Abstract

Short-acting β2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled β2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10−7) and KCNJ2 (P=1.79 × 10−7) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10−9). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.

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Acknowledgements

We thank participants and field investigators in ECLIPSE, NETT, GenKOLS and COPDGene for their willingness to contribute to medical research. This study was supported by the US National Institutes of Health Grants R01 HL089897, R01 HL089856, K12 HL089990, R01 HL094635, P01 HL105339 and P01 HL083069 (National Heart, Lung, and Blood Institute) and R01 NR013377 (National Institute of Nursing Research); The Sheila J Goodnight, MD, FCCP Clinical Research Grant in Women's Lung Health; COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprising AstraZeneca, Pfizer, Siemens, Novartis, Boehringer Ingelheim, Sunovion and GlaxoSmithKline. ECLIPSE is supported by GlaxoSmithKline. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Institute of Nursing Research or the National Institutes of Health.

Author information

Author notes

Affiliations

  1. Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • M Hardin
    • , M H Cho
    • , M-L McDonald
    • , E Wan
    •  & C P Hersh
  2. Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • M Hardin
    • , M H Cho
    • , E Wan
    • , B Celli
    •  & C P Hersh
  3. Wolfson Institute for Biomedical Research, University College London, London, UK

    • D A Lomas
  4. UBC Department of Radiology, Vancouver General Hospital, Vancouver, Canada

    • H O Coxson
  5. Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK

    • W MacNee
  6. Department of Respiratory Medicine, Manchester Academic Health Sciences Centre, University Hospital of South Manchester, Manchester, UK

    • J Vestbo
  7. GlaxoSmithKline, Research Triangle Park, NC, USA

    • J C Yates
    •  & C Crim
  8. Thorax Institute, Hospital Clinic, IDIBAPS, Univ Barcelona and CIBERES, Barcelona, Spain

    • A Agusti
  9. Department of Pulmonary and Rehabilitation Medicine, University of Liverpool, Liverpool, UK

    • P M A Calverley
  10. Pulmonary and Critical Care Division, Department of Medicine, University of Nebraska, Omaha, NE, USA

    • S Rennard
  11. Center for Chronic Diseases, University Hospital Maastricht, Maastricht, The Netherlands

    • E Wouters
  12. Department of Clinical Science, University of Bergen, Bergen, Norway

    • P Bakke
  13. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama, Birmingham, AL, USA

    • S P Bhatt
  14. Division of Pulmonary and Critical Care, Temple University Hospital, Philadelphia, PA, USA

    • V Kim
  15. University of California, San Diego, San Diego, CA, USA

    • J Ramsdell
  16. Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA

    • E A Regan
    • , B J Make
    •  & J D Crapo
  17. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Denver, CO, USA

    • J E Hokanson
  18. Johns Hopkins School of Public Health, Baltimore, MD, USA

    • T H Beaty

Consortia

  1. on behalf of the ECLIPSE and COPDGene Investigators

    ECLIPSE and COPDGene Investigators COPDGene Investigators—core units Administrative core: James Crapo, MD (PI), Edwin Silverman, MD, PhD (PI), Barry Make, MD, Elizabeth Regan, MD, PhD. Genetic analysis core: Terri Beaty, PhD, Nan Laird, PhD, Christoph Lange, PhD, Michael Cho, MD, Stephanie Santorico, PhD, John Hokanson, MPH, PhD, Dawn DeMeo, MD, MPH, Nadia Hansel, MD, MPH, Craig Hersh, MD, MPH, Peter Castaldi, MD, MSc, Merry-Lynn McDonald, PhD, Emily Wan, MD, Megan Hardin, MD, Jacqueline Hetmanski, MS, Margaret Parker, MS, Marilyn Foreman, MD, Brian Hobbs, MD, Robert Busch, MD, Adel El-Bouiez, MD, Peter Castaldi, MD, Megan Hardin, MD, Dandi Qiao, PhD, Elizabeth Regan, MD, Eitan Halper-Stromberg, Ferdouse Begum, Sungho Won, Brittney Fredericksen, Sharon Lutz, PhD. Imaging core: David A Lynch, MB, Harvey O Coxson, PhD, MeiLan K Han, MD, MS, MD, Eric A Hoffman, PhD, Stephen Humphries MS, Francine L Jacobson, MD, Philip F Judy, PhD, Ella A Kazerooni, MD, John D Newell, Jr., MD, Elizabeth Regan, MD, James C Ross, PhD, Raul San Jose Estepar, PhD, Berend C Stoel, PhD, Juerg Tschirren, PhD, Eva van Rikxoort, PhD, Bram van Ginneken, PhD, George Washko, MD, Carla G Wilson, MS, Mustafa Al Qaisi, MD, Teresa Gray, Alex Kluiber, Tanya Mann, Jered Sieren, Douglas Stinson, Joyce Schroeder, MD, Edwin Van Beek, MD, PhD. PFT QA Core, Salt Lake City, UT, USA: Robert Jensen, PhD. Data Coordinating Center and Biostatistics, National Jewish Health, Denver, CO, USA: Douglas Everett, PhD, Anna Faino, MS, Matt Strand, PhD, Carla Wilson, MS. Epidemiology Core, University of Colorado Anschutz Medical Campus, Aurora, CO, USA: John E Hokanson, MPH, PhD, Jennifer Black-Shinn, MPH, PhD, Gregory Kinney, MPH, PhD, Sharon Lutz, PhD, Katherine Pratte, MSPH.

