Format

Send to

Choose Destination
Am J Respir Cell Mol Biol. 2017 Jul;57(1):35-46. doi: 10.1165/rcmb.2016-0331OC.

Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.

Collaborators (251)

Crapo J, Silverman E, Make B, Regan E, Beaty T, Laird N, Lange C, Cho M, Santorico S, Hokanson J, DeMeo D, Hansel N, Hersh C, Castaldi P, McDonald ML, Wan E, Hardin M, Hetmanski J, Parker M, Foreman M, Hobbs B, Busch R, El-Bouiez A, Qiao D, Regan E, Halper-Stromberg E, Begum F, Won S, Lutz S, Lynch DA, Coxson HO, Han MK, Hoffman EA, Humphries S, Jacobson FL, Judy PF, Kazerooni EA, Newell JD Jr, Regan E, Ross JC, San Jose Estepar R, Stoel BC, Tschirren J, Rikxoort EV, Ginneken BV, Washko G, Wilson CG, Al Qaisi M, Gray T, Kluiber A, Mann T, Sieren J, Stinson D, Schroeder J, Van Beek E, Jensen R, Everett D, Faino A, Strand M, Wilson C, Hokanson JE, Kinney G, Lutz S, Young K, Pratte K, Duca L, Curtis JL, Martinez CH, Pernicano PG, Hanania N, Alapat P, Bandi V, Atik M, Boriek A, Guntupalli K, Guy E, Parulekar A, Nachiappan A, DeMeo D, Hersh C, Washko G, Jacobson F, Barr RG, Thomashow B, Austin J, D'Souza B, Pearson GDN, Rozenshtein A, MacIntyre N Jr, Washington L, McAdams HP, McEvoy C, Tashjian J, Wise R, Hansel N, Brown R, Horton K, Putcha N, Casaburi R, Adami A, Porszasz J, Fischer H, Budoff M, Rossiter H, Sharafkhaneh A, Lan C, Wendt C, Bell B, Foreman M, Westney G, Berkowitz E, Bowler R, Lynch D, Rosiello R, Pace D, Criner G, Ciccolella D, Cordova F, Dass C, D'Alonzo G, Desai P, Jacobs M, Kelsen S, Kim V, Mamary AJ, Marchetti N, Satti A, Shenoy K, Steiner RM, Swift A, Swift I, Vega-Sanchez ME, Dransfield M, Bailey W, Wells JM, Bhatt S, Nath H, Ramsdell J, Friedman P, Soler X, Yen A, Comellas A, Newell J Jr, Thompson B, Han M, Kazerooni E, Martinez C, Billings J, Allen T, Sciurba F, Chandra D, Weissfeld J, Fuhrman C, Bon J, Anzueto A, Adams S, Maselli-Caceres D, Ruiz ME, Silverman EK, Lomas DA, Make BJ, Agusti A, Sauleda J, Calverley PMA, Donner CF, Paré PD, Rennard S, Vestbo J, Ivanov Y, Kostov K, Bourbeau J, Fitzgerald M, Hernandez P, Killian K, Levy R, Maltais F, O'Donnell D, Krepelka J, Vestbo J, Wouters E, Quinn D, Bakke P, Kosnik M, Agusti A, Sauleda J, Feschenko Y, Gavrisyuk V, Yashina L, Monogarova N, Calverley P, Lomas D, MacNee W, Singh D, Wedzicha J, Anzueto A, Braman S, Casaburi R, Celli B, Giessel G, Gotfried M, Greenwald G, Hanania N, Mahler D, Make B, Rennard S, Rochester C, Scanlon P, Schuller D, Sciurba F, Sharafkhaneh A, Siler T, Silverman E, Wanner A, Wise R, ZuWallack R, Coxson H, Crim C, Edwards L, Lomas D, MacNee W, Silverman E, Tal Singer R, Vestbo J, Yates J, Agusti A, Calverley P, Celli B, Crim C, Miller B, MacNee W, Rennard S, Tal-Singer R, Wouters E, Yates J, Benditt J, Criner G, DeCamp M, Diaz P, Ginsburg M, Kaiser L, Katz M, Krasna M, MacIntyre N, McKenna R, Martinez F, Mosenifar Z, Reilly J, Ries A, Scanlon P, Sciurba F, Utz J.

Author information

1
1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
2
2 University of Arizona, Tucson, Arizona.
3
3 National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.
4
4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
5
5 Kangwon National University, Chuncheon, Korea.
6
6 Seoul National University College of Medicine Boramae Medical Center, Seoul, Korea.
7
7 Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona, CIBERES, Barcelona, Spain.
8
8 National Jewish Health, Denver, Colorado.
9
9 University of Liverpool, Liverpool, United Kingdom.
10
10 Mondo Medico di I.F.I.M. srl, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero, Novara, Italy.
11
11 University College London, London, United Kingdom.
12
12 University Hospital Maastricht, Maastricht, the Netherlands.
13
13 University of Manchester, Manchester, United Kingdom.
14
14 GlaxoSmithKline Research and Development, King of Prussia, Pennsylvania.
15
15 University of Bergen, Bergen, Norway.
16
16 Brigham and Women's Hospital and the Veterans Administration Medical Center-Jamaica Plain, Jamaica Plain, Massachusetts.
17
17 Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
18
18 University of Nebraska Medical Center, Omaha, Nebraska.
19
19 Department of Epidemiology, Bloomberg School of Public Health, the Johns Hopkins University, Baltimore, Maryland; and.
20
20 Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Abstract

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 × 10-8) and PPP4R4/SERPINA1 (P = 1.01 × 10-8) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ∼0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

KEYWORDS:

alpha-1 antitrypsin; chronic obstructive pulmonary disease; genetic epidemiology; genetic risk factors; genetic risk score

PMID:
28170284
PMCID:
PMC5516277
DOI:
10.1165/rcmb.2016-0331OC
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Grant support

Publication type

MeSH terms

Grant support

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center