Nitric Oxide Synthase Polymorphisms, Gene Expression and Lung Function in Chronic Obstructive Pulmonary Disease

Authors' contributions
FA carried out the genotyping assays, participated in the statistical analysis and drafted the manuscript. FA, TLH, PDP, and AJS participated in the design of the Lung Health Study and gene expression sections. FA, DS and AS performed the quantitative PCR, western blotting and immunohistochemistry. MHC performed the statistical analysis for the replication cohorts. AG, PB, AL, DAL, WHA, THB and EKS participated in study design, recruiting, and sample collection for the replication cohorts. All authors read and approved the final manuscript.

Acknowledgements
This work was supported by grants from the Canadian Institutes of Health Research and National Institutes of Health Grant 5R01HL064068-04. LA is the recipient of a UBC Four Year Doctoral Fellowship and an AllerGen NCE Inc. Canadian Allergy and Immune Diseases Training Award. AJS is the recipient of a Canada Research Chair in genetics and a Michael Smith Foundation for Health Research Senior Scholar Award.
The Lung Health Study was supported by contract N01-HR-46002 from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute.
The COPDGene® project is supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, and Sunovion. The COPDGene® project is also supported by the National Heart, Lung, and Blood Institute contracts R01HL089856 and R01HL089897. The members of the COPDGene® study group include: Ann Arbor VA: Jeffrey Curtis, MD (PI), Ella Kazerooni, MD (RAD). Baylor College of Medicine, Houston, TX: Nicola Hanania, MD, MS (PI), Philip Alapat, MD, Venkata Bandi, MD, Kalpalatha Guntupalli, MD, Elizabeth Guy, MD, Antara Mallampalli, MD, Charles Trinh, MD (RAD), Mustafa Atik, MD. Brigham and Women's Hospital, Boston, MA: Dawn DeMeo, MD, MPH (Co-PI), Craig Hersh, MD, MPH (Co-PI), George Washko, MD, Francine Jacobson, MD, MPH (RAD). Columbia University, New York, NY: R. Graham Barr, MD, DrPH (PI), Byron Thomashow, MD, John Austin, MD (RAD). Duke University Medical Center, Durham, NC: Neil MacIntyre, Jr., MD (PI), Lacey Washington, MD (RAD), H Page McAdams, MD (RAD). Fallon Clinic, Worcester, MA: Richard Rosiello, MD (PI), Timothy Bresnahan, MD (RAD). Health Partners Research Foundation, Minneapolis, MN: Charlene McEvoy, MD, MPH (PI), Joseph Tashjian, MD (RAD). Johns Hopkins University, Baltimore, MD: Robert Wise, MD (PI), Nadia Hansel, MD, MPH, Robert Brown, MD (RAD), Gregory Diette, MD. Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Los Angeles, CA: Richard Casaburi, MD (PI), Janos Porszasz, MD, PhD, Hans Fischer, MD, PhD (RAD), Matt Budoff, MD. Michael E. DeBakey VAMC, Houston, TX: Amir Sharafkhaneh, MD (PI), Charles Trinh, MD (RAD), Hirani Kamal, MD, Roham Darvishi, MD. Minneapolis VA: Dennis Niewoehner, MD (PI), Tadashi Allen, MD (RAD), Quentin Anderson, MD (RAD), Kathryn Rice, MD. Morehouse School of Medicine, Atlanta, GA: Marilyn Foreman, MD, MS (PI), Gloria Westney, MD, MS, Eugene Berkowitz, MD, PhD (RAD). National Jewish Health, Denver, CO: Russell Bowler, MD, PhD (PI), Adam Friedlander, MD, David Lynch, MB (RAD), Joyce Schroeder, MD (RAD), John Newell, Jr., MD (RAD). Temple University, Philadelphia, PA: Gerard Criner, MD (PI), Victor Kim, MD, Nathaniel Marchetti, DO, Aditi Satti, MD, A. James Mamary, MD, Robert Steiner, MD (RAD), Chandra Dass, MD (RAD). University of Alabama, Birmingham, AL: William Bailey, MD (PI), Mark Dransfield, MD (Co-PI), Hrudaya Nath, MD (RAD). University of California, San Diego, CA: Joe Ramsdell, MD (PI), Paul Friedman, MD (RAD) University of Iowa, Iowa City, IA: Geoffrey McLennan, MD, PhD (PI), Edwin JR van Beek, MD, PhD (RAD), Brad Thompson, MD (RAD), Dwight Look, MD. University of Michigan, Ann Arbor, MI: Fernando Martinez, MD (PI), MeiLan Han, MD, Ella Kazerooni, MD (RAD). University of Minnesota, Minneapolis, MN: Christine Wendt, MD (PI), Tadashi Allen, MD (RAD). University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, MD (PI), Joel Weissfeld, MD, MPH, Carl Fuhrman, MD (RAD), Jessica Bon, MD. University of Texas Health Science Center at San Antonio, San Antonio, TX: Antonio Anzueto, MD (PI), Sandra Adams, MD, Carlos