University of Toronto Coordinating Genetics Core & Clinical Trial Site

项目目标和范围。在美国，吸烟是导致过早死亡的首要原因。目前约有21%的成年人吸烟，而且吸烟率近年来没有下降。虽然现有的药物治疗可以帮助戒烟，但戒烟率在吸烟者亚组中差别很大。因此，吸烟是一个重要的临床问题，非常需要研究以改善治疗效果。尼古丁成瘾治疗药物遗传学（PNAT）研究项目的目标是为希望戒烟的个人提供优化药物治疗选择的证据基础。在过去的4年里，这个跨学科团队在转化药物遗传学（PGx）科学方面打下了坚实的基础。在这一竞争性更新中，我们建议：(a)开展一项多中心前瞻性分层PGx临床试验，以建立遗传信息生物标志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）的其他基因变异，以及影响治疗反应的药效学（PD）基因变异；(c)阐明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.