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

Li, Xingnan; Ortega, Victor E.; Ampleford, Elizabeth J.; Barr, R. Graham; Christenson, Stephanie A.; Cooper, Christopher B.; Couper, David; Dransfield, Mark T.; Han, Mei L. K.; Hansel, Nadia N.; Hoffman, Eric A.; Kanner, Richard E.; Kleerup, Eric C.; Martinez, Fernando J.; Paine, Robert; Woodruff, Prescott G.; Hawkins, Gregory A.; Bleecker, Eugene R.; Meyers, Deborah A.; SPIROMICS Research Group

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.

Genome-wide association study (GWAS) of post-bronchodilator FEV1/FVC and FEV1 was performed in 1645 non-Hispanic White European descent smokers.

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).

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.


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BMC Medical Genetics

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Academic Units
Published Here
October 1, 2018


COPD, GWAS, Lung function, rs28929474, SERPINA1, SPIROMICS