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, COPDGene Investigators, James D Crapo, Edwin K Silverman, Barry J Make, Elizabeth A Regan, Stephanie Bratschie, Rochelle Lantz, Sandra Melanson, Lori Stepp, Terri Beaty, Russell P Bowler, James D Crapo, Jeffrey L Curtis, Douglas Everett, Meilan K Han, John E Hokanson, David Lynch, Barry J Make, Elizabeth Regan, Edwin K Silverman, E Sutherland, Eugene R Bleecker, Harvey O Coxson, Ronald G Crystal, James C Hogg, Michael A Province, Stephen I Rennard, Duncan Thomas, Thomas Croxton, Weiniu Gan, Lisa Postow, John W Walsh, Randel Plant, Delia Prieto, Douglas Everett, Andre Williams, Ruthie Knowles, Carla Wilson, John Hokanson, Jennifer Black-shinn, Gregory Kinney, Terri Beaty, Peter J Castaldi, Michael Cho, Dawn L DeMeo, Marilyn G Foreman, Nadia N Hansel, Megan E Hardin, Craig Hersh, John E Hokanson, Nan Laird, Sharon M Lutz, Manuel Mattheisen, Merry-Lynn McDonald, Margaret M Parker, Elizabeth A Regan, Stephanie Santorico, Edwin K Silverman, Emily S Wan, Jin Zhou, Terri Beaty, Craig P Hersh, Edwin K Silverman, David Lynch, Mustafa Al Qaisi, Jaleh Akhavan, Christian W Cox, Harvey O Coxson, Deanna Cusick, Jennifer G Dy, Shoshana Ginsburg, Eric A Hoffman, Philip F Judy, Alex Kluiber, Alexander McKenzie, John D Newell Jr, John J Reilly Jr, James Ross, Raul San Jose Estepar, Joyce D Schroeder, Jered Sieren, Arkadiusz Sitek, Douglas Stinson, Edwin van Beek, George R Washko, Jordan Zach, Robert Jensen, E Sutherland, Homayoon Farzadegan, Samantha Bragan, Stacey Cayetano, Jeffrey Curtis, Ella Kazerooni, Nicola Hanania, Philip Alapat, Venkata Bandi, Kalpalatha Guntupalli, Elizabeth Guy, Antara Mallampalli, Charles Trinh, Mustafa Atik, Hasan Al-Azzawi, Marc Willis, Susan Pinero, Linda Fahr, Arun Nachiappan, Collin Bray, L Frigini, Carlos Farinas, David Katz, Jose Freytes, Anne Marie Marciel, Dawn DeMeo, Craig Hersh, George Washko, Francine Jacobson, Hiroto Hatabu, Peter Clarke, Ritu Gill, Andetta Hunsaker, Beatrice Trotman-Dickenson, Rachna Madan, R Barr, Byron Thomashow, John Austin, Belinda D'Souza, Neil MacIntyre Jr, H McAdams, Richard Rosiello, Timothy Bresnahan, Joseph Bradley, Steven Meller, Suzanne Roland, Charlene McEvoy, Joseph Tashjian, Robert Wise, Nadia Hansel, Robert Brown, Gregory Diette, Karen Horton, Richard Casaburi, Janos PORSZASZ, Hans Fischer, Matt Budoff, Mehdi Rambod, Michael E DeBakey, Amir Sharafkhaneh, Charles Trinh, Hirani Kamal, Roham Darvishi, Marc Willis, Susan Pinero, Linda Fahr, Arun Nachiappan, Collin Bray, L Frigini, Carlos Farinas, David Katz, Jose Freytes, Anne Marie Marciel, Dennis Niewoehner, Quentin Anderson, Kathryn Rice, Audrey Caine, Marilyn Foreman, Eugene Berkowitz, Russell Bowler, David Lynch, Joyce Schroeder, Valerie Hale, John Armstrong 3rd, Jonathan Chung, Gerard Criner, Victor Kim, Nathaniel Marchetti, Aditi Satti, A Mamary, Robert Steiner, Chandra Dass, Libby Cone, William Bailey, Mark Dransfield, Michael Wells, Surya Bhatt, Hrudaya Nath, Satinder Singh, Joe Ramsdell, Paul Friedman, Alejandro Cornellas, John Newell Jr, Edwin J R van Beek, Fernando Martinez, Meilan Han, Ella Kazerooni, Christine Wendt, Tadashi Allen, Frank Sciurba, Joel Weissfeld, Carl Fuhrman, Jessica Bon, Danielle Hooper, Sandra Adams, Carlos Orozco, Mario Ruiz, Amy Mumbower, Ariel Kruger, Carlos Restrepo, Michael Lane, 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, COPDGene Investigators, James D Crapo, Edwin K Silverman, Barry J Make, Elizabeth A Regan, Stephanie Bratschie, Rochelle Lantz, Sandra Melanson, Lori Stepp, Terri Beaty, Russell P Bowler, James D Crapo, Jeffrey L Curtis, Douglas Everett, Meilan K Han, John E Hokanson, David Lynch, Barry J Make, Elizabeth Regan, Edwin K Silverman, E Sutherland, Eugene R Bleecker, Harvey O Coxson, Ronald G Crystal, James C Hogg, Michael A Province, Stephen I Rennard, Duncan Thomas, Thomas Croxton, Weiniu Gan, Lisa Postow, John W Walsh, Randel Plant, Delia Prieto, Douglas Everett, Andre Williams, Ruthie Knowles, Carla Wilson, John Hokanson, Jennifer Black-shinn, Gregory Kinney, Terri Beaty, Peter J Castaldi, Michael Cho, Dawn L DeMeo, Marilyn G Foreman, Nadia N Hansel, Megan E Hardin, Craig Hersh, John E Hokanson, Nan Laird, Sharon M Lutz, Manuel Mattheisen, Merry-Lynn McDonald, Margaret M Parker, Elizabeth A Regan, Stephanie Santorico, Edwin K Silverman, Emily S Wan, Jin Zhou, Terri Beaty, Craig P Hersh, Edwin K Silverman, David Lynch, Mustafa Al Qaisi, Jaleh Akhavan, Christian W Cox, Harvey O Coxson, Deanna Cusick, Jennifer G Dy, Shoshana Ginsburg, Eric A Hoffman, Philip F Judy, Alex Kluiber, Alexander McKenzie, John D Newell Jr, John J Reilly Jr, James Ross, Raul San Jose Estepar, Joyce D Schroeder, Jered Sieren, Arkadiusz Sitek, Douglas Stinson, Edwin van Beek, George R Washko, Jordan Zach, Robert Jensen, E Sutherland, Homayoon Farzadegan, Samantha Bragan, Stacey Cayetano, Jeffrey Curtis, Ella Kazerooni, Nicola Hanania, Philip Alapat, Venkata Bandi, Kalpalatha Guntupalli, Elizabeth Guy, Antara Mallampalli, Charles Trinh, Mustafa Atik, Hasan Al-Azzawi, Marc Willis, Susan Pinero, Linda Fahr, Arun Nachiappan, Collin Bray, L Frigini, Carlos Farinas, David Katz, Jose Freytes, Anne Marie Marciel, Dawn DeMeo, Craig Hersh, George Washko, Francine Jacobson, Hiroto Hatabu, Peter Clarke, Ritu Gill, Andetta Hunsaker, Beatrice Trotman-Dickenson, Rachna Madan, R Barr, Byron Thomashow, John Austin, Belinda D'Souza, Neil MacIntyre Jr, H McAdams, Richard Rosiello, Timothy Bresnahan, Joseph Bradley, Steven Meller, Suzanne Roland, Charlene McEvoy, Joseph Tashjian, Robert Wise, Nadia Hansel, Robert Brown, Gregory Diette, Karen Horton, Richard Casaburi, Janos PORSZASZ, Hans Fischer, Matt Budoff, Mehdi Rambod, Michael E DeBakey, Amir Sharafkhaneh, Charles Trinh, Hirani Kamal, Roham Darvishi, Marc Willis, Susan Pinero, Linda Fahr, Arun Nachiappan, Collin Bray, L Frigini, Carlos Farinas, David Katz, Jose Freytes, Anne Marie Marciel, Dennis Niewoehner, Quentin Anderson, Kathryn Rice, Audrey Caine, Marilyn Foreman, Eugene Berkowitz, Russell Bowler, David Lynch, Joyce Schroeder, Valerie Hale, John Armstrong 3rd, Jonathan Chung, Gerard Criner, Victor Kim, Nathaniel Marchetti, Aditi Satti, A Mamary, Robert Steiner, Chandra Dass, Libby Cone, William Bailey, Mark Dransfield, Michael Wells, Surya Bhatt, Hrudaya Nath, Satinder Singh, Joe Ramsdell, Paul Friedman, Alejandro Cornellas, John Newell Jr, Edwin J R van Beek, Fernando Martinez, Meilan Han, Ella Kazerooni, Christine Wendt, Tadashi Allen, Frank Sciurba, Joel Weissfeld, Carl Fuhrman, Jessica Bon, Danielle Hooper, Sandra Adams, Carlos Orozco, Mario Ruiz, Amy Mumbower, Ariel Kruger, Carlos Restrepo, Michael Lane