  2. COPDGene Investigators—clinical centers

    Ann Arbor VA, MI, USA: Jeffrey Curtis, MD, Carlos Martinez, MD, MPH, Perry G Pernicano, MD. Baylor College of Medicine, Houston, TX, USA: Nicola Hanania, MD, MS, Philip Alapat, MD, Venkata Bandi, MD, Mustafa Atik, MD, Aladin Boriek, PhD, Kalpatha Guntupalli, MD, Elizabeth Guy, MD, Amit Parulekar, MD, Arun Nachiappan, MD. Brigham and Women’s Hospital, Boston, MA, USA: Dawn DeMeo, MD, MPH, Craig Hersh, MD, MPH, George Washko, MD, Francine Jacobson, MD, MPH. Columbia University, New York, NY, USA: R Graham Barr, MD, DrPH, Byron Thomashow, MD, John Austin, MD, Belinda D’Souza, MD, Gregory DN Pearson, MD, Anna Rozenshtein, MD, MPH, FACR. Duke University Medical Center, Durham, NC, USA: Neil MacIntyre, Jr, MD, Lacey Washington, MD, H Page McAdams, MD. Health Partners Research Foundation, Minneapolis, MN, USA: Charlene McEvoy, MD, MPH, Joseph Tashjian, MD. Johns Hopkins University, Baltimore, MD, USA: Robert Wise, MD, Nadia Hansel, MD, MPH, Robert Brown, MD, Karen Horton, MD, Nirupama Putcha, MD, MHS. Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Los Angeles, CA, USA: Richard Casaburi, MD, Alessandra Adami, PhD, Janos Porszasz, MD, PhD, Hans Fischer, MD, PhD, Matthew Budoff, MD, Dan Cannon, PhD, Harry Rossiter, PhD. Michael E DeBakey VAMC, Houston, TX, USA: Amir Sharafkhaneh, MD, PhD, Charlie Lan, DO. Minneapolis, VA, USA: Christine Wendt, MD, Brian Bell, MD. Morehouse School of Medicine, Atlanta, GA, USA: Marilyn Foreman, MD, MS, Gloria Westney, MD, MS, Eugene Berkowitz, MD, PhD. National Jewish Health, Denver, CO, USA: Russell Bowler, MD, PhD, David Lynch, MD. Reliant Medical Group, Worcester, MA, USA: Richard Rosiello, MD, David Pace, MD. Temple University, Philadelphia, PA, USA: Gerard Criner, MD, David Ciccolella, MD, Francis Cordova, MD, Chandra Dass, MD, Robert D’Alonzo, DO, Parag Desai, MD, Michael Jacobs, PharmD, Steven Kelsen, MD, PhD, Victor Kim, MD, A. James Mamary, MD, Nathaniel Marchetti, DO, Aditti Satti, MD, Kartik Shenoy, MD, Robert M. Steiner, MD, Alex Swift, MD, Irene Swift, MD, Gloria Vega-Sanchez, MD. Hrudaya Nath, MD. University of Alabama, Birmingham, AL, USA: Mark Dransfield, MD, William Bailey, MD, J Michael Wells, MD, Surya Bhatt, MD, Hrudaya Nath, MD. University of California, San Diego, CA, USA: Joe Ramsdell, MD, Paul Friedman, MD, Xavier Soler, MD, PhD, Andrew Yen, MD. University of Iowa, Iowa City, IA, USA: Alejandro Cornellas, MD, John Newell, Jr., MD, Brad Thompson, MD. University of Michigan, Ann Arbor, MI, USA: MeiLan Han, MD, Ella Kazerooni, MD, Fernando Martinez, MD. University of Minnesota, Minneapolis, MN, USA: Joanne Billings, MD, Tadashi Allen, MD. University of Pittsburgh, Pittsburgh, PA, USA: Frank Sciurba, MD, Divay Chandra, MD, MSc, Joel Weissfeld, MD, MPH, Carl Fuhrman, MD, Jessica Bon, MD. University of Texas Health Science Center at San Antonio, San Antonio, TX, USA: Antonio Anzueto, MD, Sandra Adams, MD, Diego Maselli-Caceres, MD, Mario E Ruiz, MD. ECLIPSE Principal investigators and participating centers include: Bulgaria: Y Ivanov, Pleven; K Kostov, Sofia. Canada: J Bourbeau, Montreal; M Fitzgerald, Vancouver; P Hernández, Halifax; K Killian, Hamilton; R Levy, Vancouver; F Maltais, Montreal; D O'Donnell, Kingston. Czech Republic: J Krepelka, Praha. Denmark: J Vestbo, Hvidovre. The Netherlands: E Wouters, Horn. New Zealand: D Quinn, Wellington. Norway: P Bakke, Bergen, Slovenia: M Kosnik, Golnik. Spain: A Agusti, Jaume Sauleda, Palma de Mallorca. Ukraine: Y Feschenko, Kiev; V Gavrisyuk, Kiev; L Yashina, Kiev. UK: L Yashina, W MacNee, Edinburgh; D Singh, Manchester; J Wedzicha, London. USA: A Anzueto, San Antonio, TX; S. Braman, Providence, RI; R Casaburi, Torrance, CA; B Celli, Boston, MA; G Giessel, Richmond, VA; M Gotfried, Phoenix, AZ; G Greenwald, Rancho Mirage, CA; N Hanania, Houston, TX; D Mahler, Lebanon, NH; B Make, Denver, CO; S Rennard, Omaha, NE; C Rochester, New Haven, CT; P Scanlon, Rochester, MN; D Schuller, Omaha, NE; F Sciurba, Pittsburgh, PA; A Sharafkhaneh, Houston, TX; T Siler, St Charles, MO; E Silverman, Boston, MA; A Wanner, Miami, FL; R Wise, Baltimore, MD; 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).

