Genetic association between human chitinases and lung function in COPD
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Two primary chitinases have been identified in humans—acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host’s immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case–control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV1) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV1 and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV1. Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.
KeywordsChronic Obstructive Pulmonary Disease Chronic Obstructive Pulmonary Disease Patient Chitinase Chitinase Activity Lung Function Decline
This work was supported by grants from the Canadian Institutes of Health Research and National Institutes of Health Grant 5R01HL064068-04. 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 National Emphysema Treatment Trial 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 National Emphysema Treatment Trial was also supported by the Centers for Medicare and Medicaid Services and the Agency for Healthcare Research and Quality. The Normative Aging Study is supported by the Cooperative Studies Program/ERIC of the US Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). The Norway GenKOLS study (Genetics of Chronic Obstructive Lung Disease, GSK code RES11080), the ECLIPSE study (HYPERLINK "http://clinicaltrials.gov" clinicaltrials.gov identifier NCT00292552; GSK code SCO104960) and the ICGN study are funded by GlaxoSmithKline. The COPDGene® project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, and Sunovion. 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 Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study is funded by GlaxoSmithKline. Principal investigators and centers participating in the ECLIPSE study (NCT00292552) include 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. Agustí (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. Agustí (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 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, MPH, 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. 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