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

the COPDGene and ECLIPSE Investigators

doi:10.1186/s12931-014-0097-y

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

the COPDGene and ECLIPSE Investigators

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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 (TLC_CT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLC_CT, 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, TLC_CT 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.

Original language	English
Article number	97
Journal	Respiratory Research
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s12931-014-0097-y
State	Published - 20 Aug 2014

Keywords

Chronic obstructive
DNAH5
Genome-wide association analysis
Hyperinflation
Pulmonary disease
Total lung capacity

Access to Document

10.1186/s12931-014-0097-y

Cite this

@article{6116ac0f13384d4b8e52f011a0bfd16a,

title = "DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease",

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.",

keywords = "Chronic obstructive, DNAH5, Genome-wide association analysis, Hyperinflation, Pulmonary disease, Total lung capacity",

author = "{the COPDGene and ECLIPSE Investigators} and Lee, {Jin H.} and McDonald, {Merry Lynn N.} and Cho, {Michael H.} and Wan, {Emily S.} and Castaldi, {Peter J.} and Hunninghake, {Gary M.} and Nathaniel Marchetti and Lynch, {David A.} and Crapo, {James D.} and Lomas, {David A.} and Coxson, {Harvey O.} and Bakke, {Per S.} and Silverman, {Edwin K.} and Hersh, {Craig P.} and Stephanie Bratschie and Rochelle Lantz and Sandra Melanson and Lori Stepp and Russell Bowler and Curtis, {Jeffrey L.} and Han, {Mei Lan} and Hokanson, {John E.} and Make, {Barry J.} and Sutherland, {E. Rand} and Bleecker, {Eugene R.} and Crystal, {Ronald G.} and Hogg, {James C.} and Province, {Michael A.} and Rennard, {Stephen I.} and Thomas, {Duncan C.} and Thomas Croxton and Weiniu Gan and Lisa Postow and Walsh, {John W.} and Randel Plant and Delia Prieto and Daniel Cossette and Kelly, {Roxanne K.} and Douglas Everett and Andre Williams and Ruthie Knowles and Carla Wilson and John Hokanson and Jennifer Black-Shinn and Gregory Kinney and Michael Cho and Dawn DeMeo and Foreman, {Marilyn G.} and Hansel, {Nadia N.} and Hardin, {Megan E.}",