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.

Trial registration: ClinicalTrials.gov NCT00608764 NCT00608764.

Figures

Figure 1
Figure 1
Distribution of spirometry in COPDGene. Legend: Forced expiratory volume in the first second (FEV1) is plotted on the x-axis while FEV1/FVC ratio is plotted on the y-axis. Dashed lines represent fixed-threshold criteria used to delineate Preserved Ratio Impaired Spirometry (PRISm) subjects (highlighted in blue-upper left quadrant), control (upper right quadrant), and COPD (lower left quadrant) subjects.
Figure 2
Figure 2
Overview of cluster analysis in subjects with Preserved Ratio Impaired Spirometry (PRISm).
Figure 3
Figure 3
Results of k-means clustering in fixed-threshold definedPreservedRatioImpairedSpirometry (PRISm) in non-Hispanic whites. Legend: Unsupervised k-means clustering was performed in non-Hispanic white subjects with PRISm. The first two principal components generated using the scaled 6 key input variables used for clustering (body mass index, FEV1%, predicted, FEV1/FVC ratio, percent emphysema, total lung capacity, and segmental wall area) are plotted on the x- and y-axes respectively.
Figure 4
Figure 4
Results of k-means clustering in fixed-threshold definedPreservedRatioImpairedSpirometry (PRISm) in African Americans. Legend: Unsupervised k-means clustering was performed in African American subjects with PRISm. The first two principal components generated using the scaled 6 key input variables used for clustering (body mass index, FEV1%, predicted, FEV1/FVC ratio, percent emphysema, total lung capacity, and segmental wall area) are plotted on the x- and y-axes respectively.

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