Genome-wide association study of lung function and clinical implication in heavy smokers.

MS#: 
MS073
TitleGenome-wide association study of lung function and clinical implication in heavy smokers.
Publication TypePublication
Year2018
AuthorsLi X, Ortega VE, Ampleford EJ, R Barr G, Christenson SA, Cooper CB, Couper D, Dransfield MT, Han MLan K, Hansel NN, Hoffman EA, Kanner RE, Kleerup EC, Martinez FJ, Paine R, Woodruff PG, Hawkins GA, Bleecker ER, Meyers DA
Corporate AuthorsSPIROMICS Research Group
JournalBMC Med Genet
Volume19
Issue1
Pagination134
Date Published2018 Aug 01
ISSN1471-2350
Abstract

BACKGROUND: The aim of this study is to identify genetic loci associated with post-bronchodilator FEV/FVC and FEV, and develop a multi-gene predictive model for lung function in COPD.METHODS: Genome-wide association study (GWAS) of post-bronchodilator FEV/FVC and FEV 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 FEV/FVC (p = 1.2 × 10) and FEV (p = 2.1 × 10). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10) 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 FEV/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P <  2.2 × 10).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.

DOI10.1186/s12881-018-0656-z
Alternate JournalBMC Med. Genet.
PubMed ID30068317
PubMed Central IDPMC6090900
Grant ListHHSN268200900013C / / National Heart, Lung, and Blood Institute /
K08 HL118128 / HL / NHLBI NIH HHS / United States
HHSN268200900014C / / National Heart, Lung, and Blood Institute /
HHSN268200900016C / / National Heart, Lung, and Blood Institute /
HHSN268200900018C / / National Heart, Lung, and Blood Institute /
U01 HL137880 / HL / NHLBI NIH HHS / United States
HHSN268200900020C / / National Heart, Lung, and Blood Institute /
HHSN268200900015C / / National Heart, Lung, and Blood Institute /
HHSN268200900017C / / National Heart, Lung, and Blood Institute /
HHSN268200900019C / / National Heart, Lung, and Blood Institute /
Manuscript Lead/Corresponding Author Affiliation: 
Clinical Center: Tucson (University of Arizona)
ECI: 
Manuscript Status: 
Published