CHRNA3 and CYP3A5*3 genotype, lung function and chronic obstructive pulmonary disease in the general population

TY - JOUR

T1 - CHRNA3 and CYP3A5*3 genotype, lung function and chronic obstructive pulmonary disease in the general population

AU - Kaur-Knudsen, Diljit

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

PY - 2014/4

Y1 - 2014/4

N2 - Objective: Genetic variations are most likely an additional risk factor besides tobacco smoking per se for the risk of chronic obstructive pulmonary disease (COPD). In this study, we compared genetic variants influencing the effect of smoking on COPD, that is, the effect of the well-known splicing defect polymorphism, CYP3A5*3 (rs776746), identified before genome-wide association studies, with the genome-wide association studies identified CHRNA3 (rs1051730) polymorphism on the risk of decreased lung function and COPD. Materials and methods: In all, 10 605 participants from the general population were genotyped. Information on spirometry, hospital admissions and smoking behaviour was recorded. Endpoints were lung function and COPD. Results: For CHRNA3, the percentage of forced expiratory volume in 1 s (FEV1%) predicted was 89.3, 90.6 and 92.4% in homozygous, heterozygous and noncarrier ever-smokers (P-trend<0.001). The corresponding values for forced vital capacity percentage (FVC%) predicted were 94.5, 95.2 and 96.7% (P-trend<0.001), and for FEV1/FVC ratio, the values were 0.753, 0.760 and 0.764 (P-trend=0.008). The odds ratio for COPD in homozygous versus noncarrier ever-smokers was 1.5 [95% confidence interval (CI) 1.3-1.9] for COPD hospitalization, 1.3 (95% CI 1.1-1.6) for COPD defined as FEV1/FVC less than lower limit of normal, 1.3 (95% CI 1.0-1.5) for the Global Initiative for Chronic Obstructive Lung Disease category 1-4 (GOLD 1-4), 1.2 (95% CI 1.0-1.5) for GOLD 2-4 and 1.5 (95% CI 1.1-2.2) for GOLD 3-4. This association could not be found in never-smokers. No association was found for CYP3A5*3. Conclusion: The CHRNA3 genotype is associated with decreased lung function and risk of COPD among ever-smokers, whereas this was not the case for CYP3A5*3.

AB - Objective: Genetic variations are most likely an additional risk factor besides tobacco smoking per se for the risk of chronic obstructive pulmonary disease (COPD). In this study, we compared genetic variants influencing the effect of smoking on COPD, that is, the effect of the well-known splicing defect polymorphism, CYP3A5*3 (rs776746), identified before genome-wide association studies, with the genome-wide association studies identified CHRNA3 (rs1051730) polymorphism on the risk of decreased lung function and COPD. Materials and methods: In all, 10 605 participants from the general population were genotyped. Information on spirometry, hospital admissions and smoking behaviour was recorded. Endpoints were lung function and COPD. Results: For CHRNA3, the percentage of forced expiratory volume in 1 s (FEV1%) predicted was 89.3, 90.6 and 92.4% in homozygous, heterozygous and noncarrier ever-smokers (P-trend<0.001). The corresponding values for forced vital capacity percentage (FVC%) predicted were 94.5, 95.2 and 96.7% (P-trend<0.001), and for FEV1/FVC ratio, the values were 0.753, 0.760 and 0.764 (P-trend=0.008). The odds ratio for COPD in homozygous versus noncarrier ever-smokers was 1.5 [95% confidence interval (CI) 1.3-1.9] for COPD hospitalization, 1.3 (95% CI 1.1-1.6) for COPD defined as FEV1/FVC less than lower limit of normal, 1.3 (95% CI 1.0-1.5) for the Global Initiative for Chronic Obstructive Lung Disease category 1-4 (GOLD 1-4), 1.2 (95% CI 1.0-1.5) for GOLD 2-4 and 1.5 (95% CI 1.1-2.2) for GOLD 3-4. This association could not be found in never-smokers. No association was found for CYP3A5*3. Conclusion: The CHRNA3 genotype is associated with decreased lung function and risk of COPD among ever-smokers, whereas this was not the case for CYP3A5*3.

KW - Adult

KW - Aged

KW - Cytochrome P-450 CYP3A

KW - Denmark

KW - Forced Expiratory Volume

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Lung

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Pulmonary Disease, Chronic Obstructive

KW - Receptors, Nicotinic

KW - Smoking

U2 - 10.1097/fpc.0000000000000038

DO - 10.1097/fpc.0000000000000038

M3 - Journal article

C2 - 24535486

SN - 1744-6872

VL - 24

SP - 220

EP - 229

JO - Pharmacogenetics

JF - Pharmacogenetics

IS - 4

ER -