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

for the SPIROMICS Research Group

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number134
JournalBMC Medical Genetics
Volume19
Issue number1
DOIs
StatePublished - Aug 1 2018

Fingerprint

Genome-Wide Association Study
Chronic Obstructive Pulmonary Disease
Bronchodilator Agents
Lung
Genotype
Genes
Genetic Loci
Emphysema
Heterozygote
Single Nucleotide Polymorphism
Smoking
Demography
Outcome Assessment (Health Care)
Genome

Keywords

  • COPD
  • GWAS
  • Lung function
  • Rs28929474
  • SERPINA1
  • SPIROMICS

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide association study of lung function and clinical implication in heavy smokers. / for the SPIROMICS Research Group.

In: BMC Medical Genetics, Vol. 19, No. 1, 134, 01.08.2018.

Research output: Contribution to journalArticle

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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 David Couper and Dransfield, {Mark T.} and Han, {Mei Lan K.} and Nadia Hansel 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 Couper, {David J.} and Criner, {Gerard J.} and Crystal, {Ronald G.} and Curtis, {Jeffrey L.} and Doerschuk, {Claire M.} and Freeman, {Christine M.} and Han, {Mei Lan K.} 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}",
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T1 - Genome-wide association study of lung function and clinical implication in heavy smokers

AU - for the SPIROMICS Research Group

AU - Li, Xingnan

AU - Ortega, Victor E.

AU - Ampleford, Elizabeth J.

AU - Graham Barr, R.

AU - Christenson, Stephanie A.

AU - Cooper, Christopher B.

AU - Couper, David

AU - Dransfield, Mark T.

AU - Han, Mei Lan K.

AU - Hansel, Nadia

AU - Hoffman, Eric A.

AU - Kanner, Richard E.

AU - Kleerup, Eric C.

AU - Martinez, Fernando J.

AU - Paine, Robert

AU - Woodruff, Prescott G.

AU - Hawkins, Gregory A.

AU - Bleecker, Eugene R.

AU - Meyers, Deborah A.

AU - Alexis, Neil E.

AU - Anderson, Wayne H.

AU - Graham Barr, R.

AU - Boucher, Richard C.

AU - Bowler, Russell P.

AU - Carretta, Elizabeth E.

AU - Comellas, Alejandro P.

AU - Couper, David J.

AU - Criner, Gerard J.

AU - Crystal, Ronald G.

AU - Curtis, Jeffrey L.

AU - Doerschuk, Claire M.

AU - Freeman, Christine M.

AU - Han, Mei Lan K.

AU - Hastie, Annette T.

AU - Kaner, Robert J.

AU - Krishnan, Jerry A.

AU - LaVange, Lisa M.

AU - Lazarus, Stephen C.

AU - Newell, John D.

AU - Oelsner, Elizabeth C.

AU - O'Neal, Wanda K.

AU - Putcha, Nirupama

AU - Rennard, Stephen I.

AU - Tashkin, Donald P.

AU - Scholand, Mary Beth

AU - Michael Wells, J.

AU - Wise, Robert A

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

KW - COPD

KW - GWAS

KW - Lung function

KW - Rs28929474

KW - SERPINA1

KW - SPIROMICS

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DO - 10.1186/s12881-018-0656-z

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VL - 19

JO - BMC Medical Genetics

JF - BMC Medical Genetics

SN - 1471-2350

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ER -