Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

Abstract

RATIONALE, Genome-wide association studies, GWAS, have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease, COPD, are known. OBJECTIVES, Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. METHODS, Fifteen cohorts were studied for discovery, affected, unaffected, and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up, cases, control subjects, . Airflow obstruction was defined as FEV, and its ratio to FVC, FEV, FVC, both less than their respective lower limits of normal as determined by published reference equations. MEASUREMENTS AND MAIN RESULTS, The discovery meta-analyses identified one region on chromosome, q, ., meeting genome-wide significance in ever smokers that includes AGPHD, IREB, and CHRNA, CHRNA, genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA, in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR, a gene previously related to FEV, FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM, RARB, PPAP, B, and ADAMTS, were nominally replicated in the COPD meta-analysis. CONCLUSIONS, These results suggest an important role for the CHRNA, region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR, gene in the etiology of airflow obstruction.