note = "Funding Information: In the past 3 years, Drs Lee, McDonald, Wan, Castaldi, Hunninghake, Marchetti, Lynch, Crapo, Lomas, Coxson and Bakke have no competing interests related to the subject of the manuscript. In the past 3 years, Dr Silverman reports grants from NIH, grants and other support from COPD Foundation, grants and personal fees from GlaxoSmithKline, during the conduct of the study; personal fees from Merck and travel support from Novartis, outside the submitted work. In the past 3 years, Dr Cho has received NIH grant and consulted for Merck (outside the submitted work). In the past 3 years, Dr Hersh has received NIH grant and consulted for Novartis, CSL Behring (outside the submitted work). Funding Information: This work was supported by NIH R01 HL094635 (C.P.H.), R01 NR013377 (C.P.H.), R01 HL089856 (E.K.S.), P01 HL105339 (E.K.S.), and R01HL089897 (J.D.C.) The COPDGene study (NCT00608764) 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 Norway GenKOLS study (Genetics of Chronic Obstructive Lung Disease, GSK code RES11080) and the ECLIPSE study (NCT00292552; GSK code SCO104960) were sponsored by GlaxoSmithKline. We acknowledge and thank the COPDGene Core Teams: Administrative Core: James D. Crapo, MD (PI); Edwin K. Silverman, MD, PhD (PI); Barry J. Make, MD; Elizabeth A. Regan, MD, PhD; Stephanie Bratschie, MPH; Rochelle Lantz; Sandra Melanson, MSW, LCSW; Lori Stepp Executive Committee: Terri Beaty, PhD; Russell P. Bowler, MD, PhD; James D. Crapo, MD; Jeffrey L. Curtis, MD; Douglas Everett, PhD; MeiLan K. Han, MD, MS; John E. Hokanson, MPH, PhD; David Lynch, MB; Barry J. Make, MD; Elizabeth A. Regan, MD, PhD; Edwin K. Silverman, MD, PhD; E. Rand Sutherland, MD External Advisory Committee: Eugene R. Bleecker, MD; Harvey O. Coxson, PhD; Ronald G. Crystal, MD; James C. Hogg, MD; Michael A. Province, PhD; Stephen I. Rennard, MD; Duncan C. Thomas, PhD NHLBI: Thomas Croxton, MD, PhD; Weiniu Gan, PhD; Lisa Postow, PhD COPD Foundation: John W. Walsh; Randel Plant; Delia Prieto Biorepository Visit 1 (Baltimore): Homayoon Farzadegan, PhD; Samantha Bragan; Stacey Cayetano Biorepository Visit 2 (Boston): Daniel Cossette; Roxanne K. Kelly, MBA Data Coordinating Center: Douglas Everett, PhD; Andre Williams, PhD; Ruthie Knowles; Carla Wilson, MS Epidemiology Core: John Hokanson, MPH, PhD; Jennifer Black-Shinn, MPH; Gregory Kinney, MPH Genetic Analysis Core: Terri Beaty, PhD; Peter J. Castaldi, MD, MSc; Michael Cho, MD; Dawn L. DeMeo, MD, MPH; Marilyn G. Foreman, MD, MS; Nadia N. Hansel, MD, MPH; Megan E. Hardin, MD; Craig Hersh, MD, MPH; Jacqueline Hetmanski, MS; John E. Hokanson, MPH, PhD; Nan Laird, PhD; Christoph Lange, PhD; Sharon M. Lutz, MPH, PhD; Manuel Mattheisen, MD; Merry-Lynn McDonald, MSc, PhD; Margaret M. Parker, MHS; Elizabeth A. Regan, MD, PhD; Stephanie Santorico, PhD; Edwin K. Silverman, MD, PhD; Emily S. Wan, MD; Jin Zhou, PhD Genotyping Cores: Genome-Wide Core: Terri Beaty, PhD; Candidate Genotyping Core: Craig P. Hersh, MD, MPH; Edwin K. Silverman, MD, PhD Imaging Core: David Lynch, MB; Mustafa Al Qaisi, MD; Jaleh Akhavan; Christian W. Cox, MD; Harvey O. Coxson, PhD; Deanna Cusick; Jennifer G. Dy, PhD; Shoshana Ginsburg, MS; Eric A. Hoffman, PhD; Philip F. Judy, PhD; Alex Kluiber; Alexander McKenzie; John D. Newell, Jr., MD; John J. Reilly, Jr., MD; James Ross, MSc; Raul San Jose Estepar, PhD; Joyce D. Schroeder, MD; Jered Sieren; Arkadiusz Sitek, PhD; Douglas Stinson; Edwin van Beek, MD, PhD, MEd; George R. Washko, MD; Jordan Zach PFT QA Core: Robert Jensen, PhD; E. Rand Sutherland, MD Biological Repository, Johns Hopkins University, Baltimore, MD: Homayoon Farzadegan, PhD: Samantha Bragan; Stacey Cayetano We further wish to acknowledge the COPDGene Investigators from the participating Clinical Centers: Ann Arbor VA: Jeffrey Curtis, MD, Ella Kazerooni, MD Baylor College of Medicine, Houston, TX: Nicola Hanania, MD, MS, Philip Alapat, MD, Venkata Bandi, MD, Kalpalatha Guntupalli, MD, Elizabeth Guy, MD, Antara Mallampalli, MD, Charles Trinh, MD, Mustafa Atik, MD, Hasan Al-Azzawi, MD, Marc Willis, DO, Susan Pinero, MD, Linda Fahr, MD, Arun Nachiappan, MD, Collin Bray, MD, L. Alexander Frigini, MD, Carlos Farinas, MD, David Katz, MD, Jose Freytes, MD, Anne Marie Marciel, MD Brigham and Women{\textquoteright}s Hospital, Boston, MA: Dawn DeMeo, MD, MPH, Craig Hersh, MD, MPH, George Washko, MD, Francine Jacobson, MD, MPH, Hiroto Hatabu, MD, PhD, Peter Clarke, MD, Ritu Gill, MD, Andetta Hunsaker, MD, Beatrice Trotman-Dickenson, MBBS, Rachna