Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6)
Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6)
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DOI：
10.1111/add.12353
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发表时间：
2014-01-01
期刊：
影响因子：
6
通讯作者：
Bierut, Laura
中科院分区：
文献类型：
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作者：
Chen, Li-Shiun;Bloom, A. Joseph;Bierut, Laura
背景和目的有证据表明，烟碱受体5亚单位（CHRNA 5）和细胞色素P450 2A 6（CYP 2A 6）基因型影响戒烟成功率和药物治疗反应。我们研究了CYP 2A 6基因型对戒烟成功和对戒烟药物治疗反应的影响，并将这些影响与CHRNA 5基因型的影响相结合。尼古丁替代疗法或安非他酮和尼古丁替代疗法的组合。测量生存分析用于使用来自基于CYP 2A 6基因型估计的尼古丁代谢来模拟复发时间。慢代谢定义为估计代谢功能的最低四分位数。结果CYP 2A 6定义的尼古丁代谢功能调节了戒烟药物治疗对90天以上吸烟复发的影响[风险比（HR）=2.81，95%置信区间（CI）=1.32-5.99，P=0.0075]，快速戒烟药物治疗显著减缓了吸烟复发。（HR=0.39，95%CI =0.28-0.55，P=1.97x10（-8）），但不是慢代谢型（HR=1.09，95%CI =0.55-2.17，P=0.80）。此外，只有尼古丁替代的影响，而不是安非他酮，与CYP 2A 6定义的代谢功能。尼古丁替代对持续戒断的影响受到来自CYP 2A 6和CHRNA 5的联合遗传风险的调节（Wald=7.44，d.f.=结论尼古丁替代疗法对CYP 2A 6定义的尼古丁代谢快而不慢的个体有效。根据CYP 2A 6基因型估计，安非他酮对复发可能性的影响不太可能受到尼古丁代谢的影响。基因吸烟者之间治疗反应的差异可能会指导未来的个性化戒烟干预。
Background and aimsEvidence suggests that both the nicotinic receptor 5 subunit (CHRNA5) and Cytochrome P450 2A6 (CYP2A6) genotypes influence smoking cessation success and response to pharmacotherapy. We examine the effect of CYP2A6 genotype on smoking cessation success and response to cessation pharmacotherapy, and combine these effects with those of CHRNA5 genotypes.DesignPlacebo-controlled randomized smoking cessation trial.SettingAmbulatory care facility in Wisconsin, USA.ParticipantsSmokers (n=709) of European ancestry were randomized to placebo, bupropion, nicotine replacement therapy or combined bupropion and nicotine replacement therapy.MeasurementsSurvival analysis was used to model time to relapse using nicotine metabolism derived from CYP2A6 genotype-based estimates. Slow metabolism is defined as the lowest quartile of estimated metabolic function.FindingsCYP2A6-defined nicotine metabolic function moderated the effect of smoking cessation pharmacotherapy on smoking relapse over 90 days [hazard ratio (HR)=2.81, 95% confidence interval (CI)=1.32-5.99, P=0.0075], with pharmacotherapy significantly slowing relapse in fast (HR=0.39, 95% CI=0.28-0.55, P=1.97x10(-8)), but not slow metabolizers (HR=1.09, 95% CI=0.55-2.17, P=0.80). Further, only the effect of nicotine replacement, and not bupropion, varies with CYP2A6-defined metabolic function. The effect of nicotine replacement on continuous abstinence is moderated by the combined genetic risks from CYP2A6 and CHRNA5 (Wald=7.44, d.f.=1, P=0.0064).ConclusionsNicotine replacement therapy is effective among individuals with fast, but not slow, CYP2A6-defined nicotine metabolism. The effect of bupropion on relapse likelihood is unlikely to be affected by nicotine metabolism as estimated from CYP2A6 genotype. The variation in treatment responses among smokers with genes may guide future personalized smoking cessation interventions.