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

Abstract

The aim of this study is to identify genetic loci associated with post-bronchodilator FEV 1 /FVC and FEV 1 , and develop a multi-gene predictive model for lung function in COPD. Genome-wide association study (GWAS) of post-bronchodilator FEV 1 /FVC and FEV 1 was performed in 1645 non-Hispanic White European descent smokers. A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV 1 /FVC ( p = 1.2 × 10 − 8 ) and FEV 1 ( 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 FEV 1 /FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking ( P < 2.2 × 10 − 16 ). 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.