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Competing interests

Dr Michael Cho receives funding from the NIH and the Alpha-1 Foundation. Dr David Lomas has received grant support, honoraria and consultancy fees from GlaxoSmithKline. He chairs the GSK Respiratory Therapy Area Board. Dr Harvey Coxson has received $4800 in the years 2009–2012 for serving on the steering committee for the ECLIPSE project for GSK, he was the co-investigator on two multicenter studies sponsored by GSK and has received travel expenses to attend meetings related to the project. Dr Coxson has three contract service agreements with GSK (including the ECLIPSE study) to quantify the CT scans in subjects with COPD and a service agreement with Spiration to measure changes in lung volume in subjects with severe emphysema. He has received a fee for speaking at a conference and related travel expenses from AstraZeneca (Australia). Dr Coxson was the recipient of a GSK Clinical Scientist Award in 2010. Dr Jørgen Vestbo has received honoraria for consulting and presenting from Almirall, AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Novartis and Takeda. Julie Yates is an employee of and owns stock in GlaxoSmithKline. Dr Alvar Agusti has consulted and received honoraria for lecturing at meeting from different pharmaceutical companies commercializing bronchodilators, including GSK, Boheringer-Ingelheim, AstraZeneca, Almirall, Novartis and Chiesi. Dr Celli has worked as a researcher or consultant for the following companies: GSK, Almirall, Novartis, Forrest, Aeris, Boehringer-Ingelheim, Dey, Altana, Pfizer, and Rox. Dr Courtney Crim is an employee of GlaxoSmithKline LLC, the sponsor of the ECLIPSE trial. He holds stock/stock options in GSK as a portion of his compensation as an employee. As it relates to this manuscript, Dr Crim declares no conflict of interest. Dr Rennard has had or currently has a number of relationships with companies who provide products and/or services relevant to outpatient management of chronic obstructive pulmonary disease. These relationships include serving as a consultant, advising regarding clinical trials, speaking at continuing medical education programs and performing funded research both at basic and clinical levels. He does not own any stock in any pharmaceutical companies. These companies include: AARC, American Board of Internal Medicine, Able Associates, Align2 Acton, Almirall, APT, AstraZeneca, American Thoracic Society, Beilenson, Boehringer Ingelheim, Chiesi, CIPLA, Clarus Acuity, CME Incite, COPDFoundation, Cory Paeth, CSA, CSL Behring, CTS Carmel, Dailchi Sankyo, Decision Resources, Dunn Group, Easton Associates, Elevation Pharma, FirstWord, Forest, GLG Research, Gilead, Globe Life Sciences, GlaxoSmithKline, Guidepoint, Health Advance, HealthStar, HSC Medical Education, Johnson and Johnson, Leerink Swan, LEK, McKinsey, Medical Knowledge, Medimmune, Merck, Navigant, Novartis, Nycomed, Osterman, Pearl, PeerVoice, Penn Technology, Pennside, Pfizer, Prescott, Pro Ed Communications, PriMed, Pulmatrix, Quadrant, Regeneron, Saatchi and Saatchi, Sankyo, Schering, Schlesinger Associates, Shaw Science, Strategic North, Summer Street Research, Synapse, Takeda, Telecon SC and ThinkEquity. Dr Per Bakke has consulted for Boehringer Ingelheim and received compensation. Professor Calverley has received funding from the UK MRC and holds an NIHR programme grant. He has been compensated for work on clinical trials steering committees for GSK, Boehringher Ingelheim and Takeda. He has spoken at meetings supported by these companies and by AstraZeneca, Novartis and Almirall. He holds no stock in any relevant concern and has no contacts with the tobacco industry. Dr Victor Kim has nothing to disclose in relationship to this manuscript but has served on an advisory committee for CSA and has participated in clinical trials sponsored by Boehringer Ingelheim, Glaxo-Smith-Kline and Roche pharmaceuticals. VK is supported by NHLBI K23HL094696-03. Dr Craig Hersh has received consulting fees from Novartis and CSL Behring.

Corresponding author

Correspondence to M Hardin.

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DOI

https://doi.org/10.1038/tpj.2015.65

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj)

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