Nicotine Dependence to Smoking Cessation: Sequencing Common and Rare Variants

戒烟对尼古丁的依赖：对常见和罕见变异进行测序

• 批准号: 9271304
• 负责人: Laura J. Bierut
• 金额: $ 0.58万
• 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: 2014-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271304
• 关键词: Affect; African American; American; Area; Bioinformatics; Cataloging; Catalogs; Cessation of life; Chantix; Chromosomes; Chronic Obstructive Airway Disease; Cigarette; Cigarette Smoker; Clinical Trials; Collaborations; Custom; Data; Data Set; Development; Disease; European; Funding; Genes; Genetic; Genetic study; Genomic Segment; Genomics; Genotype; Goals; Health; Human Genome; Inherited; Intervention; Investigator-Initiated Research; Knowledge; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Measures; Medical; Meta-Analysis; Molecular; Natural History; Nicotine; Nicotine Dependence; Nicotinic Receptors; Pathway interactions; Phenotype; Procedures; Receptor Gene; Recruitment Activity; Reporting; Research; Resources; Role; Sampling; Science; Signal Transduction; Smoker; Smoking; Smoking Behavior; TNFRSF5 gene; Technology; Testing; Tobacco; Tobacco use; Translating; United States; United States National Institutes of Health; Universities; Variant; Wisconsin; Work; adverse outcome; age group; aged; case control; cholinergic; clinically relevant; epidemiologic data; genetic association; genetic variant; genome wide association study; improved; mortality; next generation sequencing; population based; premature; rare variant; receptor; risk variant; smoking cessation; targeted sequencing; tool; varenicline

DESCRIPTION (provided by applicant): A revolution in technology has moved genetic studies forward at a remarkable pace over the last 5 years, and clear genetic contributions to smoking behavior have been identified. Our group was the first to report the association of nicotine dependence with the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotine receptor subunit genes. The strongest genetic association findings for nicotine dependence, lung cancer and chronic obstructive pulmonary disease then converged to implicate this region. Our studies and several meta-analyses have convincingly shown that SNPs in the CHRNA6-CHRNB3 receptor subunits and nicotine metabolizing gene CYP2A6 are also associated with heavy smoking and nicotine dependence. The goal of this project is to further identify and characterize genetic findings for nicotine dependence and to integrate how these associations contribute to successful smoking cessation. Specific Aim 1 is to catalogue, characterize, and test identified variants and fine map nicotinic receptor genes and nicotine metabolizing genes. This aim will build upon custom targeted sequencing from the Center for Inherited Disease Research (CIDR) to catalogue variation in the nicotinic receptors and nicotine metabolizing genes in almost 3,000 nicotine dependent or non-dependent subjects. Specific Aim 2 is to evaluate genetic associations for nicotine dependence in large-scale studies, including our own replication sample and through participation in meta-analyses and consortia. Specific Aim 3 is to evaluate genetic associations for smoking cessation in large-scale studies. We will actively generate and participate in meta-analyses and consortia assessing smoking cessation related phenotypes, and we will also build upon our collaboration with Dr. Timothy Baker, who has data from smoking cessation trials along with phenotypic and genetic data from the Pfizer clinical trial of varenicline (Chantix(R)). This project will continueto accelerate the discovery of variation in molecular pathways that govern the development of nicotine dependence and extend our work toward the understanding of smoking cessation. By capitalizing on the resources and collaborations we have previously developed, this study will take an important next step along the cutting edge of genomic science and move the field to the next level of understanding the genetics of nicotine dependence and smoking cessation.

描述（由申请人提供）：在过去的5年中，技术革命以显着的速度向前迈进了遗传学研究，并且已经确定了对吸烟行为的明确遗传贡献。我们的小组是第一个报告尼古丁依赖性与15q25.1染色体区域的关联的人，其中包括CHRNA5-CHRNA3-CHRNB4胆碱能受体受体亚基基因。然后，尼古丁依赖性，肺癌和慢性阻塞性肺疾病的最强遗传关联发现融合了该区域。我们的研究和几个荟萃分析令人信服地表明，CHRNA6-CHRNB3受体亚基中的SNP和尼古丁代谢基因CYP2A6也与大烟和尼古丁依赖性有关。该项目的目的是进一步识别和表征尼古丁依赖性的遗传发现，并整合这些关联如何促进成功戒烟。具体目的1是对目录，表征和测试确定的变体以及细MAP烟碱受体基因和尼古丁代谢基因。这个目标将基于从遗传性疾病研究中心（CIDR）到烟碱受体的目录变化和近3,000名尼古丁依赖性或非依赖性受试者的尼古丁代谢基因的定制测序。具体目的2是在大规模研究中评估尼古丁依赖性的遗传关联，包括我们自己的复制样本以及通过参与荟萃分析和财团。特定目的3是评估大规模研究中戒烟的遗传关联。我们将积极生成并参与评估与戒烟相关表型的荟萃分析和财团，我们还将在与蒂莫西·贝克（Timothy Baker）博士的合作基础上进行，后者来自戒烟试验的数据以及来自VarenicLine（chantix（r）的辉透临床试验的表型和遗传数据的数据。该项目将继续加速控制尼古丁依赖发展的分子途径变化，并将我们的工作扩展到对戒烟的理解。通过利用我们先前开发的资源和合作，这项研究将沿着基因组科学的最前沿迈出重要的下一步，并将该领域提升到更高的了解尼古丁依赖性和戒烟的遗传学水平。