Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene

The COPDGene Investigators

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Background: Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported. Methods: Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45-80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering. Results: The prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter's syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative "COPD-subtype", "Restrictive-subtype", and a highly symptomatic "Metabolic-subtype". Conclusions: PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted. Trial registration: Clinicaltrials.gov Identifier: NCT000608764.

Original languageEnglish (US)
Article number89
JournalRespiratory Research
Volume15
Issue number1
DOIs
StatePublished - Aug 6 2014
Externally publishedYes

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Molecular Epidemiology
Spirometry
Genome-Wide Association Study
Chronic Obstructive Pulmonary Disease
Cluster Analysis
Klinefelter Syndrome
Total Lung Capacity
Emphysema
Dyspnea
Thorax
Multivariate Analysis
Cross-Sectional Studies
Smoking
Inflammation

Keywords

  • Lung diseases
  • Restriction
  • Smoking
  • Spirometry

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene. / The COPDGene Investigators.

In: Respiratory Research, Vol. 15, No. 1, 89, 06.08.2014.

Research output: Contribution to journalArticle

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title = "Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene",
abstract = "Background: Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported. Methods: Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45-80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering. Results: The prevalence of PRISm in COPDGene is 12.3{\%}. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter's syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative {"}COPD-subtype{"}, {"}Restrictive-subtype{"}, and a highly symptomatic {"}Metabolic-subtype{"}. Conclusions: PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted. Trial registration: Clinicaltrials.gov Identifier: NCT000608764.",
keywords = "Lung diseases, Restriction, Smoking, Spirometry",
author = "{The COPDGene Investigators} and Wan, {Emily S.} and Castaldi, {Peter J.} and Cho, {Michael H.} and Hokanson, {John E.} and Regan, {Elizabeth A.} and Make, {Barry J.} and Beaty, {Terri H.} and Han, {Mei Lan K.} and Curtis, {Jeffrey L.} and Douglas Curran-Everett and Lynch, {David A.} and DeMeo, {Dawn L.} and Crapo, {James D.} and Silverman, {Edwin K.} and Rochelle Lantz and Lori Stepp and Sandra Melanson and Barbara Klanderman and Nan Laird and Christoph Lange and Stephanie Santorico and McDonald, {Merry Lynn} and Jin Zhou and Manuel Mattheissen and Megan Hardin and Jacqueline Hetmanski and Margaret Parker and Tanda Murray and John Reilly and Harvey Coxson and Philip Judy and Eric Hoffman and {San Jose Estepar}, Raul and James Ross and {Al Qaisi}, Mustafa and Jordan Zach and Alex Kluiber and Jered Sieren and Tanya Mann and Deanna Richert and Alexander McKenzie and Jaleh Akhavan and Douglas Stinson and Robert Jensen and Homayoon Farzadegan and Stacey Meyerer and Shivam Chandan and Samantha Bragan and Douglas Everett and Andre Williams",
year = "2014",
month = "8",
day = "6",
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T1 - Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene

AU - The COPDGene Investigators

AU - Wan, Emily S.

AU - Castaldi, Peter J.

AU - Cho, Michael H.

AU - Hokanson, John E.

AU - Regan, Elizabeth A.

AU - Make, Barry J.

AU - Beaty, Terri H.

AU - Han, Mei Lan K.

AU - Curtis, Jeffrey L.

AU - Curran-Everett, Douglas

AU - Lynch, David A.

AU - DeMeo, Dawn L.

AU - Crapo, James D.

AU - Silverman, Edwin K.

AU - Lantz, Rochelle

AU - Stepp, Lori

AU - Melanson, Sandra

AU - Klanderman, Barbara

AU - Laird, Nan

AU - Lange, Christoph

AU - Santorico, Stephanie

AU - McDonald, Merry Lynn

AU - Zhou, Jin

AU - Mattheissen, Manuel

AU - Hardin, Megan

AU - Hetmanski, Jacqueline

AU - Parker, Margaret

AU - Murray, Tanda

AU - Reilly, John

AU - Coxson, Harvey

AU - Judy, Philip

AU - Hoffman, Eric

AU - San Jose Estepar, Raul

AU - Ross, James

AU - Al Qaisi, Mustafa

AU - Zach, Jordan

AU - Kluiber, Alex

AU - Sieren, Jered

AU - Mann, Tanya

AU - Richert, Deanna

AU - McKenzie, Alexander

AU - Akhavan, Jaleh

AU - Stinson, Douglas

AU - Jensen, Robert

AU - Farzadegan, Homayoon

AU - Meyerer, Stacey

AU - Chandan, Shivam

AU - Bragan, Samantha

AU - Everett, Douglas

AU - Williams, Andre

PY - 2014/8/6

Y1 - 2014/8/6

N2 - Background: Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported. Methods: Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45-80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering. Results: The prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter's syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative "COPD-subtype", "Restrictive-subtype", and a highly symptomatic "Metabolic-subtype". Conclusions: PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted. Trial registration: Clinicaltrials.gov Identifier: NCT000608764.

AB - Background: Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported. Methods: Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45-80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering. Results: The prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter's syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative "COPD-subtype", "Restrictive-subtype", and a highly symptomatic "Metabolic-subtype". Conclusions: PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted. Trial registration: Clinicaltrials.gov Identifier: NCT000608764.

KW - Lung diseases

KW - Restriction

KW - Smoking

KW - Spirometry

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DO - 10.1186/s12931-014-0089-y

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