Advertisement

Human Genetics

, Volume 131, Issue 7, pp 1105–1114 | Cite as

Genetic association between human chitinases and lung function in COPD

  • F. Aminuddin
  • L. Akhabir
  • D. Stefanowicz
  • P. D. Paré
  • J. E. Connett
  • N. R. Anthonisen
  • J. V. Fahy
  • M. A. Seibold
  • E. G. Burchard
  • C. Eng
  • A. Gulsvik
  • P. Bakke
  • M. H. Cho
  • A. Litonjua
  • D. A. Lomas
  • W. H. Anderson
  • T. H. Beaty
  • J. D. Crapo
  • E. K. Silverman
  • A. J. SandfordEmail author
Original Investigation

Abstract

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.

Keywords

Chronic Obstructive Pulmonary Disease Chronic Obstructive Pulmonary Disease Patient Chitinase Chitinase Activity Lung Function Decline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

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. 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. Co-investigators in the National Emphysema Treatment Trial 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.

References

  1. Bierbaum S, Nickel R, Koch A, Lau S, Deichmann KA, Wahn U, Superti-Furga A, Heinzmann A (2005) Polymorphisms and haplotypes of acid mammalian chitinase are associated with bronchial asthma. Am J Respir Crit Care Med 172:1505–1509PubMedCrossRefGoogle Scholar
  2. Carter KW, McCaskie PA, Palmer LJ (2008) SimHap GUI: an intuitive graphical user interface for genetic association analysis. BMC Bioinformatics 9:557PubMedCrossRefGoogle Scholar
  3. Cho MH, Boutaoui N, Klanderman BJ, Sylvia JS, Ziniti JP, Hersh CP, DeMeo DL, Hunninghake GM, Litonjua AA, Sparrow D, Lange C, Won S, Murphy JR, Beaty TH, Regan EA, Make BJ, Hokanson JE, Crapo JD, Kong X, Anderson WH, Tal-Singer R, Lomas DA, Bakke P, Gulsvik A, Pillai SG, Silverman EK (2010) Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat Genet 42:200–202PubMedCrossRefGoogle Scholar
  4. Cho MH, Castaldi PJ, Wan ES, Siedlinski M, Hersh CP, Demeo DL, Himes BE, Sylvia JS, Klanderman BJ, Ziniti JP, Lange C, Litonjua AA, Sparrow D, Regan EA, Make BJ, Hokanson JE, Murray T, Hetmanski JB, Pillai SG, Kong X, Anderson WH, Tal-Singer R, Lomas DA, Coxson HO, Edwards LD, Macnee W, Vestbo J, Yates JC, Agusti A, Calverley PM, Celli B, Crim C, Rennard S, Wouters E, Bakke P, Gulsvik A, Crapo JD, Beaty TH, Silverman EK (2011) A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. Hum Mol Genet [Epub ahead of print]Google Scholar
  5. Chupp GL, Lee CG, Jarjour N, Shim YM, Holm CT, He S, Dziura JD, Reed J, Coyle AJ, Kiener P, Cullen M, Grandsaigne M, Dombret MC, Aubier M, Pretolani M, Elias JA (2007) A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med 357:2016–2027PubMedCrossRefGoogle Scholar
  6. Connett JE, Kusek JW, Bailey WC, O’Hara P, Wu M (1993) Design of the lung health study: a randomized clinical trial of early intervention for chronic obstructive pulmonary disease. Control Clin Trials 14:3S–19SPubMedCrossRefGoogle Scholar
  7. Da Silva CA, Pochard P, Lee CG, Elias JA (2010) Chitin particles are multifaceted immune adjuvants. Am J Respir Crit Care Med 182:1482–1491PubMedCrossRefGoogle Scholar
  8. Gaunt TR, Rodriguez S, Day IN (2007) Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool ‘CubeX’. BMC Bioinformatics 8:428PubMedCrossRefGoogle Scholar
  9. Khoury MJ, Beaty TH, Tockman MS, Self SG, Cohen BH (1985) Familial aggregation in chronic obstructive pulmonary disease: use of the loglinear model to analyze intermediate environmental and genetic risk factors. Genet Epidemiol 2:155–166PubMedCrossRefGoogle Scholar
  10. Lee CG (2009) Chitin, chitinases and chitinase-like proteins in allergic inflammation and tissue remodeling. Yonsei Med J 50:22–30PubMedCrossRefGoogle Scholar
  11. Lee CG, Da Silva CA, Lee JY, Hartl D, Elias JA (2008) Chitin regulation of immune responses: an old molecule with new roles. Curr Opin Immunol 20:684–689PubMedCrossRefGoogle Scholar
  12. Létuvé S, Kozhich A, Arouche N, Grandsaigne M, Reed J, Dombret MC, Kiener PA, Aubier M, Coyle AJ, Pretolani M (2008) YKL-40 is elevated in patients with chronic obstructive pulmonary disease and activates alveolar macrophages. J Immunol 181:5167–5173PubMedGoogle Scholar
