1 meeting genome-wide significance in ever Intedanib smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

Keywords: chronic obstructive pulmonary disease, single-nucleotide polymorphism, genes At a Glance Commentary Scientific Knowledge on the Subject Genome-wide association studies of pulmonary function in population-based studies have discovered numerous loci, but association to a standardized definition of airflow obstruction has not yet been evaluated within population-based studies. What This Study Adds to the Field This is the largest study to date to evaluate genetic predictors of airflow obstruction. We confirm the association to the chromosome 15 CHRNA5/CHRNA3 gene cluster and demonstrate nominal association to the region in never smokers with airflow obstruction. We also implicate the HTR4 gene in the pathogenesis of airflow obstruction.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, and cigarette smoking is the most widely recognized risk factor for this disease. COPD is defined based on spirometry as airflow obstruction that is not fully reversible after administration of a bronchodilator. Airflow obstruction is a key pathophysiologic characteristic of COPD that is assessed by spirometry. Both COPD and spirometry measures of lung function have been demonstrated to have a genetic component. Family studies have reported an increased risk for COPD in relatives of a COPD proband (1) as well as significant heritability of pulmonary function measured by spirometry in population-based cohorts (2).

The ��1-antitrypsin gene (SERPINA1/A1AT) is known to AV-951 be associated with COPD and leads to increased risk for early-onset disease among individuals carrying the susceptibility alleles, but few other genes have such a conclusive relationship to COPD. Recent genome-wide association studies (GWAS) have examined two spirometry measures of lung function, FEV1 and its ratio to FVC (FEV1/FVC). Two large-scale GWAS meta-analyses identified a total of 11 loci related to FEV1 or FEV1/FVC (3, 4), and a larger meta-analysis incorporating these studies along with new studies identified an additional 16 loci (5).