CHRNA3 genotype, nicotine dependence, lung function and disease in the general population

The CHRNA3 rs1051730 polymorphism has been associated to chronic obstructive pulmonary disease (COPD), lung cancer and nicotine dependence in case-control studies with high smoking exposure; however, its influence on lung function and COPD severity in the general population is largely unknown. We genotyped 57,657 adult individuals from the Copenhagen General Population Study, of whom 34,592 were ever-smokers. Information on spirometry, hospital admissions, smoking behaviour and use of nicotinic replacement therapy was recorded. In homozygous (11%), heterozygous (44%) and noncarrier (45%) ever-smokers, forced expiratory volume in 1 s (FEV(1)) was 94.1% predicted, 95.3% pred and 96.5% pred, forced vital capacity (FVC) was 97.1% pred, 97.5% pred and 98.3% pred, and FEV(1)/FVC was 0.770, 0.773 and 0.777, respectively (all p<0.001 for trend). Smoking interacted with genotype on FEV(1) % pred and FEV(1)/FVC (both p<0.001). When adjusted for cumulative tobacco consumption, these associations remained significant. In ever-smokers, odds ratios for COPD in homozygotes versus noncarriers were 1.3 (95% CI 1.2-1.4) for Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV, 1.4 (95% CI 1.2-1.6) for GOLD II-IV and 1.7 (95% CI 1.3-2.1) for GOLD III-IV. The corresponding value for lung cancer was 1.8 (95% CI 1.2-2.6). Genotype was also associated with daily and cumulative tobacco consumption and with use of nicotinic replacement therapy in former smokers. In ever-smokers, the CHRNA3 rs1051730 genotype associated with reduced lung function and increased COPD severity.