University of Toronto Coordinating Genetics Core & Clinical Trial Site

计划目标和范围。烟草使用是美国过早死亡的首要原因。大约21%的成年人目前吸烟，吸烟率近年来并没有下降。虽然现有的药物疗法可以帮助戒烟，但吸烟者亚群的戒烟率差别很大。因此，吸烟是一个重要的临床问题，非常需要研究来改善治疗结果。尼古丁成瘾治疗药物遗传学(PNAT)研究计划的目标是生成证据基础，以优化希望戒烟的个人的药物治疗选择。建立在翻译药物遗传学(PGx)科学的坚实基础上，由这个跨学科团队在过去4年中进行。在这项竞争性更新中，我们建议：(A)进行一项多中心前瞻性分层PGx临床试验，以确定遗传信息生物标记物的预测有效性和成本效益，以优化戒烟治疗；(B)确定改变尼古丁药代动力学(PK)的更多基因变异，以及影响治疗反应的药效学(PD)基因变异；以及(C)阐明我们的PGx标记物与戒烟相关的因果机制。

Program Goals and Scope. Tobacco use is the foremost cause of premature death in the U.S. About 21% of adults are current smokers and smoking rates have not declined in recent years. Although available pharmacotherapies can aid in quitting smoking, quit rates vary substantially in subgroups of smokers. Thus, smoking is a significant clinical problem with a great need for research to improve treatment outcomes. The goal of the Pharmacogenetics of Nicotine Addiction Treatment (PNAT) research program is to generate the evidence base to optimize pharmacotherapeutic choices for individuals who wish to quit smoking. Building upon a strong foundation of translational pharmacogenetic (PGx) science conducted by this transdisciplinary team during the past 4 years. we propose in this competing renewal to: (a) conduct a multi-center prospective stratified PGx clinical trial to establish the predictive validity and cost-effectiveness of a genetically-informed biomarker to optimize smoking cessation treatment; (b) identify additional gene variants altering nicotine pharmacokinetics (PK), as well as pharmacodynamic (PD) gene variants influencing therapeutic response; and (c) elucidate causal mechanisms underlying associations of our PGx marker with smoking cessation.