DMET Genes, Nicotine Metabolism and Prospective Abstinence

DMET 基因、尼古丁代谢和预期戒烟

基本信息

批准号：
8320573
负责人：
ANDREW W BERGEN
金额：
$ 28.86万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320573
关键词：
Abstinence Accounting Alleles Behavioral Binding Biological Markers Candidate Disease Gene Carcinogens Cigarette Clinical Clinical Protocols Clinical Trials Collection Cotinine Cytochrome P450 Data Development Disease Dose Drug Kinetics Enrollment Future Genes Genetic Genetic Variation Genotype Heritability Individual Knowledge Laboratories Link Measures Metabolic Metabolism Modeling Nicotine Nicotinic Receptors Outcome Outcome Measure Participant Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacotherapy Phenotype Play Prevalence Proteins Protocols documentation Randomized Randomized Clinical Trials Research Risk Risk Factors Role Sampling Smoke Smoker Smoking Smoking Behavior Smoking History Staging Tobacco Tobacco smoking Tobacco smoking behavior Translating Translations Validation Variant Withholding Treatment addiction base cohort cytochrome P-450 CYP2A6 (human)drug metabolism effective therapy genetic risk assessment genotyping technology hydroxycotinine improved modifiable risk mortality next generation novel prospective response smoking cessation smoking prevalence trait

项目摘要

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. PUBLIC HEALTH RELEVANCE: The objectives of the proposed research are to identify novel genes contributing to nicotine metabolism and to smoking cessation. Nicotine metabolism is associated with the number of cigarettes smoked per day (CPD), how cigarettes are smoked (smoking topography), with responsiveness to smoking cessation treatment, and with carcinogen activation and level. Enhanced knowledge of the genes that influence nicotine metabolism and smoking cessation clinical trial outcomes will identify novel targets for the development of smoking cessation therapies, and may help personalize smoking cessation treatment and genetic risk assessment for smoking- attributable disease.

描述（由申请人提供）：拟议研究的目的是鉴定有助于尼古丁代谢和戒烟以及预期戒烟的新基因。尼古丁代谢与每天吸烟的数量（CPD）、吸烟方式（吸烟地形）、对戒烟治疗的反应以及致癌物质的激活和水平有关。尼古丁成瘾仍然是最大的可改变危险因素，导致美国 30% 的死亡，每年有 50 万人死于吸烟。我们将通过分析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 NMR）数据样本中的现有和新基因型数据来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，并将研究这些新的 PK 基因的变异是否会影响预期的戒烟。这些分析将首次将与参与临床实验室方案的个体的固定剂量 NMR 相关的 PK SNP 明确转化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 NMR，然后转化为多个 RCT 进行研究与预期戒烟的关联（总体戒烟和药物治疗）。队列数量 (10) 和要进行基因分型的个体数量 (3,784) 代表了最大的信息研究和要进行基因分型的个体的集合，以识别与尼古丁代谢和预期戒烟相关的 PK SNP。增强对影响尼古丁代谢和戒烟临床试验结果的遗传变异的了解将提高我们对代谢的理解，确定戒烟疗法开发的新靶标，并帮助表征 PK 基因变异对吸烟行为的影响、对戒烟治疗的反应和烟草引起的疾病。公共健康相关性：拟议研究的目的是确定有助于尼古丁代谢和戒烟的新基因。尼古丁代谢与每天吸烟的数量（CPD）、吸烟方式（吸烟地形）、对戒烟治疗的反应以及致癌物质的激活和水平有关。增强对影响尼古丁代谢和戒烟临床试验结果的基因的了解将确定开发戒烟疗法的新靶标，并可能有助于个性化戒烟治疗和吸烟所致疾病的遗传风险评估。