Abstract
Background: Due to the pleiotropic effects of nitric oxide (NO) within the lungs, it is likely that NO is a significant factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to test for association between single nucleotide polymorphisms (SNPs) in three NO synthase (NOS) genes and lung function, as well as to examine gene expression and protein levels in relation to the genetic variation.Methods: One SNP in each NOS gene (neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3)) was genotyped in the Lung Health Study (LHS) and correlated with lung function. One SNP (rs1800779) was also analyzed for association with COPD and lung function in four COPD case-control populations. Lung tissue expression of NOS3 mRNA and protein was tested in individuals of known genotype for rs1800779. Immunohistochemistry of lung tissue was used to localize NOS3 expression.Results: For the NOS3 rs1800779 SNP, the baseline forced expiratory volume in one second in the LHS was significantly higher in the combined AG + GG genotypic groups compared with the AA genotypic group. Gene expression and protein levels in lung tissue were significantly lower in subjects with the AG + GG genotypes than in AA subjects. NOS3 protein was expressed in the airway epithelium and subjects with the AA genotype demonstrated higher NOS3 expression compared with AG and GG individuals. However, we were not able to replicate the associations with COPD or lung function in the other COPD study groups.Conclusions: Variants in the NOS genes were not associated with lung function or COPD status. However, the G allele of rs1800779 resulted in a decrease of NOS3 gene expression and protein levels and this has implications for the numerous disease states that have been associated with this polymorphism.
| Original language | English (US) |
|---|---|
| Article number | 64 |
| Journal | BMC pulmonary medicine |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - Nov 6 2013 |
Keywords
- Chronic obstructive pulmonary disease
- Gene expression
- Nitric oxide synthase
- Polymorphism
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
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In: BMC pulmonary medicine, Vol. 13, No. 1, 64, 06.11.2013.
Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Nitric oxide synthase polymorphisms, gene expression and lung function in chronic obstructive pulmonary disease
AU - Aminuddin, Farzian
AU - Hackett, Tillie Louise
AU - Stefanowicz, Dorota
AU - Saferali, Aabida
AU - Paré, Peter D.
AU - Gulsvik, Amund
AU - Bakke, Per
AU - Cho, Michael H.
AU - Litonjua, Augusto
AU - Lomas, David A.
AU - Anderson, Wayne H.
AU - Beaty, Terri H.
AU - Silverman, Edwin K.
AU - Sandford, Andrew J.
N1 - Funding Information: 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.
PY - 2013/11/6
Y1 - 2013/11/6
N2 - Background: Due to the pleiotropic effects of nitric oxide (NO) within the lungs, it is likely that NO is a significant factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to test for association between single nucleotide polymorphisms (SNPs) in three NO synthase (NOS) genes and lung function, as well as to examine gene expression and protein levels in relation to the genetic variation.Methods: One SNP in each NOS gene (neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3)) was genotyped in the Lung Health Study (LHS) and correlated with lung function. One SNP (rs1800779) was also analyzed for association with COPD and lung function in four COPD case-control populations. Lung tissue expression of NOS3 mRNA and protein was tested in individuals of known genotype for rs1800779. Immunohistochemistry of lung tissue was used to localize NOS3 expression.Results: For the NOS3 rs1800779 SNP, the baseline forced expiratory volume in one second in the LHS was significantly higher in the combined AG + GG genotypic groups compared with the AA genotypic group. Gene expression and protein levels in lung tissue were significantly lower in subjects with the AG + GG genotypes than in AA subjects. NOS3 protein was expressed in the airway epithelium and subjects with the AA genotype demonstrated higher NOS3 expression compared with AG and GG individuals. However, we were not able to replicate the associations with COPD or lung function in the other COPD study groups.Conclusions: Variants in the NOS genes were not associated with lung function or COPD status. However, the G allele of rs1800779 resulted in a decrease of NOS3 gene expression and protein levels and this has implications for the numerous disease states that have been associated with this polymorphism.
AB - Background: Due to the pleiotropic effects of nitric oxide (NO) within the lungs, it is likely that NO is a significant factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to test for association between single nucleotide polymorphisms (SNPs) in three NO synthase (NOS) genes and lung function, as well as to examine gene expression and protein levels in relation to the genetic variation.Methods: One SNP in each NOS gene (neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3)) was genotyped in the Lung Health Study (LHS) and correlated with lung function. One SNP (rs1800779) was also analyzed for association with COPD and lung function in four COPD case-control populations. Lung tissue expression of NOS3 mRNA and protein was tested in individuals of known genotype for rs1800779. Immunohistochemistry of lung tissue was used to localize NOS3 expression.Results: For the NOS3 rs1800779 SNP, the baseline forced expiratory volume in one second in the LHS was significantly higher in the combined AG + GG genotypic groups compared with the AA genotypic group. Gene expression and protein levels in lung tissue were significantly lower in subjects with the AG + GG genotypes than in AA subjects. NOS3 protein was expressed in the airway epithelium and subjects with the AA genotype demonstrated higher NOS3 expression compared with AG and GG individuals. However, we were not able to replicate the associations with COPD or lung function in the other COPD study groups.Conclusions: Variants in the NOS genes were not associated with lung function or COPD status. However, the G allele of rs1800779 resulted in a decrease of NOS3 gene expression and protein levels and this has implications for the numerous disease states that have been associated with this polymorphism.
KW - Chronic obstructive pulmonary disease
KW - Gene expression
KW - Nitric oxide synthase
KW - Polymorphism
UR - http://www.scopus.com/inward/record.url?scp=84887050999&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887050999&partnerID=8YFLogxK
U2 - 10.1186/1471-2466-13-64
DO - 10.1186/1471-2466-13-64
M3 - Article
C2 - 24192154
AN - SCOPUS:84887050999
SN - 1471-2466
VL - 13
JO - BMC pulmonary medicine
JF - BMC pulmonary medicine
IS - 1
M1 - 64
ER -