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BMC Med Genet. 2018 Aug 1;19(1):134. doi: 10.1186/s12881-018-0656-z.

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

Author information

1
Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, BioScience Research Lab, Room 253, 1230 N. Cherry Avenue, PO Box 210242, Tucson, AZ, 85721, USA. lixingnan1@deptofmed.arizona.edu.
2
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
3
Department of Medicine, Columbia University, New York, NY, USA.
4
Division of Pulmonary, Critical Care, Sleep & Allergy, Department of Medicine and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California, USA.
5
Department of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
6
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
7
Division of Pulmonary, Allergy & Critical Care Medicine, Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA.
8
Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, MI, USA.
9
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
10
Department of Radiology, University of Iowa, Iowa City, Iowa, USA.
11
Department of Internal Medicine/Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT, USA.
12
Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.
13
Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, BioScience Research Lab, Room 253, 1230 N. Cherry Avenue, PO Box 210242, Tucson, AZ, 85721, USA.

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

PMID:
30068317
PMCID:
PMC6090900
DOI:
10.1186/s12881-018-0656-z
[Indexed for MEDLINE]
Free PMC Article

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