Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk

Abstract

Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal-Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.

Figure 1

Association of CYP2A6 and CHRNA5-A3-B4 genotype with smoking behaviors. A) Self-reported cigarettes smoked per day and B) Fagerström Test for Nicotine Dependence (FTND) scores are displayed for control subjects who were current smokers and are shown as the mean with 95% confidence intervals (CIs) by genotype group. The genotypes analyzed include the CYP2A6 genotype alone, the CHRNA5-A3-B4 genotype alone, and the combined CYP2A6 and CHRNA5-A3-B4 genotype groups according to the number of risk genotypes. The low-risk group (0 risk) included CYP2A6 reduced metabolizers with the CHRNA5-A3-B4 GG and GA genotypes. The intermediate-risk group (one risk) included participants with either the CYP2A6 normal metabolizer genotypes or the CHRNA5-A3-B4 AA genotype, and the high-risk group (two risk) included CYP2A6 normal metabolizers with the CHRNA5-A3-B4 AA genotype. P values were calculated by Kruskal–Wallis tests. *P < .05, **P < .001. P_trend was calculated by a generalized linear model. †P_trend < .05. All statistical tests were two-sided.

Figure 2

Lung cancer risk by CYP2A6 and CHRNA5-A3-B4 genotype. A) Overall risk of lung cancer and B) risk of lung cancer in the lighter-smoking stratum are shown as adjusted odds ratios with 95% confidence intervals (CIs). The lighter-smoking stratum was defined as individuals smoking 20 cigarettes or less per day on the basis of the median cigarette consumption in patients and control subjects. For each odds ratio, the lower-risk genotype group served as the reference (ref), ie, ref. CYP2A6 reduced metabolizers and/or CHRNA5-A3-B4 GG or GA. Odds ratios were adjusted by age (continuous), sex (male or female), and log pack–years (continuous). Lung cancer odds ratios and P values were estimated by logistic regression analysis with P < .05 denoted by an asterisk. All statistical tests were two-sided.