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; SERPINA1; SPIROMICS; rs28929474.

Conflict of interest statement

Participants were recruited at each center through physician referral, advertisement in clinical areas or self-referral using the SPIROMICS study website (www.spiromics.com). The research protocol was approved by the institutional review boards of all participating institutions (Wake Forest School of Medicine, Columbia University, University of California at San Francisco, University of California at Los Angeles, University of North Carolina at Chapel Hill, University of Alabama at Birmingham, University of Michigan, Johns Hopkins University School of Medicine, University of Iowa, University of Utah, Weill Cornell Medical College of Cornell University) with written informed consent from all participants.

Not applicable.

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.

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.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Association plot of SERPINA1 region with post-bronchodilator FEV1/FVC. Negative logarithm-transformed P value (left) and recombination rate (right). Red color scale represents the strength of linkage disequilibrium of SNPs with rs28929474

Fig. 2

Association plot of SERPINA1 region with post-bronchodilator percent predicted FEV1. Negative logarithm-transformed P value (left) and recombination rate (right). Red color scale represents the strength of linkage disequilibrium of SNPs with rs28929474

Fig. 3

Joint analysis of 10 candidate SNPs in 1077 SPIROMICS non-Hispanic White smokers with COPD. 10 SNPs include rs28929474 in SERPINA1, rs1980057 in HHIP, rs2869967 in FAM13A1, rs2070600 in AGER, rs1435867 in PID1, rs12477314 in HDAC4, rs1529672 in RARB, rs12914385 in CHRNA3, rs10498635 in RIN3, and rs615098 in MMP12. Blue bars represent post-bronchodilator percent predicted FEV1, and red bars represent percentages of subjects with severe COPD (GOLD stage 3–4)