CHRNA3genotype, nicotine dependence, lung function and disease in the general population

Abstract

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 (FEV1) 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 FEV1/FVC was 0.770, 0.773 and 0.777, respectively (all p,0.001 for trend). Smoking interacted with genotype on FEV1 % pred and FEV1/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.

Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium

“…Using a genetic marker of exposure should support stronger causal inference because genetic variants should not be associated with the usual confounding factors, they will indicate long-term levels of exposure, and are not affected by the onset of disease and thus protected from reverse causation. The smoking-associated rs16969968/rs1051730 genotype is strongly and consistently associated with smoking heaviness among smokers, has shown to be a solid instrument for smoking, and has shown the expected causal associations with increased all-cause mortality, decreased lung function, and BMI 30–35 . However, using more than a single SNP, e.g., SNPs reflecting different pathways to the exposure, may reduce the risk of pleiotropy, but we know of no other smoking-associated SNP with strength and consistency similar to the rs16969968/rs1051730 genotype, so this might introduce weak instrument bias 36 .…”

Time to first cigarette and serum cholesterol levels

“…While no genetic risks common to ND and cholesterol appear to have been identified, similar findings have been reported in other smoking outcomes. For example, genetic variations on the nicotinic receptor CHRNA3/5 have been simultaneously linked to ND, lung cancer, and pulmonary impairment, independently of smoking behavior (Hancock et al, 2015; Improgo et al, 2010; Kaur-Knudsen et al, 2012; Pillai et al, 2009). …”

Effect of Smoking on Blood Pressure and Resting Heart Rate

“…The rs16969968/rs1051730 variant has been used in a similar way (i.e. stratified on smoking status) in a number of other Mendelian Randomisation studies to demonstrate the expected causal associations of smoking with increased all-cause mortality, 50 decreased lung function, 51 and body mass index. The fact that stratification by smoking status has been used to show that smoking is, as expected, causally related these phenotypes, supports our view that this approach is appropriate.…”