Pilot Study of CYP2B6 Genetic Variation to Explore the Contribution of Nitrosamine Activation to Lung Carcinogenesis

We explored the contribution of nitrosamine metabolism to lung cancer in a pilot investigation of genetic variation in <i>CYP2B6</i>, a high-affinity enzymatic activator of tobacco-specific nitrosamines with a negligible role in nicotine metabolism. Previously we found that variation in <i>CYP2A6</i> and <i>CHRNA5-CHRNA3-CHRNB4</i> combined to increase lung cancer risk in a case-control study in European American ever-smokers (<i>n</i> = 860). However, these genes are involved in the pharmacology of both nicotine, through which they alter smoking behaviours, and carcinogenic nitrosamines. Herein, we separated participants by <i>CYP2B6</i> genotype into a high- <i>vs.</i> low-risk group (<i>*1/*1</i> + <i>*1/*6</i> <i>vs.</i> <i>*6/*6</i>). Odds ratios estimated through logistic regression modeling were 1.25 (95% CI 0.68–2.30), 1.27 (95% CI 0.89–1.79) and 1.56 (95% CI 1.04–2.31) for <i>CYP2B6</i>, <i>CYP2A6</i> and <i>CHRNA5-CHRNA3-CHRNB4</i>, respectively, with negligible differences when all genes were evaluated concurrently. Modeling the combined impact of high-risk genotypes yielded odds ratios that rose from 2.05 (95% CI 0.39–10.9) to 2.43 (95% CI 0.47–12.7) to 3.94 (95% CI 0.72–21.5) for those with 1, 2 and 3 <i>vs.</i> 0 high-risk genotypes, respectively. Findings from this pilot point to genetic variation in <i>CYP2B6</i> as a lung cancer risk factor supporting a role for nitrosamine metabolic activation in the molecular mechanism of lung carcinogenesi