American Journal of Respiratory and Critical Care Medicine vol:181 issue:5 pages:486-493
RATIONALE: Genome-wide association studies have identified genetic variants in the nicotinic acetylcholine receptor (nAChR) on chromosome 15q24/25 as a risk for nicotine dependence, lung cancer and chronic obstructive pulmonary disease (COPD). Assessment of bronchial obstruction by spirometry, typically used for diagnosing COPD, fails, however, to detect emphysema. OBJECTIVES: To determine the association of the 15q24/25 locus with emphysema. METHODS: The rs1051730 variant on 15q24/25 was genotyped in two independent Caucasian cohorts of 661 and 456 heavy smokers. Participants underwent pulmonary function tests, computed tomography (CT) of the chest and took questionnaires assessing smoking behaviour and health status. MEASUREMENTS AND MAIN RESULTS: The rs1051730 A-allele correlated with reduced forced expiratory volume in 1 second (FEV1) and with increased susceptibility for bronchial obstruction with a pooled odds ratio (OR) of 1.33 (95% confidence interval [CI]=1.11-1.61; P=0.0026). In both studies a correlation between the rs1051730 A-allele and lung diffusing capacity (DLCO) and diffusing capacity per unit alveolar volume (KCO) was observed. Consistently, the rs1051730 A-allele conferred increased risk for emphysema as assessed by CT (P=0.0097 and P=0.019), with a pooled OR of 1.39 (CI=1.15-1.68; P=0.00051). Visual emphysema scores and scores based on densities quantified on CT were more pronounced in A-allele carriers, indicating that rs1051730 correlates with the severity of emphysema. CONCLUSIONS: The 15q24/25 locus in nAChR is associated with the presence and severity of emphysema. This association was independent of pack-years smoking, suggesting that nAChR is causally involved in alveolar destruction, as a potentially shared pathogenic mechanism in lung cancer and COPD.