Johnstone Elaine C, Yudkin Patricia L, Hey Kate, Roberts Sarah J, Welch Sarah J, Murphy Michael F, Griffiths Siân E, Walton Robert T
Cancer Research UK General Practice Research Group, Department of Clinical Pharmacology, University of Oxford, Oxford, UK.
Pharmacogenetics. 2004 Feb;14(2):83-90. doi: 10.1097/00008571-200402000-00002.
Polymorphisms in the dopamine D2 receptor (DRD2 C/T and DRD2 A/G) and in dopamine beta hydroxylase (DBH A/G) have been implicated in modulation of smoking and other reward-seeking behaviours. We hypothesized that these alleles would predict the outcome of nicotine patch therapy for smoking cessation. In 1991-93, we performed a randomized controlled trial of the nicotine patch on 1686 heavy smokers (> or = 15 cigarettes/day). In 1999-2000, we contacted 1532 of the 1612 subjects still available; 767 (50%) completed a questionnaire and gave a blood sample. In the 755 cases in which DNA was successfully genotyped, we examined associations between the polymorphisms in DRD2 and DBH, and smoking cessation. At 1 week, the patch was more effective for smokers with DRD2 CT/TT genotype [patch/placebo odds ratio (OR) 2.8, 95% confidence interval (CI) 1.7-4.6] than with CC (OR 1.4, 0.9-2.1; P for difference in ORs 0.04). Smokers with both DRD2 CT/TT and DBH GA/AA genotypes had an OR of 3.6 (2.0-6.5) compared to 1.4 (1.0-2.1) for others (P = 0.01). At 12 weeks, the ORs for these genotypic groups were 3.6 (1.7-7.8) and 1.4 (0.9-2.3), respectively (P = 0.04). There was no association between patch effectiveness and DRD2 exon 8. Short-term effectiveness of the nicotine patch may be related to dopamine beta-hydroxylase and dopamine D2 receptor genotype. Our results support the need for further investigation into personalized therapies for smoking cessation based on individual genotype.
多巴胺D2受体（DRD2 C/T和DRD2 A/G）及多巴胺β羟化酶（DBH A/G）的多态性与吸烟及其他寻求奖励行为的调节有关。我们假设这些等位基因可预测尼古丁贴片疗法戒烟的效果。1991年至1993年，我们对1686名重度吸烟者（≥15支/天）进行了尼古丁贴片的随机对照试验。1999年至2000年，我们联系了1612名仍可找到的受试者中的1532名；767名（50%）完成了问卷调查并提供了血样。在成功进行DNA基因分型的755例中，我们研究了DRD2和DBH多态性与戒烟之间的关联。在第1周时，对于DRD2 CT/TT基因型的吸烟者，贴片比CC基因型更有效[贴片/安慰剂比值比（OR）2.8，95%置信区间（CI）1.7 - 4.6]，而CC基因型的OR为1.4（0.9 - 2.1）；OR差异的P值为0.04。与其他吸烟者相比，同时具有DRD2 CT/TT和DBH GA/AA基因型的吸烟者OR为3.6（2.0 - 6.5），而其他吸烟者为1.4（1.0 - 2.1）（P = 0.01）。在第12周时，这些基因型组的OR分别为3.6（1.7 - 7.8）和1.4（0.9 - 2.3）（P = 0.04）。贴片效果与DRD2第8外显子之间无关联。尼古丁贴片的短期效果可能与多巴胺β羟化酶和多巴胺D2受体基因型有关。我们的结果支持有必要进一步研究基于个体基因型的戒烟个性化疗法。
