@article{5888629fb7834f6f8e680ef232869aff,
title = "Genome-wide association study of lung function and clinical implication in heavy smokers",
abstract = "Background: The aim of this study is to identify genetic loci associated with post-bronchodilator FEV1/FVC and FEV1, and develop a multi-gene predictive model for lung function in COPD. Methods: Genome-wide association study (GWAS) of post-bronchodilator FEV1/FVC and FEV1 was performed in 1645 non-Hispanic White European descent smokers. Results: A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV1/FVC (p = 1.2 × 10- 8) and FEV1 (p = 2.1 × 10- 9). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10- 4) and severity (OR = 4.1; p = 0.0036). Heterozygous subjects (CT genotype) had significantly lower lung function and higher percentage of COPD and more severe COPD than subjects with the CC genotype. 8.6% of the variance of post-bronchodilator FEV1/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P < 2.2 × 10- 16). Conclusions: This study is the first to show genome-wide significant association of rs28929474 in SERPINA1 with lung function. Of clinical importance, heterozygotes of rs28929474 (4.7% of subjects) have significantly reduced pulmonary function, demonstrating a major impact in smokers. The multi-gene model is significantly associated with CT-based emphysema and clinical outcome measures of severity. Combining genetic information with demographic and environmental factors will further increase the predictive power for assessing reduced lung function and COPD severity.",
keywords = "COPD, GWAS, Lung function, Rs28929474, SERPINA1, SPIROMICS",
author = "{for the SPIROMICS Research Group} and Xingnan Li and Ortega, {Victor E.} and Ampleford, {Elizabeth J.} and {Graham Barr}, R. and Christenson, {Stephanie A.} and Cooper, {Christopher B.} and Couper, {David J.} and Dransfield, {Mark T.} and Han, {Meilan K.} and Hansel, {Nadia N.} and Hoffman, {Eric A.} and Kanner, {Richard E.} and Kleerup, {Eric C.} and Martinez, {Fernando J.} and Robert Paine and Woodruff, {Prescott G.} and Hawkins, {Gregory A.} and Bleecker, {Eugene R.} and Meyers, {Deborah A.} and Alexis, {Neil E.} and Anderson, {Wayne H.} and {Graham Barr}, R. and Boucher, {Richard C.} and Bowler, {Russell P.} and Carretta, {Elizabeth E.} and Comellas, {Alejandro P.} and Criner, {Gerard J.} and Crystal, {Ronald G.} and Curtis, {Jeffrey L.} and Doerschuk, {Claire M.} and Freeman, {Christine M.} and Hastie, {Annette T.} and Kaner, {Robert J.} and Krishnan, {Jerry A.} and LaVange, {Lisa M.} and Lazarus, {Stephen C.} and Newell, {John D.} and Oelsner, {Elizabeth C.} and O'Neal, {Wanda K.} and Nirupama Putcha and Rennard, {Stephen I.} and Tashkin, {Donald P.} and Scholand, {Mary Beth} and {Michael Wells}, J. and Wise, {Robert A.}",
note = "Funding Information: X.L.: Associate Editor of BMC Medical Genetics. V.E.O.: funding from the Foundation for the NIH NHLBI in the form of a K08 training award; consultancy fees from CSL Behring. E.J.A.: no conflicts of interest to disclose. R.G.B.: grants from the Foundation for the NIH, Alpha1 Foundation and personal fees from UpToDate and the COPD Foundation all outside of the submitted work. S.A.C.: no conflicts of interest to disclose. C.B.C.: grants from the Foundation for the NIH and NIH NHLBI; part-time employment by the Global Respiratory Franchise in the GlaxoSmithKline. D.C.: grants from the Foundation for the NIH and NIH NHLBI. M.T.D.: grants from the NIH, the Department of Defense, and the American Heart. Association; consultancy fees from Boehringer Ingelheim, Boston Scientific, and GlaxoSmithKline and contracted clinical trials from Boehringer Ingelheim, Boston Scientific, GlaxoSmithKline, Pearl, Pulmonx, PneumRx, AstraZeneca, Novartis, and Yungjin. M.H.: grants from the NIH NHLBI and the Foundation for the NIH; consultancy fees from GlaxoSmithKline, Boehringer-Ingelheim, Novartis, and AstraZeneca. N.N.H.: grants from the Foundation for the NIH and NIH NHLBI. E.A.H.: grants from the Foundation for the NIH and NIH NHLBI; founder and shareholder of VIDA Diagnostics. R.E.K.: grants from the Foundation for the NIH and NIH NHLBI. E.K.: grants from the Foundation for the NIH and NIH NHLBI; grants from Boehringer-Ingelheim, Novartis, Pearl, AstraZeneca, and Sunovion outside of the submitted work. F.J.M.: grants from National Institutes of Health, Clarion, Continuing Education, Potomac, Afferent, and Adept; personal fees from Forest, Janssen, GlaxoSmithKline, Nycomed/Takeda, Amgen, Astra Zeneca, Boehringer-Ingelheim, Ikaria/Bellerophon, Genentech, Janssen, Johnson & Johnson, Novartis, Pearl, Pfizer, Roche, Sunovion, Theravance, Axon Communication, CME Incite, California Society for Allergy and Immunology, Annenberg, Integritas, InThought, Miller Medical, National Association for Continuing Education, Paradigm, Peer Voice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, Bioscale, Unity Biotechnology, ConCert, Lucid, Methodist Hospital, Prime, WebMD, Mereo, Kadmon, Pfizer, Veracyte, American Thoracic Society, Academic CME, Falco, and the National Association for Continuing Education. R.P.: grants from the Foundation for the NIH and NIH NHLBI. P.G.W.: grants from Medimmune and consultancy fees from Genentech/ Roche, Astra Zeneca, Novartis, Neostem, Janssen outside the submitted work; a patent with Asthma diagnostics pending. Funding Information: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), which were supplemented by contributions made through the Foundation for the NIH from AstraZeneca; Bellerophon Pharmaceuticals; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farm-aceutici SpA; Forest Research Institute, Inc.; GSK; Grifols Therapeutics, Inc.; Ikaria, Inc.; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; and Sanofi. The funders had no role in the study design, data collection, data analysis, decision to publish, or preparation of the manuscript. Funding Information: G.A.H.: no conflicts of interest to disclose. E.R.B.: grants from the NIH NHLBI for the Severe Asthma Research Program, AsthmaNet, SPIROMICS, and the Foundation for the NIH; consultancy fees from Amgen, AstraZeneca-MedImmune, Boehringer-Ingelheim, Genentech/ Roche, GlaxoSmithKline, Knopp, Novartis, and Sanofi/Regeneron; funds for clinical trials administered through the Wake Forest School of Medicine from Amgen, AstraZeneca-MedImmune, Boehringer-Ingelheim, Genentech/Roche, GlaxoSmithKline, Janssen/Johnson & Johnson, Novartis, Pzifer, Sanofi-Regeneron, and Teva. D.A.M.: no conflicts of interest to disclose. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = aug,
day = "1",
doi = "10.1186/s12881-018-0656-z",
language = "English (US)",
volume = "19",
journal = "BMC Medical Genomics",
issn = "1755-8794",
publisher = "BioMed Central",
number = "1",
}