Genome-wide association study of lung function and clinical implication in heavy smokers
Ortega, Victor E.
Ampleford, Elizabeth J.
Graham Barr, R.
Christenson, Stephanie A.
Cooper, Christopher B.
Dransfield, Mark T.
Han, Mei Lan K.
Hansel, Nadia N.
Hoffman, Eric A.
Kanner, Richard E.
Kleerup, Eric C.
Martinez, Fernando J.
Woodruff, Prescott G.
Hawkins, Gregory A.
Bleecker, Eugene R.
Meyers, Deborah A.
AffiliationUniv Arizona, Div Genet Genom & Precis Med, Dept Med, BioSci Res Lab
MetadataShow full item record
CitationLi et al. BMC Medical Genetics (2018) 19:134
JournalBMC MEDICAL GENETICS
Rights© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractBackground: 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 x 10(-8)) and FEV1 (p = 2.1 x 10(-9)). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 x 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 < 2.2x10(-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.
NoteOpen access journal.
VersionFinal published version
SponsorsNIH/NHLBI [HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C]
- The Effects of Rare <i>SERPINA1</i> Variants on Lung Function and Emphysema in SPIROMICS.
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