Pharmacogenetics of Nicotine Addiction and Treatment

说明(申请人提供)：在美国和世界大部分地区，烟草使用是导致过早残疾和死亡的最重要的可预防原因。作为对RFA-GM-04-002的回应，我们建议创建一个药物遗传学研究网络(PGRN)小组，以解决与尼古丁成瘾有关的药物遗传学问题，尼古丁成瘾是烟草依赖的一个基本因素，以及治疗。拟议的尼古丁成瘾和治疗的药物遗传学(PNAT)计划，包括临床、遗传学、统计学和生物信息学核心，将进行一系列多学科研究，以调查尼古丁作为滥用药物的药代动力学和药效学方面的遗传基础，以及尼古丁替代疗法和安非他酮作为烟草依赖治疗方法的个体差异。我们还计划对目前正在临床开发的两种新型戒烟药物varenicline和rimonabant进行探索性研究。PNAT计划有五个目标：(1)通过对现有和预期招募的临床人群中的5,061名参与者进行遗传关联分析，评估候选基因在尼古丁代谢、依赖性和治疗结果中的独立和协同作用(S)。我们将描述候选基因中的个体多态和单倍型，以及基因与基因的相互作用。(2)在分子、细胞和动物模型水平上表征显著相关的遗传多态的功能作用。(3)通过进行前瞻性的基因型分层药代动力学和药效学研究，在临床上验证有意义的基因多态。(4)通过基于通路的贝叶斯分层模型，综合评价遗传因素与药物干预的交互作用。除了确定人群水平的危险因素外，我们的目标是最终使用这些模型来预测个体结果，以便在戒烟治疗计划中设计定制的药物干预措施。(5)向PharmGKb数据库提供信息丰富的药物遗传数据，并创建一个共享的研究资源，供PGRN的其他成员和社区中那些侧重于了解烟草依赖和更广泛的药物成瘾的人使用。这项拟议的研究将使人们更好地了解尼古丁成瘾的遗传基础，以及基因对药物治疗反应的影响，以帮助戒烟。这项工作的长期目标是更好地个体化治疗烟草依赖，促进新药的开发，并减少吸烟作为主要健康问题的影响。

DESCRIPTION (provided by applicant): Tobacco use is the most important preventable cause of premature disability and death in the United States and in much of the world. In response to RFA-GM-04-002, we propose to create a Pharmacogenetics Research Network (PGRN) group to address pharmacogenetic questions related to nicotine addiction, an essential element of tobacco dependence, and treatment. The proposed Pharmacogenetics of Nicotine Addiction and Treatment (PNAT) program, consisting of Clinical, Genetics, Statistics, and Bioinformatics Cores, will conduct a series of multidisciplinary studies to investigate the genetic basis for both pharmacokinetic and pharmacodynamic aspects of nicotine as a drug of abuse, as well as individual variation in response to nicotine replacement therapy and bupropion as treatments for tobacco dependence. We also plan to carry out exploratory studies on varenicline and rimonabant, two novel smoking cessation medications currently under clinical development. The PNAT program has five goals: (1) To assess the independent and synergistic roles of candidate genes in nicotine metabolism, dependence and treatment outcome(s) by conducting genetic association analyses involving 5,061 participants in existing and prospectively recruited clinical populations. We will characterize both individual polymorphisms and haplotypes in the candidate genes, as well as gene-gene interactions. (2) To characterize the functional role of significantly associated genetic polymorphisms at molecular, cellular and animal model levels. (3) To clinically validate functionally significant genetic polymorphisms by conducting prospective genotype-stratified pharmacokinetic and pharmacodynamic studies. (4) To comprehensively evaluate the interaction of genetic factors and pharmacological interventions via pathway-based Bayesian hierarchical modeling. In addition to identification of population-level risk factors, we aim to ultimately use these models for the prediction of individual outcomes so as to design tailored pharmacological interventions within a smoking cessation treatment program. (5) To contribute informative pharmacogenetic data to the PharmGKB database and to create a shared research resource both for use by other members of the PGRN and by those in the communities focused on the understanding of tobacco dependence and, more broadly, drug addiction. The proposed research will lead to increased understanding of the genetic bases for nicotine addiction and genetic influences on responses to pharmacotherapy to aid smoking cessation. The long-term objective of this work is to better individualize treatment for tobacco dependence, to facilitate the development of novel medications, and to reduce the impact of smoking as a major health problem.