DMET Genes, Nicotine Metabolism and Prospective Abstinence

描述(由申请人提供)：拟议研究的目标是确定有助于尼古丁代谢和戒烟以及未来戒烟的新基因。尼古丁代谢与每天吸烟的数量(CPD)、香烟的吸烟方式(吸烟地形)、对戒烟治疗的反应性以及致癌物的活性和水平有关。尼古丁成瘾仍然是最大的可改变的风险因素，占美国死亡率的30%，每年有50万人死于吸烟。我们将通过对通过临床实验室方案获得的固定剂量尼古丁代谢率(固定剂量核磁共振)样本中现有的和新的基因型数据的分析，识别与尼古丁代谢相关的基因(药代动力学(PK)基因)。我们将使用从寻求治疗的吸烟者获得的随机剂量核磁共振数据来验证新的PK基因，并将调查这些新的PK基因的变异是否会影响预期的戒烟。这些分析将首次明确地将与参与临床实验室方案的个人的固定剂量核磁共振相关的PK SNPs转换为从参与临床试验样本的寻求治疗的吸烟者获得的随机剂量核磁共振，然后转换为多个随机对照试验，以研究与预期戒烟(总体和通过药物治疗)的相关性。队列数量(10)和要进行基因分型的个人数量(3,784)是为确定与尼古丁代谢和预期戒烟相关的PK SNP而进行的信息性研究和个人的最大集合。加强对影响尼古丁代谢和戒烟临床试验结果的基因变异的了解，将提高我们对新陈代谢的理解，为戒烟疗法的发展确定新的靶点，并有助于表征PK基因变异对吸烟行为、戒烟治疗和烟草可归因性疾病的影响。

DESCRIPTION (provided by applicant): The objectives of the proposed research are to identify novel genes contributing to nicotine metabolism and smoking cessation and to prospective smoking cessation. Nicotine metabolism is associated with the number of cigarettes smoked per day (CPD), how cigarettes are smoked (smoking topography), responsiveness to smoking cessation treatment, and with carcinogen activation and level. Addiction to nicotine remains the largest modifiable risk factor and contributes to 30% of mortality in the U.S., with 0.5 M individuals dying annually from smoking. We will identify genes associated with nicotine metabolism (pharmacokinetic (PK) genes) through analysis of existing and novel genotype data in samples with fixed dose nicotine metabolic rate (fixed dose NMR) data obtained through a clinical laboratory protocol. We will validate the novel PK genes using random dose NMR data obtained from treatment-seeking smokers, and will investigate whether variation at these novel PK genes influences prospective smoking cessation. These analyses will be the first to explicitly translate PK SNPs associated with the fixed dose NMR from individuals participating in a clinical laboratory protocol to the random dose NMR obtained from treatment-seeking smokers participating in a clinical trial sample, and then into multiple RCTs to investigate association wih prospective smoking cessation (overall and by pharmacotherapy). The number of Cohorts (10) and the number of individuals to be genotyped (3,784) represent the largest collection of informative studies and individuals to be genotyped to identify PK SNPs associated with nicotine metabolism and prospective smoking cessation. Enhanced knowledge of the genetic variation that influences nicotine metabolism and smoking cessation clinical trial outcomes will improve our understanding of metabolism, identify novel targets for the development of smoking cessation therapies, and help characterize PK gene variant effects on smoking behaviors, response to smoking cessation treatment and tobacco-attributable disease.