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

Emily S. Wan, Peter J. Castaldi, Michael H. Cho, John E. Hokanson, Elizabeth A. Regan, Barry J. Make, Terri H. Beaty, MeiLan K. Han, Jeffrey L. Curtis, Douglas Curran-Everett, David A. Lynch, Dawn L. DeMeo, James D. Crapo, Edwin K. Silverman, Rochelle Lantz, Lori Stepp, Sandra Melanson, Barbara Klanderman, Nan Laird, Christoph LangeStephanie Santorico, Merry Lynn McDonald, Jin Zhou, Manuel Mattheissen, Megan Hardin, Jacqueline Hetmanski, Margaret Parker, Tanda Murray, John Reilly, Harvey Coxson, Philip Judy, Eric Hoffman, Raul San Jose Estepar, James Ross, Mustafa Al Qaisi, Jordan Zach, Alex Kluiber, Jered Sieren, Tanya Mann, Deanna Richert, Alexander McKenzie, Jaleh Akhavan, Douglas Stinson, Robert Jensen, Homayoon Farzadegan, Stacey Meyerer, Shivam Chandan, Samantha Bragan, Dennis Niewoehner, Tadashi Allen, The COPDGene Investigators

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

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

Bibliographical note

Funding Information:
Emily S. Wan, Douglas Curran-Everett, Elizabeth A. Regan, Jeffrey L. Curtis, Dawn L. DeMeo, Peter J. Castaldi, Terri H. Beaty, John E. Hokanson, and James D. Crapo have no conflicts to disclose. Edwin K. Silverman received grant support from GlaxoSmithKline for studies of COPD genetics and has received honoraria and consulting fees from AstraZeneca, Merck, and GlaxoSmithKline. Michael H. Cho has received consulting fees from Merck. MeiLan K. Han has participated in advisory boards for Boehringer Ingelheim GmbH, Pfizer, GlaxoSmithKline, Novartis, Forest and Medimmune, has participated on speaker’s bureaus for Boehringer Ingelheim GmbH, Pfizer, GlaxoSmithKline, Forest, Grifols, the National Association for Continuing Education, and WebMD, has served as a consultant for Novartis, Nycomed and Ikaria and has received royalties from UpToDate and ePocrates, Inc. David A. Lynch’s institution and laboratory receives research support from the National Heart Lung and Blood Institute, Siemens, Inc, Perceptive Imaging, Inc, and Centocor, Inc, Inc. Dr Lynch is a consultant to Perceptive Imaging, Inc, Boehringer Ingelheim, Inc, Genentech, Inc, Gilead, Inc, and Intermune, Inc. Related to the general topic area of COPD over the last 3 years, Barry J. Make has served on medical advisory boards for AstraZeneca, Sunovian, Boehringer-Ingelheim, GlaxoSmithKline, Forest, Ikaria, Aerocrine, Novartis, MedImmune, Coviden, Breathe. Funds for multi-center studies have been provided to and controlled by National Jewish Health from NHLBI, AstraZeneca, Sunovian, Boehringer-Ingelheim, GlaxoSmithKline, Forest, NABI. He has been on the Speaker’s Bureaus for GlaxoSmithKline, Boehringer-Ingelhim, GlaxoSmithKline and Forest.

Funding Information:
NIH R01 HL089856 and NIH P01 HL105339 (E.K.S.), NIH R01 HL089897 (J.D.C.), NIH K12 089990 (E.S.W.), Brigham & Women’s Center for Faculty Development and Diversity Career Development Award (E.S.W.), and a Parker B. Francis Foundation Fellowship (E.S.W.) The COPDGene® project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, GlaxoSmithKline, and Sunovion. The content of this manuscript is solely the responsibility of the authors; none of the above named entities participated in the design or conduct of the study; the collection, management, analysis, or interpretation of the data; or the preparation, review, approval, or decision to submit the manuscript for publication.

Publisher Copyright:
© 2014 Wan et al.; licensee BioMed Central Ltd.

Keywords

  • Lung diseases
  • Restriction
  • Smoking
  • Spirometry

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