  13. Létuvé S, Kozhich A, Humbles A, Brewah Y, Dombret MC, Grandsaigne M, Adle H, Kolbeck R, Aubier M, Coyle AJ, Pretolani M (2010) Lung chitinolytic activity and chitotriosidase are elevated in chronic obstructive pulmonary disease and contribute to lung inflammation. Am J Pathol 176:638–649PubMedCrossRefGoogle Scholar
  14. Ober C, Tan Z, Sun Y, Possick JD, Pan L, Nicolae R, Radford S, Parry RR, Heinzmann A, Deichmann KA, Lester LA, Gern JE, Lemanske RF Jr, Nicolae DL, Elias JA, Chupp GL (2008) Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function. N Engl J Med 358:1682–1691PubMedCrossRefGoogle Scholar
  15. Piras I, Falchi A, Melis A, Ghiani ME, Calo CM, Varesi L, Vona G (2007) 24 bp duplication of CHIT1 gene is not correlated with coronary artery disease in Corsica Island (France). Exp Mol Pathol 83:490–492PubMedCrossRefGoogle Scholar
  16. Seibold MA, Donnelly S, Solon M, Innes A, Woodruff PG, Boot RG, Burchard EG, Fahy JV (2008) Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit. J Allergy Clin Immunol 122:944–950 (e943)PubMedCrossRefGoogle Scholar
  17. Seibold MA, Reese TA, Choudhry S, Salam MT, Beckman K, Eng C, Atakilit A, Meade K, Lenoir M, Watson HG, Thyne S, Kumar R, Weiss KB, Grammer LC, Avila P, Schleimer RP, Fahy JV, Rodriguez-Santana J, Rodriguez-Cintron W, Boot RG, Sheppard D, Gilliland FD, Locksley RM, Burchard EG (2009) Differential enzymatic activity of common haplotypic versions of the human acidic mammalian chitinase protein. J Biol Chem 284:19650–19658PubMedCrossRefGoogle Scholar
  18. Verweij PE, Kerremans JJ, Voss A, Meis JF (2000) Fungal contamination of tobacco and marijuana. JAMA 284:2875PubMedCrossRefGoogle Scholar
  19. Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards L, Hagan G, Knobil K, Lomas DA, MacNee W, Silverman EK, Tal-Singer R (2008) Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). Eur Respir J 31:869–873PubMedCrossRefGoogle Scholar
  20. Zhao X, Tang R, Gao B, Shi Y, Zhou J, Guo S, Zhang J, Wang Y, Tang W, Meng J, Li S, Wang H, Ma G, Lin C, Xiao Y, Feng G, Lin Z, Zhu S, Xing Y, Sang H, St Clair D, He L (2007) Functional variants in the promoter region of chitinase 3-like 1 (CHI3L1) and susceptibility to schizophrenia. Am J Hum Genet 80:12–18PubMedCrossRefGoogle Scholar
  21. Zhu Z, Zheng T, Homer RJ, Kim YK, Chen NY, Cohn L, Hamid Q, Elias JA (2004) Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304:1678–1682PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • F. Aminuddin
    • 1
  • L. Akhabir
    • 1
  • D. Stefanowicz
    • 1
  • P. D. Paré
    • 1
  • J. E. Connett
    • 2
  • N. R. Anthonisen
    • 3
  • J. V. Fahy
    • 4
  • M. A. Seibold
    • 5
  • E. G. Burchard
    • 6
  • C. Eng
    • 6
  • A. Gulsvik
    • 7
  • P. Bakke
    • 7
  • M. H. Cho
    • 8
  • A. Litonjua
    • 8
  • D. A. Lomas
    • 9
  • W. H. Anderson
    • 10
  • T. H. Beaty
    • 11
  • J. D. Crapo
    • 5
  • E. K. Silverman
    • 12
  • A. J. Sandford
    • 1
    Email author
  1. 1.James Hogg Research Centre, Providence Heart and Lung Institute, St. Paul’s HospitalThe University of British ColumbiaVancouverCanada
  2. 2.Division of BiostatisticsUniversity of MinnesotaMinneapolisUSA
  3. 3.Faculty of MedicineUniversity of ManitobaWinnipegCanada
  4. 4.Department of Medicine, Howard Hughes Medical InstituteUniversity of CaliforniaSan FranciscoUSA
  5. 5.Department of MedicineNational Jewish HealthDenverUSA
  6. 6.Department of Bioengineering and Therapeutic Sciences, Lung Biology Center, Institute for Human GeneticsUniversity of CaliforniaSan FranciscoUSA
  7. 7.Haukeland University Hospital and Institute of MedicineUniversity of BergenBergenNorway
  8. 8.Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  9. 9.Cambridge Institute for Medical ResearchUniversity of CambridgeCambridgeUK
  10. 10.GlaxoSmithKline Research and DevelopmentDurhamUSA
  11. 11.Johns Hopkins School of Public HealthBaltimoreUSA
  12. 12.Channing Laboratory and Pulmonary and Critical Care Division, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations