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

76 Scopus citations


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
Issue number1
StatePublished - Aug 6 2014


  • Lung diseases
  • Restriction
  • Smoking
  • Spirometry

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