DMET Genes, Nicotine Metabolism and Prospective Abstinence

DMET 基因、尼古丁代谢和预期戒烟

• 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
• 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

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）：拟议研究的目标是确定有助于尼古丁代谢和戒烟以及前瞻性吸烟的新基因。尼古丁代谢与每天吸烟的香烟数量（CPD），香烟如何熏制（吸烟地形），对戒烟治疗的反应能力以及致癌物的激活和水平有关。对尼古丁的成瘾仍然是最大的可修改风险因素，在美国导致30％的死亡率，每年有0.5 m的个体死于吸烟。我们将通过分析通过固定剂量的尼古丁代谢率（固定剂量NMR）数据来鉴定与尼古丁代谢（药代动力学（PK）基因）相关的基因。我们将使用从寻求治疗的吸烟者获得的随机剂量NMR数据来验证新型PK基因，并将研究这些新型PK基因的变异是否影响前瞻性吸烟。这些分析将是第一个明确地转化与参与临床实验室方案的个体的固定剂量NMR相关的PK SNP，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，然后参与多个RCT，然后将其用于多个RCT，以调查未来的吸烟液（整体和药物治疗）。人群（10）和要进行基因分型的个体的数量（3,784）代表了最大的信息研究和旨在识别与尼古丁代谢和前瞻性吸烟戒烟相关的PK SNP的信息和个体。对影响尼古丁代谢和戒烟临床试验的影响的遗传变异的知识增强，将改善我们对新陈代谢的理解，确定戒烟疗法发展的新颖目标，并有助于表征PK Gene对吸烟行为的影响，对吸烟治疗和戒毒治疗的反应和托巴纳科症的反应。 公共卫生相关性：拟议研究的目标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香烟数量（CPD），香烟如何吸烟（吸烟地形）以及对戒烟治疗以及致癌物的激活和水平有关。对影响尼古丁代谢和戒烟临床试验结果的基因的知识增强，将确定戒烟疗法发展的新颖目标，并可能有助于个性化吸烟治疗和遗传风险评估，以评估吸烟疾病。