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 email@example.com.
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.
- Authors: Ortega VE, Li X, O'Neal WK, Lackey L, Ampleford E, Hawkins GA, Grayeski PJ, Laederach A, Barjaktarevic I, Barr RG, Cooper C, Couper D, Han MK, Kanner RE, Kleerup EC, Martinez FJ, Paine R 3rd, Peters SP, Pirozzi C, Rennard SI, Woodruff PG, Hoffman EA, Meyers DA, Bleecker ER, NHLBI Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS).
- Issue date: 2020 Mar 1
- A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.
- Authors: Lutz SM, Cho MH, Young K, Hersh CP, Castaldi PJ, McDonald ML, Regan E, Mattheisen M, DeMeo DL, Parker M, Foreman M, Make BJ, Jensen RL, Casaburi R, Lomas DA, Bhatt SP, Bakke P, Gulsvik A, Crapo JD, Beaty TH, Laird NM, Lange C, Hokanson JE, Silverman EK, ECLIPSE Investigators., COPDGene Investigators.
- Issue date: 2015 Dec 3
- A Genome-Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos.
- Authors: Burkart KM, Sofer T, London SJ, Manichaikul A, Hartwig FP, Yan Q, Soler Artigas M, Avila L, Chen W, Davis Thomas S, Diaz AA, Hall IP, Horta BL, Kaplan RC, Laurie CC, Menezes AM, Morrison JV, Oelsner EC, Rastogi D, Rich SS, Soto-Quiros M, Stilp AM, Tobin MD, Wain LV, Celedón JC, Barr RG
- Issue date: 2018 Jul 15
- Alpha-1 Antitrypsin PiMZ Genotype Is Associated with Chronic Obstructive Pulmonary Disease in Two Racial Groups.
- Authors: Foreman MG, Wilson C, DeMeo DL, Hersh CP, Beaty TH, Cho MH, Ziniti J, Curran-Everett D, Criner G, Hokanson JE, Brantly M, Rouhani FN, Sandhaus RA, Crapo JD, Silverman EK, Genetic Epidemiology of COPD (COPDGene) Investigators * .
- Issue date: 2017 Aug
- The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers.
- Authors: Tulah AS, Parker SG, Moffatt MF, Wardlaw AJ, Connolly MJ, Sayers I
- Issue date: 2011 Dec 29