Madan, MD Columbia University, New York, NY: R. Graham Barr, MD, DrPH, Byron Thomashow, MD, John Austin, MD, Belinda D{\textquoteright}Souza, MD Duke University Medical Center, Durham, NC: Neil MacIntyre, Jr., MD, Lacey Washington, MD, H Page McAdams, MD Reliant Medical Group, Worcester, MA: Richard Rosiello, MD, Timothy Bresnahan, MD, Joseph Bradley, MD, Sharon Kuong, MD, Steven Meller, MD, Suzanne Roland, MD Health Partners Research Foundation, Minneapolis, MN: Charlene McEvoy, MD, MPH, Joseph Tashjian, MD Johns Hopkins University, Baltimore, MD: Robert Wise, MD, Nadia Hansel, MD, MPH, Robert Brown, MD, Gregory Diette, MD, Karen Horton, MD Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Los Angeles, CA: Richard Casaburi, MD, Janos Porszasz, MD, PhD, Hans Fischer, MD, PhD, Matt Budoff, MD, Mehdi Rambod, MD Michael E. DeBakey VAMC, Houston, TX: Amir Sharafkhaneh, MD, Charles Trinh, MD, Hirani Kamal, MD, Roham Darvishi, MD, Marc Willis, DO, Susan Pinero, MD, Linda Fahr, MD, Arun Nachiappan, MD, Collin Bray, MD, L. Alexander Frigini, MD, Carlos Farinas, MD, David Katz, MD, Jose Freytes, MD, Anne Marie Marciel, MD Minneapolis VA: Dennis Niewoehner, MD, Quentin Anderson, MD, Kathryn Rice, MD, Audrey Caine, MD Morehouse School of Medicine, Atlanta, GA: Marilyn Foreman, MD, MS, Gloria Westney, MD, MS, Eugene Berkowitz, MD, PhD National Jewish Health, Denver, CO: Russell Bowler, MD, PhD, David Lynch, MB, Joyce Schroeder, MD, Valerie Hale, MD, John Armstrong, II, MD, Debra Dyer, MD, Jonathan Chung, MD, Christian Cox, MD Temple University, Philadelphia, PA: Gerard Criner, MD, Victor Kim, MD, Nathaniel Marchetti, DO, Aditi Satti, MD, A. James Mamary, MD, Robert Steiner, MD, Chandra Dass, MD, Libby Cone, MD University of Alabama, Birmingham, AL: William Bailey, MD, Mark Dransfield, MD, Michael Wells, MD, Surya Bhatt, MD, Hrudaya Nath, MD, Satinder Singh, MD University of California, San Diego, CA: Joe Ramsdell, MD, Paul Friedman, MD University of Iowa, Iowa City, IA: Alejandro Cornellas, MD, John Newell, Jr., MD, Edwin JR van Beek, MD, PhD University of Michigan, Ann Arbor, MI: Fernando Martinez, MD, MeiLan Han, MD, Ella Kazerooni, MD University of Minnesota, Minneapolis, MN: Christine Wendt, MD, Tadashi Allen, MD University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, MD, Joel Weissfeld, MD, MPH, Carl Fuhrman, MD, Jessica Bon, MD, Danielle Hooper, MD University of Texas Health Science Center at San Antonio, San Antonio, TX: Antonio Anzueto, MD, Sandra Adams, MD, Carlos Orozco, MD, Mario Ruiz, MD, Amy Mumbower, MD, Ariel Kruger, MD, Carlos Restrepo, MD, Michael Lane, MD We acknowledge and thank the ECLIPSE investigators: Investigators — Bulgaria: Y. Ivanov, Pleven; K. Kostov, Sofia. Canada: J. Bourbeau, Montreal; M. Fitzgerald, Vancouver, BC; P. Hernandez, Halifax, NS; K. Killian, Hamilton, ON; R. Levy, Vancouver, BC; F. Maltais, Montreal; D. O'Donnell, Kingston, ON. Czech Republic: J. Krepelka, Prague. Denmark: J. Vestbo, Hvidovre. The Netherlands: E. Wouters, Horn-Maastricht. New Zealand: D. Quinn, Wellington. Norway: P. Bakke, Bergen. Slovenia: M. Kosnik, Golnik. Spain: A. Agusti, J. Sauleda, P. de Mallorca. Ukraine: Y. Feschenko, V. Gavrisyuk, L. Yashina, Kiev; N. Monogarova, Donetsk. United Kingdom: P. Calverley, Liverpool; D. Lomas, Cambridge; W. MacNee, Edinburgh; D. Singh, Manchester; J. Wedzicha, London. United States: A. Anzueto, San Antonio, TX; S. Braman, Providence, RI; R. Casaburi, Torrance CA; B. Celli, Boston; G. Giessel, Richmond, VA; M. Gotfried, Phoenix, AZ; G. Greenwald, Rancho Mirage, CA; N. Hanania, Houston; D. Mahler, Lebanon, NH; B. Make, Denver; S. Rennard, Omaha, NE; C. Rochester, New Haven, CT; P. Scanlon, Rochester, MN; D. Schuller, Omaha, NE; F. Sciurba, Pittsburgh; A. Sharafkhaneh, Houston; T. Siler, St. Charles, MO; E. Silverman, Boston; A. Wanner, Miami; R. Wise, Baltimore; R. ZuWallack, Hartford, CT. Steering Committee: H. Coxson (Canada), C. Crim (GlaxoSmithKline, USA), L. Edwards (GlaxoSmithKline, USA), D. Lomas (UK), W. MacNee (UK), E. Silverman (USA), R. Tal Singer (Co-chair, GlaxoSmithKline, USA), J. Vestbo (Co-chair, Denmark), J. Yates (GlaxoSmithKline, USA). Scientific Committee: A. Agusti (Spain), P. Calverley (UK), B. Celli (USA), C. Crim (GlaxoSmithKline, USA), B. Miller (GlaxoSmithKline, USA), W. MacNee (Chair, UK), S. Rennard (USA), R. Tal-Singer (GlaxoSmithKline, USA), E. Wouters (The Netherlands), J. Yates (GlaxoSmithKline, USA). Publisher Copyright: {\textcopyright} 2014 Lee et al.; licensee BioMed Central Ltd.",

