Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Michael H Cho; Merry-Lynn N McDonald; Xiaobo Zhou; Manuel Mattheisen; Peter J Castaldi; Craig P Hersh; Dawn L Demeo; Jody S Sylvia; John Ziniti; Nan M Laird; Christoph Lange; Augusto A Litonjua; David Sparrow; Richard Casaburi; R Graham Barr; Elizabeth A Regan; Barry J Make; John E Hokanson; Sharon Lutz; Tanda Murray Dudenkov; Homayoon Farzadegan; Jacqueline B Hetmanski; Ruth Tal-Singer; David A Lomas; Per Bakke; Amund Gulsvik; James D Crapo; Edwin K Silverman; Terri H Beaty; NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators

doi:10.1016/S2213-2600(14)70002-5

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Lancet Respir Med. 2014 Mar;2(3):214-25. doi: 10.1016/S2213-2600(14)70002-5. Epub 2014 Feb 7.

Authors

Michael H Cho¹, Merry-Lynn N McDonald², Xiaobo Zhou³, Manuel Mattheisen⁴, Peter J Castaldi², Craig P Hersh³, Dawn L Demeo³, Jody S Sylvia², John Ziniti², Nan M Laird⁵, Christoph Lange⁵, Augusto A Litonjua³, David Sparrow⁶, Richard Casaburi⁷, R Graham Barr⁸, Elizabeth A Regan⁹, Barry J Make¹⁰, John E Hokanson¹¹, Sharon Lutz¹², Tanda Murray Dudenkov¹³, Homayoon Farzadegan¹³, Jacqueline B Hetmanski¹³, Ruth Tal-Singer¹⁴, David A Lomas¹⁵, Per Bakke¹⁶, Amund Gulsvik¹⁶, James D Crapo¹⁰, Edwin K Silverman³, Terri H Beaty¹³; NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators

Collaborators

NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators:
J Crapo, E K Silverman, B Make, E Regan, R Lantz, L Stepp, S Melanson, T Beaty, N Laird, C Lange, M Cho, S Santorico, J Hokanson, D DeMeo, N Hansel, C Hersh, P Castaldi, M-L McDonald, J Zhou, M Mattheisen, E Wan, M Hardin, J Hetmanski, M Parker, T M Dudenkov, D Lynch, J Schroeder, J Newell Jr, J Reilly, H Coxson, P Judy, E Hoff man, G Washko, R S J Estepar, J Ross, M Al Qaisi, J Zach, A Kluiber, J Sieren, T Mann, D Richert, A McKenzie, J Akhavan, D Stinson, R Jensen, H Farzadegan, S Meyerer, S Chandan, S Bragan, D Everett, A Williams, C Wilson, A Forssen, A Powell, J Piccoli, J Hokanson, M Sontag, J Black-Shinn, G Kinney, S Lutz, J Curtis, E Kazerooni, N Hanania, P Alapat, V Bandi, K Guntupalli, E Guy, A Mallampalli, C Trinh, M Atik, H Al-Azzawi, M Willis, S Pinero, L Fahr, A Nachiappan, C Bray, L A Frigini, C Farinas, D Katz, J Freytes, A M Marciel, D DeMeo, C Hersh, G Washko, F Jacobson, H Hatabu, P Clarke, R Gill, A Hunsaker, B Trotman-Dickenson, R Madan, R G Barr, B Thomashow, J Austin, B D'Souza, N MacIntyre Jr, L Washington, H P McAdams, R Rosiello, T Bresnahan, J Bradley, S Kuong, S Meller, S Roland, C McEvoy, J Tashjian, R Wise, N Hansel, R Brown, G Diette, K Horton, R Casaburi, J Porszasz, H Fischer, M Budoff, Michael E DeBakey, A Sharafkhaneh, C Trinh, H Kamal, R Darvishi, M Willis, S Pinero, L Fahr, A Nachiappan, C Bray, L A Frigini, C Farinas, D Katz, J Freytes, A M Marciel, D Niewoehner, Q Anderson, K Rice, A Caine, M Foreman, G Westney, E Berkowitz, R Bowler, D Lynch, J Schroeder, V Hale, J Armstrong 2nd, D Dyer, J Chung, C Cox, G Criner, V Kim, N Marchetti, A Satti, A J Mamary, R Steiner, C Dass, L Cone, W Bailey, M Dransfi eld, M Wells, S Bhatt, H Nath, S Singh, J Ramsdell, P Friedman, A Cornellas, J Newell Jr, E J R van Beek, F Martinez, M Han, E Kazerooni, C Wendt, T Allen, F Sciurba, J Weissfeld, C Fuhrman, J Bon, D Hooper, A Anzueto, S Adams, C Orozco, M Ruiz, A Mumbower, A Kruger, C Restrepo, M Lane, Y Ivanov, K Kostov, J Bourbeau, F Maltais, M Fitzgerald, R Levy, P Hernández, K Killian, D O'Donnell, J Krepelka, J Vestbo, E Wouters, D Quinn, P Bakke, M Kosnik, A Agusti, J Sauleda, Y Feschenko, V Gavrisyuk, L Yashina, L Yashina, W MacNee, D Singh, J Wedzicha, A Anzueto, S Braman, R Casaburi, B Celli, E Silverman, G Giessel, M Gotfried, G Greenwald, N Hanania, A Sharafkhaneh, D Mahler, B Make, S Rennard, D Schuller, C Rochester, P Scanlon, F Sciurba, T Siler, A Wanner, R Wise, R ZuWallack, H Coxson, C Crim, L Edwards, R Tal Singer, J Yates, D Lomas, W MacNee, E Silverman, J Vestbo, A Agusti, P Calverley, B Celli, S Rennard, C Crim, B Miller, R Tal-Singer, J Yates, W MacNee, E Wouters, 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, J Utz, E K Silverman, D A Lomas, B J Make, A Agusti, J Sauleda, P M A Calverley, C F Donner, S Maugeri, R D Levy, P D Paré, S Rennard, J Vestbo, E F M Wouters

Affiliations

¹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: remhc@channing.harvard.edu.
² Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard School of Public Health, Boston, MA, USA.
⁵ Harvard School of Public Health, Boston, MA, USA.
⁶ School of Public Health and School of Medicine, Boston University, Boston, MA, USA; Veterans Administration Boston Healthcare System, Boston, MA, USA.
⁷ Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA.
⁸ Department of Medicine, College of Physicians and Surgeons, Mailman School of Public Health, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁹ National Jewish Health, Denver, CO, USA; Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
¹⁰ National Jewish Health, Denver, CO, USA.
¹¹ Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
¹² Department of Bioinformatics and Statistics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
¹³ Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ GlaxoSmithKline Research and Development, King Of Prussia, PA, USA.
¹⁵ University College London, London, UK.
¹⁶ Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.

Abstract

Background: The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies.

Methods: We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10(-7) in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p<5 × 10(-8)).

Findings: Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10(-14)), FAM13A (p=1·12 × 10(-14)), and HHIP (p=1·57 × 10(-12)). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10(-9)). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10(-9)). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p<0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6 × 10(-9)) and TGFB2 (overall joint meta-analysis p=8·3 × 10(-9)).

Interpretation: We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD.

Funding: US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Genetic Loci / genetics*
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Humans
Pulmonary Disease, Chronic Obstructive / genetics*

Abstract

Publication types

MeSH terms

Grants and funding