Abstract 21287: The Gene Polymorphisms of CYP2A6 and the Nicotinic Acetylcholine Receptor α4 Subunit Influence Nicotine Dependence, Which is One of the Cardiovascular Risk Factors, in Japanese Smokers.
Introduction: Smoking cessation is critical for the prevention against cardiovascular diseases; however, quitting smoking is difficult due to nicotine dependence (ND). Interindividual differences in pharmacokinetics (PK) and pharmacodynamics (PD) of nicotine result partially from genetic backgrounds. Nicotine is metabolized principally by CYP2A6, and CYP2A6 gene polymorphisms influence PK of nicotine, while genetic mutations in nicotinic nerve systems could modulate PD of nicotine. Here, we assessed whether these genetic variations associated with ND severity.
Methods: The study subjects were consisted of 413 Japanese male smokers. ND was assessed based on the Heaviness of Smoking Index. In addition to CYP2A6 genotypes (*1, 4, *7, *9), 37 single nucleotide polymorphisms (SNPs) were selected from 18 nicotinic neuron-related genes including nicotinic acetylcholine receptor (nAChR), dopamine transporter, 5-HT receptor & transporter and GABA receptor. Genotyping was performed with PCR-based methods. Chi-square test was used to examine the association between each genotype and ND.
Results: CYP2A6 genotypes were divided two groups according to thier enzyme activities, such as the higher; CYP2A6 *1/*1, *1/*9, *1/*4, *1/*7 and *9/*9, and the lower; *4/*4, *4/*7, *4/*9 and *7/*9). The smokers with the higher-activity genotypes of CYP2A6 (n=330) show severer ND, compared with those with the lower (n=83) (72.1% vs 46.9%, P <0.001, ODs 2.92, 95%CI 1.78-4.78). In addition, nAChR α4 subunit (CHRNA4) rs2273504 showed the strongest association with ND (G/A or G/G, 72.4%, n=330; A/A, 45.87%, n=83; P <0.001, OR=3.11, 95%CI=1.90-5.10). Interestingly, the same tendency was observed in the subjects with CYP2A6 high activity (G/A or G/G, 77.2%, n=272; A/A, 48.3%, n=58; P <0.001, OR=3.63, 95%CI=2.02-6.53).
Conclusion: CYP2A6 and CHRNA4 gene polymorphisms are the critical determinants for ND severity. Nicotine patch and valenicline, an α4β2 nAChR partial agonist, are used for smoking cessation medications. Personalized smoking cessation program could be designed based on CYP2A6 and CHRNA4 genotypes, contributing effective smoking cessation therapy.
- © 2010 by American Heart Association, Inc.