year = "2014",

month = aug,

day = "20",

doi = "10.1186/s12931-014-0097-y",

language = "English",

volume = "15",

journal = "Respiratory Research",

issn = "1465-9921",

publisher = "BioMed Central Ltd.",

number = "1",

}

TY - JOUR

T1 - DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease

AU - the COPDGene and ECLIPSE Investigators

AU - Lee, Jin H.

AU - McDonald, Merry Lynn N.

AU - Cho, Michael H.

AU - Wan, Emily S.

AU - Castaldi, Peter J.

AU - Hunninghake, Gary M.

AU - Marchetti, Nathaniel

AU - Lynch, David A.

AU - Crapo, James D.

AU - Lomas, David A.

AU - Coxson, Harvey O.

AU - Bakke, Per S.

AU - Silverman, Edwin K.

AU - Hersh, Craig P.

AU - Bratschie, Stephanie

AU - Lantz, Rochelle

AU - Melanson, Sandra

AU - Stepp, Lori

AU - Bowler, Russell

AU - Curtis, Jeffrey L.

AU - Han, Mei Lan

AU - Hokanson, John E.

AU - Make, Barry J.

AU - Sutherland, E. Rand

AU - Bleecker, Eugene R.

AU - Crystal, Ronald G.

AU - Hogg, James C.

AU - Province, Michael A.

AU - Rennard, Stephen I.

AU - Thomas, Duncan C.

AU - Croxton, Thomas

AU - Gan, Weiniu

AU - Postow, Lisa

AU - Walsh, John W.

AU - Plant, Randel

AU - Prieto, Delia

AU - Cossette, Daniel

AU - Kelly, Roxanne K.

AU - Everett, Douglas

AU - Williams, Andre

AU - Knowles, Ruthie

AU - Wilson, Carla

AU - Hokanson, John

AU - Black-Shinn, Jennifer

AU - Kinney, Gregory

AU - Cho, Michael

AU - DeMeo, Dawn

AU - Foreman, Marilyn G.

AU - Hansel, Nadia N.

AU - Hardin, Megan E.

N1 - Funding Information: In the past 3 years, Drs Lee, McDonald, Wan, Castaldi, Hunninghake, Marchetti, Lynch, Crapo, Lomas, Coxson and Bakke have no competing interests related to the subject of the manuscript. In the past 3 years, Dr Silverman reports grants from NIH, grants and other support from COPD Foundation, grants and personal fees from GlaxoSmithKline, during the conduct of the study; personal fees from Merck and travel support from Novartis, outside the submitted work. In the past 3 years, Dr Cho has received NIH grant and consulted for Merck (outside the submitted work). In the past 3 years, Dr Hersh has received NIH grant and consulted for Novartis, CSL Behring (outside the submitted work). Funding Information: This work was supported by NIH R01 HL094635 (C.P.H.), R01 NR013377 (C.P.H.), R01 HL089856 (E.K.S.), P01 HL105339 (E.K.S.), and R01HL089897 (J.D.C.) The COPDGene study (NCT00608764) 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 Norway GenKOLS study (Genetics of Chronic Obstructive Lung Disease, GSK code RES11080) and the ECLIPSE study (NCT00292552; GSK code SCO104960) were sponsored by GlaxoSmithKline. We acknowledge and thank the COPDGene Core Teams: Administrative Core: James D. Crapo, MD (PI); Edwin K. Silverman, MD, PhD (PI); Barry J. Make, MD; Elizabeth A. Regan, MD, PhD; Stephanie Bratschie, MPH; Rochelle Lantz; Sandra Melanson, MSW, LCSW; Lori Stepp Executive Committee: Terri Beaty, PhD; Russell P. Bowler, MD, PhD; James D. Crapo, MD; Jeffrey L. Curtis, MD; Douglas Everett, PhD; MeiLan K. Han, MD, MS; John E. Hokanson, MPH, PhD; David Lynch, MB; Barry J. Make, MD; Elizabeth A. Regan, MD, PhD; Edwin K. Silverman, MD, PhD; E. Rand Sutherland, MD External Advisory Committee: Eugene R. Bleecker, MD; Harvey O. Coxson, PhD; Ronald G. Crystal, MD; James C. Hogg, MD; Michael A. Province, PhD; Stephen I. Rennard, MD; Duncan C. Thomas, PhD NHLBI: Thomas Croxton, MD, PhD; Weiniu Gan, PhD; Lisa Postow, PhD COPD Foundation: John W. Walsh; Randel Plant; Delia Prieto Biorepository Visit 1 (Baltimore): Homayoon Farzadegan, PhD; Samantha Bragan; Stacey Cayetano Biorepository Visit 2 (Boston): Daniel Cossette; Roxanne K. Kelly, MBA Data Coordinating Center: Douglas Everett, PhD; Andre Williams, PhD; Ruthie Knowles; Carla Wilson, MS Epidemiology Core: John Hokanson, MPH, PhD; Jennifer Black-Shinn, MPH; Gregory Kinney, MPH Genetic Analysis Core: Terri Beaty, PhD; Peter J. Castaldi, MD, MSc; Michael Cho, MD; Dawn L. DeMeo, MD, MPH; Marilyn G. Foreman, MD, MS; Nadia N. Hansel, MD, MPH; Megan E. Hardin, MD; Craig Hersh, MD, MPH; Jacqueline Hetmanski, MS; John E. Hokanson, MPH, PhD; Nan Laird, PhD; Christoph Lange, PhD; Sharon M. Lutz, MPH, PhD; Manuel Mattheisen, MD; Merry-Lynn McDonald, MSc, PhD; Margaret M. Parker, MHS; Elizabeth A. Regan, MD, PhD; Stephanie Santorico, PhD; Edwin K. Silverman, MD, PhD; Emily S. Wan, MD; Jin Zhou, PhD Genotyping Cores: Genome-Wide Core: Terri Beaty, PhD; Candidate Genotyping Core: Craig P. Hersh, MD, MPH; Edwin K. Silverman, MD, PhD Imaging Core: David Lynch, MB; Mustafa Al Qaisi, MD; Jaleh Akhavan; Christian W. Cox, MD; Harvey O. Coxson, PhD; Deanna Cusick; Jennifer G. Dy, PhD; Shoshana Ginsburg, MS; Eric A. Hoffman, PhD; Philip F. Judy, PhD; Alex