Orozco, MD, Mario Ruiz, MD (RAD). Administrative Core: James Crapo, MD (PI), Edwin Silverman, MD, PhD (PI), Barry Make, MD, Elizabeth Regan, MD, Sarah Moyle, MS, Douglas Stinson. Genetic Analysis Core: Terri Beaty, PhD, Barbara Klanderman, 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, Jacqueline Hetmanski, MS, Tanda Murray. Imaging Core: David Lynch, MB, Joyce Schroeder, MD, John Newell, Jr., MD, John Reilly, MD, Harvey Coxson, PhD, Philip Judy, PhD, Eric Hoffman, PhD, George Washko, MD, Raul San Jose Estepar, PhD, James Ross, MSc, Rebecca Leek, Jordan Zach, Alex Kluiber, Jered Sieren, Heather Baumhauer, Verity McArthur, Dzimitry Kazlouski, Andrew Allen, Tanya Mann, Anastasia Rodionova. PFT QA Core, LDS Hospital, Salt Lake City, UT: Robert Jensen, PhD. Biological Repository, Johns Hopkins University, Baltimore, MD: Homayoon Farzadegan, PhD, Stacey Meyerer, Shivam Chandan, Samantha Bragan. Data Coordinating Center and Biostatistics, National Jewish Health, Denver, CO: James Murphy, PhD, Douglas Everett, PhD, Carla Wilson, MS, Ruthie Knowles, Amber Powell, Joe Piccoli, Maura Robinson, Margaret Forbes, Martina Wamboldt. Epidemiology Core, University of Colorado School of Public Health, Denver, CO: John Hokanson, MPH, PhD, Marci Sontag, PhD, Jennifer Black-Shinn, MPH, Gregory Kinney, MPH.
The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study (clinicaltrials.govidentifier NCT00292552; GSK code SCO104960) is funded by GlaxoSmithKline. Principal investigators and centers participating in the ECLIPSE study (NCT00292552): Bulgaria: Y. Ivanov (Pleven), and K. Kostov (Sofia); Canada: J. Bourbeau (Montreal, QC), M. Fitzgerald (Vancouver, BC), P. Hernandez (Halifax, NS), K. Killian (Hamilton, ON), R. Levy (Vancouver, BC), F. Maltais (Montreal, QC), and D. O'Donnell (Kingston, ON); Czech Republic: J. Krepelka (Prague); Denmark: J. Vestbo (Hvidovre); the Netherlands: E. Wouters (Horn and Maastricht); New Zealand: D. Quinn (Wellington); Norway: P. Bakke (Bergen); Slovenia: M. Kosnik (Golnik); Spain: A. Agustı' (Palma de Mallorca), and J. Sauleda (Palma de Mallorca); Ukraine: Y. Feschenko (Kiev), V. Gavrisyuk (Kiev), N. Monogarova (Donetsk), and L. Yashina (Kiev); UK: P. Calverley (Liverpool), D. Lomas (Cambridge), W. MacNee (Edinburgh), D. Singh (Manchester), and J. Wedzicha (London); and 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), and R. ZuWallack (Hartford, CT). Steering committee: H. Coxson (Vancouver, Canada); L. Edwards (GlaxoSmithKline, Research Triangle Park, NC, USA); K. Knobil (cochair; GlaxoSmithKline, Research Triangle Park, NC, USA); D. Lomas (Cambridge, UK); W. MacNee (Edinburgh, UK); E. Silverman (Boston, MA, USA); R. Tal-Singer (GlaxoSmithKline, King of Prussia, PA, USA); J. Vestbo (co-chair; Hvidovre, Denmark); and J. Yates (GlaxoSmithKline, Research Triangle Park, NC, USA). Scientific committee: A. Agustı' (Barcelona, Spain); P. Calverley (Liverpool, UK); B. Celli (Boston, MA, USA); C. Crim (GlaxoSmithKline, Research Triangle Park, NC, USA); B. Miller (GlaxoSmithKline, King of Prussia, PA, USA); W. MacNee (chair; Edinburgh, UK); S. Rennard (Omaha, NE, USA); R. Tal-Singer (GlaxoSmithKline, King of Prussia, PA, USA); E. Wouters (Horn, Maastricht, the Netherlands); and J. Yates (GlaxoSmithKline, Research Triangle Park, NC, USA).
The National Emphysema Treatment Trial (NETT) was supported by the National Heart, Lung, and Blood Institute contracts N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01HR76119. The NETT was also supported by the Centers for Medicare and Medicaid Services and the Agency for Healthcare Research and Quality. Co-investigators in the NETT Genetics Ancillary Study also include J. Benditt, G. Criner, M. DeCamp, P. Diaz, M. Ginsburg, L. Kaiser, M. Katz, M. Krasna, N. MacIntyre, R. McKenna, F. Martinez, Z. Mosenifar, J. Reilly, A. Ries, P. Scanlon, F. Sciurba, and J. Utz.
The Normative Aging Study (NAS) is supported by the Cooperative Studies Program/Epidemiology Research and Information Center (ERIC) of the US Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston, Massachusetts.
The Norway GenKOLS study (Genetics of Chronic Obstructive Lung Disease, GSK code RES11080) is funded by GlaxoSmithKline.