Pharmacology Research Institute, Los Alamitos, CA 90720, USA.
J Investig Med. 2011 Dec;59(8):1280-3. doi: 10.2130/JIM.0b013e31823581fa.
Polymorphism of the DRD2 gene (rs1800497), previously termed Taq1A, includes the A1 and A2 alleles. The A1⁺ genotype (A1/A1, A1/A2) has been associated with smoking dependence. The present study determined which polymorphism of the DRD2 gene had a salutary outcome in administration of rimonabant, a drug used in smoking cessation and obesity studies.
Seventy-six (76) smokers enrolled into a double-blind, placebo-versus-rimonabant, 10-week smoking cessation drug trial. Subjects provided a blood sample to determine whether they had the DRD2 A1⁺ genotype (A1/A1, A1/A2) or the DRD2 A1⁻ genotype (A2/A2). Smoking cessation (or continuation) was monitored on a weekly basis with on-site carbon monoxide (CO) monitoring.
Smokers in the rimonabant A1⁻ group were significantly more successful in completely stopping smoking compared to subjects in the placebo A1⁻ group (P < 0.05). However, there was no difference in smoking cessation when the rimonabant A1⁺ group was compared to the placebo A1⁺ group. With respect to quantified verifiable/objective smoking cessation outcomes, exhaled CO (parts per million) was monitored during each week of the study. The rimonabant A1⁻ group compared to the placebo A1⁻ group was quantifiably smoking less at weeks 5, 6, and 7 (P < 0.05), at week 8 (P < 0.01), and at weeks 9 and 10 (P < 0.001). No significant difference was found in exhaled CO levels between rimonabant A1⁺ group and the placebo A1⁺ group in any of the weeks studied.
These findings further support the rationale for incorporating genotyping into clinical trials, particularly smoking cessation trials. Rimonabant demonstrated early and sustained smoking cessation efficacy only in noncarriers of the A1 allele. These results also underscore the risks of heterogeneity contributing to type 2 errors, when analyzing (phase 2 or 3) data. The potential clinical, regulatory, and commercial benefits associated with expediting and enhancing drug development, vis-à-vis the integration of biomarkers in clinical research, is supported by our findings.
DRD2 基因（rs1800497）的多态性，以前称为 Taq1A，包括 A1 和 A2 等位基因。A1⁺基因型（A1/A1、A1/A2）与吸烟依赖有关。本研究旨在确定 DRD2 基因的哪种多态性在利莫那班（一种用于戒烟和肥胖研究的药物）治疗中具有有益的结果。
76 名吸烟者参加了一项为期 10 周的双盲、安慰剂对照利莫那班戒烟药物试验。受试者提供血液样本以确定他们是否具有 DRD2 A1⁺基因型（A1/A1、A1/A2）或 DRD2 A1⁻基因型（A2/A2）。每周通过现场一氧化碳（CO）监测来监测戒烟（或继续吸烟）情况。
与安慰剂 A1⁻组相比，利莫那班 A1⁻组的吸烟者完全戒烟的成功率显著更高（P < 0.05）。然而，与安慰剂 A1⁺组相比，利莫那班 A1⁺组的戒烟效果没有差异。就可量化的可核实/客观戒烟结果而言，在研究的每一周都监测呼出的 CO（百万分之几）。与安慰剂 A1⁻组相比，利莫那班 A1⁻组在第 5、6 和 7 周（P < 0.05）、第 8 周（P < 0.01）以及第 9 和 10 周（P < 0.001）时的吸烟量可量化地减少。在研究的任何一周内，利莫那班 A1⁺组与安慰剂 A1⁺组之间的呼出 CO 水平均无显著差异。
这些发现进一步支持将基因分型纳入临床试验，特别是戒烟试验的原理。利莫那班仅在非 A1 等位基因携带者中表现出早期和持续的戒烟效果。这些结果还强调了当分析（2 期或 3 期）数据时，异质性导致 2 型错误的风险。我们的研究结果支持将生物标志物整合到临床研究中，从而加快和增强药物开发的潜在临床、监管和商业效益。