Kluiber; Alexander McKenzie; John D. Newell, Jr., MD; John J. Reilly, Jr., MD; James Ross, MSc; Raul San Jose Estepar, PhD; Joyce D. Schroeder, MD; Jered Sieren; Arkadiusz Sitek, PhD; Douglas Stinson; Edwin van Beek, MD, PhD, MEd; George R. Washko, MD; Jordan Zach PFT QA Core: Robert Jensen, PhD; E. Rand Sutherland, MD Biological Repository, Johns Hopkins University, Baltimore, MD: Homayoon Farzadegan, PhD: Samantha Bragan; Stacey Cayetano We further wish to acknowledge the COPDGene Investigators from the participating Clinical Centers: Ann Arbor VA: Jeffrey Curtis, MD, Ella Kazerooni, MD Baylor College of Medicine, Houston, TX: Nicola Hanania, MD, MS, Philip Alapat, MD, Venkata Bandi, MD, Kalpalatha Guntupalli, MD, Elizabeth Guy, MD, Antara Mallampalli, MD, Charles Trinh, MD, Mustafa Atik, MD, Hasan Al-Azzawi, MD, Marc Willis, DO, Susan Pinero, MD, Linda Fahr, MD, Arun Nachiappan, MD, Collin Bray, MD, L. Alexander Frigini, MD, Carlos Farinas, MD, David Katz, MD, Jose Freytes, MD, Anne Marie Marciel, MD Brigham and Women’s Hospital, Boston, MA: Dawn DeMeo, MD, MPH, Craig Hersh, MD, MPH, George Washko, MD, Francine Jacobson, MD, MPH, Hiroto Hatabu, MD, PhD, Peter Clarke, MD, Ritu Gill, MD, Andetta Hunsaker, MD, Beatrice Trotman-Dickenson, MBBS, Rachna Madan, MD Columbia University, New York, NY: R. Graham Barr, MD, DrPH, Byron Thomashow, MD, John Austin, MD, Belinda D’Souza, MD Duke University Medical Center, Durham, NC: Neil MacIntyre, Jr., MD, Lacey Washington, MD, H Page McAdams, MD Reliant Medical Group, Worcester, MA: Richard Rosiello, MD, Timothy Bresnahan, MD, Joseph Bradley, MD, Sharon Kuong, MD, Steven Meller, MD, Suzanne Roland, MD Health Partners Research Foundation, Minneapolis, MN: Charlene McEvoy, MD, MPH, Joseph Tashjian, MD Johns Hopkins University, Baltimore, MD: Robert Wise, MD, Nadia Hansel, MD, MPH, Robert Brown, MD, Gregory Diette, MD, Karen Horton, MD Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Los Angeles, CA: Richard Casaburi, MD, Janos Porszasz, MD, PhD, Hans Fischer, MD, PhD, Matt Budoff, MD, Mehdi Rambod, MD Michael E. DeBakey VAMC, Houston, TX: Amir Sharafkhaneh, MD, Charles Trinh, MD, Hirani Kamal, MD, Roham Darvishi, MD, Marc Willis, DO, Susan Pinero, MD, Linda Fahr, MD, Arun Nachiappan, MD, Collin Bray, MD, L. Alexander Frigini, MD, Carlos Farinas, MD, David Katz, MD, Jose Freytes, MD, Anne Marie Marciel, MD Minneapolis VA: Dennis Niewoehner, MD, Quentin Anderson, MD, Kathryn Rice, MD, Audrey Caine, MD Morehouse School of Medicine, Atlanta, GA: Marilyn Foreman, MD, MS, Gloria Westney, MD, MS, Eugene Berkowitz, MD, PhD National Jewish Health, Denver, CO: Russell Bowler, MD, PhD, David Lynch, MB, Joyce Schroeder, MD, Valerie Hale, MD, John Armstrong, II, MD, Debra Dyer, MD, Jonathan Chung, MD, Christian Cox, MD Temple University, Philadelphia, PA: Gerard Criner, MD, Victor Kim, MD, Nathaniel Marchetti, DO, Aditi Satti, MD, A. James Mamary, MD, Robert Steiner, MD, Chandra Dass, MD, Libby Cone, MD University of Alabama, Birmingham, AL: William Bailey, MD, Mark Dransfield, MD, Michael Wells, MD, Surya Bhatt, MD, Hrudaya Nath, MD, Satinder Singh, MD University of California, San Diego, CA: Joe Ramsdell, MD, Paul Friedman, MD University of Iowa, Iowa City, IA: