NOVEL APPROACHES TO INVESTIGATE GENETIC CORRELATES OF SMOKING BEHAVIORS

研究吸烟行为遗传相关性的新方法

• 批准号: 8634957
• 负责人: ADAM JOSEPH BLOOM
• 金额: $ 14.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634957
• 关键词: 19q13; 5' Untranslated Regions; Affect; Alleles; American; Area; Behavioral; Biological; Biology; Brain; CYP2B6 gene; Candidate Disease Gene; Carbon Monoxide; Cations; Cell Culture Techniques; Cell Hypoxia; Cessation of life; Cigarette; Complex; Consumption; Data; Disease; Drug abuse; Enzymes; Exhalation; Exons; FMO3; Family; Gene Expression; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Grant; Hepatic; Human; Human Genetics; Hypoxia; Hypoxia Inducible Factor; In Vitro; Intervention; Lead; Liver; Measurement; Measures; Mentors; Messenger RNA; Metabolic; Metabolism; Methods; Modeling; Nicotine; Nicotine Dependence; Oral; Pathway interactions; Pharmacotherapy; Phenotype; Process; Procollagen-Proline Dioxygenase; Public Health; RNA Splicing; Relative (related person); Sampling; Smoker; Smoking; Smoking Behavior; Substance abuse problem; Testing; Tissue Sample; Tissues; Training; Variant; Withholding Treatment; Work; Wound Healing; addiction; base; career; cigarette smoking; cytochrome P-450 CYP2A6 (human); disorder risk; gene function; genetic association; genome wide association study; genome-wide; human tissue; improved; in vivo; mRNA Expression; novel; novel strategies; oxidation; protein expression; public health relevance; research study; response; smoking cessation; stroke recovery; success; trait; tumor growth

Project Summary/Abstract: Disease associated with cigarette smoking remains the largest cause of preventable death. A large margin for improvement in smoking cessation treatment exists, with great potential to benefit public health: more than half of American smokers attempt to quit every year, but only ~6% succeed annually. Differences in smoking phenotypes, including cessation, have significant genetic components, but the large majority of this influence is unexplained. Genetic studies of smoking behavior that reveal the mechanisms underlying variation in these traits will identify further targets for pharmacotherapy and aid in improving personalized cessation treatment. Utilizing measurements from an in vivo nicotine metabolism experiment, I developed a predictive genetic model that explains >70% of the variation in oral nicotine C-oxidation (the primary nicotine metabolism pathway), based on CYP2A6 genotype. Model predictions were significantly associated with different measures of cigarette consumption and smoking cessation success in further subjects. The model also allowed me to demonstrate two key novel findings: the independent influences upon smoking behaviors of polymorphisms in 1) EGLN2, a.k.a. Hypoxia Inducible Factor Prolyl Hydroxylase, which initiates a transcriptional cascade in response to cellular hypoxia, and 2) in FMO3 and CYP2B6, further nicotine metabolism genes that may have important extra-hepatic activity. The specific aims of this grant are: 1) Develop a comprehensive predictive genetic model of nicotine metabolism incorporating all three nicotine metabolism pathways and their associated genes, focusing on CYP2A6, the UGTs and FMOs. The improved model will then be applied in further samples to determine the influence of heritable differences in nicotine metabolism upon smoking phenotypes; 2) Identify variants that alter nicotine metabolism gene function and demonstrate the mechanisms of their effects. I will focus especially on protein and mRNA expression, and splicing, in human brain and liver samples; 3) Identify variants in EGLN2 and other hypoxia-response candidate genes, and determine the mechanisms of their effects on smoking phenotypes. My preliminary data indicate an EGLN2 variant associated with nicotine dependence and cigarette consumption alters the relative expression of different EGLN2 5'UTR mRNA splice-variants. I will identify differences in gene and protein expression influenced by EGLN2 genotype in cells cultured under normal and hypoxic conditions. The goal of this K01 proposal is to obtain further training in statistical human genetics and cell culture under special conditions and to apply this expertise to problems of substance abuse.

项目概要/摘要： 与吸烟有关的疾病仍然是可预防死亡的最大原因。一个很大的利润空间， 戒烟治疗的改善存在，具有极大的潜力，有利于公共卫生：超过 每年有一半的美国吸烟者试图戒烟，但每年只有6%的人成功戒烟。吸烟的区别 表型，包括停止，有显着的遗传成分，但这种影响的绝大多数是 无法解释吸烟行为的遗传学研究揭示了这些变化的潜在机制， 这些特征将确定药物治疗的进一步目标，并有助于改善个性化的戒烟治疗。 利用体内尼古丁代谢实验的测量结果，我开发了一种预测遗传学的方法， 解释口服尼古丁C-氧化（主要尼古丁代谢）中>70%变化的模型 途径），基于CYP 2A 6基因型。模型预测与不同的 在其他受试者中测量香烟消耗和戒烟成功。该模型还 这使我能够证明两个关键的新发现： 在1）EGLN 2，a.k.a.缺氧诱导因子脯氨酰羟化酶，它启动一个 响应细胞缺氧的转录级联，和2）在FMO 3和CYP 2B 6中，进一步尼古丁 可能具有重要肝外活性的代谢基因。该补助金的具体目标是：1） 开发一个综合的尼古丁代谢预测遗传模型，将所有三种尼古丁 代谢途径及其相关基因，重点是CYP 2A 6，UGT和FMO。改进的 然后将模型应用于进一步的样本，以确定尼古丁遗传差异的影响 2）鉴定改变尼古丁代谢基因功能的变体， 展示其作用机制。我将特别关注蛋白质和mRNA的表达， 剪接，在人脑和肝脏样品中; 3）鉴定EGLN 2和其他缺氧反应中的变体 候选基因，并确定其对吸烟表型的作用机制。我的初步数据 表明与尼古丁依赖相关的EGLN 2变异体和香烟消费改变了相对的 不同EGLN 2 5 'UTR mRNA剪接变体的表达。我会找出基因和蛋白质的差异 在正常和缺氧条件下培养的细胞中，EGLN 2基因型的表达受到影响。的目标 本K 01建议是在以下条件下获得统计人类遗传学和细胞培养方面的进一步培训 特别条件，并将这种专门知识应用于药物滥用问题。