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

Jin Hwa Lee, Merry-Lynn N McDonald, Michael H Cho, Emily S Wan, Peter J Castaldi, Gary M Hunninghake, Nathaniel Marchetti, David A Lynch, James D Crapo, David A Lomas, Harvey O Coxson, Per S Bakke, Edwin K Silverman, Craig P Hersh, COPDGene and ECLIPSE Investigators, James D Crapo, Edwin K Silverman, Barry J Make, Elizabeth 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 C 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, 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, 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, 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, Y Ivanov, K Kostov, J Bourbeau, M Fitzgerald, P Hernandez, K Killian, R Levy, F Maltais, J Krepelka, E Wouters, D Quinn, P Bakke, M Kosnik, A Agusti, J Sauleda, Y Feschenko, V Gavrisyuk, L Yashina, N Monogarova, P Calverley, D Lomas, W MacNee, D Singh, J Wedzicha, A Anzueto, S Braman, R Casaburi, B Celli, G Giessel, M Gotfried, G Greenwald, D Mahler, B Make, S Rennard, C Rochester, P Scanlon, F Sciurba, A Sharafkhaneh, T Siler, E Silverman, A Wanner, R Wise, H Coxson, C Crim, D Lomas, W MacNee, E Silverman, J Vestbo, J Yates, A Agusti, P Calverley, B Celli, C Crim, B Miller, W MacNee, S Rennard, R Tal-Singer, E Wouters, J Yates, Jin Hwa Lee, Merry-Lynn N McDonald, Michael H Cho, Emily S Wan, Peter J Castaldi, Gary M Hunninghake, Nathaniel Marchetti, David A Lynch, James D Crapo, David A Lomas, Harvey O Coxson, Per S Bakke, Edwin K Silverman, Craig P Hersh, COPDGene and ECLIPSE Investigators, James D Crapo, Edwin K Silverman, Barry J Make, Elizabeth 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 C 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, 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, 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, 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, Y Ivanov, K Kostov, J Bourbeau, M Fitzgerald, P Hernandez, K Killian, R Levy, F Maltais, J Krepelka, E Wouters, D Quinn, P Bakke, M Kosnik, A Agusti, J Sauleda, Y Feschenko, V Gavrisyuk, L Yashina, N Monogarova, P Calverley, D Lomas, W MacNee, D Singh, J Wedzicha, A Anzueto, S Braman, R Casaburi, B Celli, G Giessel, M Gotfried, G Greenwald, D Mahler, B Make, S Rennard, C Rochester, P Scanlon, F Sciurba, A Sharafkhaneh, T Siler, E Silverman, A Wanner, R Wise, H Coxson, C Crim, D Lomas, W MacNee, E Silverman, J Vestbo, J Yates, A Agusti, P Calverley, B Celli, C Crim, B Miller, W MacNee, S Rennard, R Tal-Singer, E Wouters, J Yates

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) <0.7 and FEV1 < 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.

Trial registration: ClinicalTrials.gov NCT00292552 NCT00608764.

Figures

Figure 1
Figure 1
The three-cohort meta-analysis including 1000 Genomes project imputed data for total lung capacity measured by chest CT in COPD subjects after adjustment for age, gender, height, pack-years of cigarette smoking and genetic ancestry-based principal components. (a) The quantile–quantile plot and (b) Manhattan plot of –log10 P values.
Figure 2
Figure 2
The meta-analysis for total lung capacity measured by chest CT in COPD subjects. Regional association plots for (a) one genome-wide significant locus and (b-e) the other four suggestive loci. The x-axis is chromosomal position, and the y-axis shows the -log10 P value. The most significant SNP at each locus is labeled in purple, with other SNPs colored by degress of linkage disequilibrium (r2). Plots were generated using LocusZoom.

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