Alejandro Cornellas, MD, John Newell, Jr., MD, Edwin JR van Beek, MD, PhD University of Michigan, Ann Arbor, MI: Fernando Martinez, MD, MeiLan Han, MD, Ella Kazerooni, MD University of Minnesota, Minneapolis, MN: Christine Wendt, MD, Tadashi Allen, MD University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, MD, Joel Weissfeld, MD, MPH, Carl Fuhrman, MD, Jessica Bon, MD, Danielle Hooper, MD University of Texas Health Science Center at San Antonio, San Antonio, TX: Antonio Anzueto, MD, Sandra Adams, MD, Carlos Orozco, MD, Mario Ruiz, MD, Amy Mumbower, MD, Ariel Kruger, MD, Carlos Restrepo, MD, Michael Lane, MD We acknowledge and thank the ECLIPSE investigators: Investigators — Bulgaria: Y. Ivanov, Pleven; K. Kostov, Sofia. Canada: J. Bourbeau, Montreal; M. Fitzgerald, Vancouver, BC; P. Hernandez, Halifax, NS; K. Killian, Hamilton, ON; R. Levy, Vancouver, BC; F. Maltais, Montreal; D. O'Donnell, Kingston, ON. Czech Republic: J. Krepelka, Prague. Denmark: J. Vestbo, Hvidovre. The Netherlands: E. Wouters, Horn-Maastricht. New Zealand: D. Quinn, Wellington. Norway: P. Bakke, Bergen. Slovenia: M. Kosnik, Golnik. Spain: A. Agusti, J. Sauleda, P. de Mallorca. Ukraine: Y. Feschenko, V. Gavrisyuk, L. Yashina, Kiev; N. Monogarova, Donetsk. United Kingdom: P. Calverley, Liverpool; D. Lomas, Cambridge; W. MacNee, Edinburgh; D. Singh, Manchester; J. Wedzicha, London. United States: A. Anzueto, San Antonio, TX; S. Braman, Providence, RI; R. Casaburi, Torrance CA; B. Celli, Boston; G. Giessel, Richmond, VA; M. Gotfried, Phoenix, AZ; G. Greenwald, Rancho Mirage, CA; N. Hanania, Houston; D. Mahler, Lebanon, NH; B. Make, Denver; S. Rennard, Omaha, NE; C. Rochester, New Haven, CT; P. Scanlon, Rochester, MN; D. Schuller, Omaha, NE; F. Sciurba, Pittsburgh; A. Sharafkhaneh, Houston; T. Siler, St. Charles, MO; E. Silverman, Boston; A. Wanner, Miami; R. Wise, Baltimore; R. ZuWallack, Hartford, CT. Steering Committee: H. Coxson (Canada), C. Crim (GlaxoSmithKline, USA), L. Edwards (GlaxoSmithKline, USA), D. Lomas (UK), W. MacNee (UK), E. Silverman (USA), R. Tal Singer (Co-chair, GlaxoSmithKline, USA), J. Vestbo (Co-chair, Denmark), J. Yates (GlaxoSmithKline, USA). Scientific Committee: A. Agusti (Spain), P. Calverley (UK), B. Celli (USA), C. Crim (GlaxoSmithKline, USA), B. Miller (GlaxoSmithKline, USA), W. MacNee (Chair, UK), S. Rennard (USA), R. Tal-Singer (GlaxoSmithKline, USA), E. Wouters (The Netherlands), J. Yates (GlaxoSmithKline, USA). Publisher Copyright: © 2014 Lee et al.; licensee BioMed Central Ltd.

PY - 2014/8/20

Y1 - 2014/8/20

N2 - 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.

AB - 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.

KW - Chronic obstructive

KW - DNAH5

KW - Genome-wide association analysis

KW - Hyperinflation

KW - Pulmonary disease

KW - Total lung capacity

UR - http://www.scopus.com/inward/record.url?scp=84908157737&partnerID=8YFLogxK

U2 - 10.1186/s12931-014-0097-y

DO - 10.1186/s12931-014-0097-y

M3 - Article

C2 - 25134640

AN - SCOPUS:84908157737

SN - 1465-9921

VL - 15

JO - Respiratory Research

JF - Respiratory Research

IS - 1

M1 - 97

ER -

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

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