David Sean P, Brown Richard A, Papandonatos George D, Kahler Christopher W, Lloyd-Richardson Elizabeth E, Munafò Marcus R, Shields Peter G, Lerman Caryn, Strong David, McCaffery Jeanne, Niaura Raymond
Brown University Center for Primary Care and Prevention, Providence, RI 02860, USA.
Nicotine Tob Res. 2007 Aug;9(8):821-33. doi: 10.1080/14622200701382033.
This randomized, double-blinded, placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation. Smokers of European ancestry (N = 291), who were randomized to receive bupropion or placebo (12 weeks) plus counseling, were genotyped for the dopamine D2 receptor (DRD2-Taq1A), dopamine transporter (SLC6A3 3' VNTR), and cytochrome P450 2B6 (CYP2B6 1459 CT) polymorphisms. Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2-, 6-, and 12-month follow-ups post quit date. Using generalized estimating equations, we found that bupropion, compared with placebo, was associated with significantly greater odds of abstinence at all time points (all p values<.01). We found a significant DRD2 x bupropion interaction (B = 1.49, SE = 0.59, p = .012) [corrected] and a three-way DRD2 x bupropion x craving interaction on 6-month smoking cessation outcomes (B = -0.45, SE = 0.22, p = .038), such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion. Furthermore, there was a significant DRD2 x CYP2B6 interaction (B = 1.43, SE = 0.56, p = .01), such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype. Because the sample size of this study was modest for pharmacogenetic investigations, the results should be interpreted with caution. Although these results require replication, the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and, further, that exploration of gene x gene and gene x craving interactions in future, larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion.
这项随机、双盲、安慰剂对照试验研究了基因对缓释安非他酮戒烟治疗反应的影响。欧洲血统的吸烟者（N = 291）被随机分为接受安非他酮或安慰剂治疗（12周）并接受咨询，对其进行多巴胺D2受体（DRD2 - Taq1A）、多巴胺转运体（SLC6A3 3' VNTR）和细胞色素P450 2B6（CYP2B6 1459 CT）多态性的基因分型。主要结局指标是治疗结束时以及戒烟日期后2个月、6个月和12个月随访时经可替宁验证的戒断点患病率。使用广义估计方程，我们发现与安慰剂相比，安非他酮在所有时间点的戒断几率均显著更高（所有p值<.01）。我们发现DRD2与安非他酮之间存在显著交互作用（B = 1.49，SE = 0.59，p = .012）[校正后]，并且在6个月戒烟结局方面存在DRD2×安非他酮×渴求的三向交互作用（B = -0.45，SE = 0.22，p = .038），即携带A2/A2基因型的吸烟者使用安非他酮时渴求降低幅度最大且戒断率最高。此外，存在显著的DRD2×CYP2B6交互作用（B = 1.43，SE = 0.56，p = .01），即只有当携带DRD2 - Taq1 A2/A2基因型的个体同时拥有CYP2B6 1459 T/T或C/T基因型时，其戒断几率才更高。由于本研究的样本量对于药物遗传学研究而言较小，因此对结果的解释应谨慎。尽管这些结果需要重复验证，但数据初步表明DRD2 - Taq1A多态性可能影响安非他酮戒烟治疗反应，此外，未来更大规模研究中对基因×基因和基因×渴求交互作用的探索可能为安非他酮复杂的药效动力学提供机制性见解。
