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

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.