M}",
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T1 - DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease

AU - the COPDGene and ECLIPSE Investigators

AU - Lee, Jin H.

AU - McDonald, Merry Lynn N

AU - Cho, Michael H.

AU - Wan, Emily S.

AU - Castaldi, Peter J.

AU - Hunninghake, Gary M.

AU - Marchetti, Nathaniel

AU - Lynch, David A.

AU - Crapo, James D.

AU - Lomas, David A.

AU - Coxson, Harvey O.

AU - Bakke, Per S.

AU - Silverman, Edwin K.

AU - Hersh, Craig P.

AU - Bratschie, Stephanie

AU - Lantz, Rochelle

AU - Melanson, Sandra

AU - Stepp, Lori

AU - Bowler, Russell P.

AU - Curtis, Jeffrey L.

AU - Han, MeiLan K.

AU - Hokanson, John E.

AU - Make, Barry J.

AU - Sutherland, E. Rand

AU - Bleecker, Eugene R.

AU - Crystal, Ronald G.

AU - Hogg, James C.

AU - Province, Michael A.

AU - Rennard, Stephen I.

AU - Thomas, Duncan C.

AU - Croxton, Thomas

AU - Gan, Weiniu

AU - Postow, Lisa

AU - Walsh, John W.

AU - Plant, Randel

AU - Prieto, Delia

AU - Cossette, Daniel

AU - Kelly, Roxanne K.

AU - Everett, Douglas

AU - Williams, Andre

AU - Knowles, Ruthie

AU - Wilson, Carla

AU - Hokanson, John

AU - Hansel, Nadia

AU - Beaty, Terri L

AU - Farzadegan, Homayoon

AU - Wise, Robert A

AU - Brown, Robert Howard

AU - Diette, Gregory B

AU - Horton, Karen M

PY - 2014/8/20

Y1 - 2014/8/20

N2 - Background: Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.Methods: We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) 1 <80% predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLCCT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLCCT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis.Results: Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10-8).Conclusions: In COPD, TLCCT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.

AB - Background: Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.Methods: We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) 1 <80% predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLCCT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLCCT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis.Results: Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10-8).Conclusions: In COPD, TLCCT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.

KW - Chronic obstructive

KW - DNAH5

KW - Genome-wide association analysis

KW - Hyperinflation

KW - Pulmonary disease

KW - Total lung capacity

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DO - 10.1186/s12931-014-0097-y

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