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: 8722284
• 负责人: Laura J. Bierut
• 金额: $ 74.53万
• 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/8722284
• 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; 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; cytochrome P-450 CYP2A6 (human); 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; 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）：过去 5 年里，技术革命以惊人的速度推动了基因研究的发展，并且已经确定了基因对吸烟行为的明显影响。我们的研究小组首次报道了尼古丁依赖与染色体15q25.1区域的关联，该区域包括CHRNA5-CHRNA3-CHRNB4胆碱能尼古丁受体亚基基因。尼古丁依赖、肺癌和慢性阻塞性肺病最强烈的遗传关联研究结果集中在该区域。我们的研究和多项荟萃分析令人信服地表明，CHRNA6-CHRNB3 受体亚基和尼古丁代谢基因 CYP2A6 中的 SNP 也与重度吸烟和尼古丁依赖相关。该项目的目标是进一步识别和表征尼古丁依赖的遗传发现，并整合这些关联如何有助于成功戒烟。具体目标 1 是对已识别的变异进行编目、表征和测试，并精细绘制烟碱受体基因和尼古丁代谢基因。这一目标将建立在遗传性疾病研究中心 (CIDR) 的定制靶向测序的基础上，对近 3,000 名尼古丁依赖或非依赖受试者的烟碱受体和尼古丁代谢基因的变异进行分类。具体目标 2 是在大规模研究中评估尼古丁依赖的遗传关联，包括我们自己的复制样本以及通过参与荟萃分析和联盟。具体目标 3 是在大规模研究中评估戒烟的遗传关联。我们将积极开展并参与评估戒烟相关表型的荟萃分析和联盟，我们还将与 Timothy Baker 博士合作，后者拥有戒烟试验的数据以及辉瑞临床试验的表型和遗传数据伐尼克兰(Chantix(R))。该项目将继续加速发现控制尼古丁依赖发展的分子途径的变异，并将我们的工作扩展到理解戒烟。通过利用我们之前开发的资源和合作，这项研究将在基因组科学的前沿迈出重要的下一步，并将该领域推向新的水平，以了解尼古丁依赖和戒烟的遗传学。