THE GENETICS OF VULNERABILITY TO NICOTINE ADDICTIONS

尼古丁成瘾易感性的遗传学

基本信息

批准号：
8261967
负责人：
Pamela Ann Madden
金额：
$ 63.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-25 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8261967
关键词：
22q12 ADRBK2 gene Accounting Alcohol or Other Drugs use Australia Behavior Beta Carotene Beta-Adrenergic Receptor Kinase 2 Biological Cancer Etiology Candidate Disease Gene Cessation of life Chemoprevention Chromosomes Chromosomes, Human, Pair 22 Cigarette Collaborations Communities Consumption DNA DNA Sequence Data Data Set Ensure Epidemiology Family Female Finland Funding Genes Genetic Genetic Predisposition to Disease Genome Scan Genotype Goals Haplotypes Hour Individual Lead Malignant neoplasm of lung Measures Mental disorders Microsatellite Repeats Nicotine Dependence Parents Participant Phase Phenotype Population Population Control Premature Mortality Psychopathology Quantitative Trait Loci Recruitment Activity Risk SNP genotyping Sampling Series Severities Siblings Signal Transduction Smoke Smoker Smoking Smoking History Source Specificity Staging Symptoms Tobacco Twin Multiple Birth Update Variant alpha Tocopherol base cancer chemoprevention cigarette smoking cohort density family genetics follow-up genetic association genetic epidemiology genetic linkage genetic linkage analysis genetic variant genome-wide high risk improved indexing male novel response smoking cessation trend

项目摘要

DESCRIPTION (provided by applicant): Long-term smoking is the leading preventable cause of cancers and of premature mortality, with approximately one billion smoking-related deaths projected globally, based on present trends, in the current century. This is the re-revised (A2) competing continuation of a genetic epidemiologic collaboration to identify genes that influence risks for heavy smoking and nicotine dependence. During the first five-year funding period, QTL linkage analyses using 10cM microsatellite marker genome scan data have identified a strong linkage signal in both Australian and Finnish sibships, for our primary heaviness-of-smoking (HoS) phenotype, on Chr 22q12 (in updated analyses, multi-point LODs of 3.05 and 3.21 respectively). Genotyping of two additional microsatellite markers flanking the linkage peaks, in both Finnish and Australian genome-scan samples, yielded a combined multipoint LOD of 5.21 (genome-wide significance p=.006) at 25cM. This competing continuation seeks to identify the gene or genes at 22q12 which are contributing to HoS using the efficiency of existing data and DNAs and large informative samples, with complementary strengths, that were drawn from the same populations in which the original linkage signal was obtained. This goal will be achieved by (i) conducting a genetic association study, with high-throughput genotyping of 1436 SNPs across a 1-LOD support interval within our primary linkage region in 1000 unrelated Finnish male heavy smokers (ATBC chemoprevention trial participants who smoked 40+ cigarettes per day) and 1000 Finnish male population controls (Health2000 participants) (Aim 1: 'Finnish series I'; 'stage 1 genotyping'); (ii) conducting follow-up genotyping of SNPs found nominally significant at stage 1 in two separate series: (a) an additional 2000 unrelated heavy smokers (who smoked 30+ cigarettes per day) and 2000 population controls ('Finnish series II'); and (b) a family-based series of 4429 siblings who are smokers (55 percent female) from a community-based series of Australian large sibships ('BIGSIB' sample) ascertained solely on the basis of large sibship size from the Australian twin panel, from the same cohorts as the Australian linkage families (Aim 2: 'stage 2 genotyping'). Combining Finnish series I and II will ensure adequate power to detect quite modest QTL effect sizes; confirmation of nominal stage 1 associations in the Australian series will ensure that we are able to detect genetic effects that may be only modest in male long-term smokers, but more potent in female smokers. For genes with SNPs confirmed to be associated with HoS, we will conduct DNA sequencing in individuals with high-risk and low-risk haplotypes, selected from the original Finnish and Australian linkage families, to attempt to identify variants that might be functional (Aim 3), and will characterize using family-based association approaches the effects of genetic variants (or haplotypes) thus identified on cigarette-smoking and related behaviors (including correlated substance use and other psychiatric disorders), using the original Finnish NAG families and the Australian BIGSIB sample (Aim 4). The importance of genetic influences on risk of becoming a long-term heavy smoker has been known for many years. Understanding the genetic mechanisms by which some individuals are at increased risk should ultimately lead to improved therapies to assist smoking cessation.

描述（由申请人提供）：长期吸烟是癌症和过早死亡的主要可预防原因，根据目前的趋势，本世纪预计全球约有 10 亿人因吸烟而死亡。这是遗传流行病学合作的重新修订 (A2) 竞争性延续，旨在识别影响重度吸烟和尼古丁依赖风险的基因。在第一个五年资助期间，使用 10cM 微卫星标记基因组扫描数据进行的 QTL 连锁分析在澳大利亚和芬兰同胞中发现了强烈的连锁信号，对于我们的主要吸烟重度 (HoS) 表型，在 Chr 22q12 (in更新的分析，多点 LOD 分别为 3.05 和 3.21）。在芬兰和澳大利亚基因组扫描样本中，对连锁峰两侧的另外两个微卫星标记进行基因分型，在 25cM 处产生的组合多点 LOD 为 5.21（全基因组显着性 p=.006）。这一竞争性的延续旨在利用现有数据和 DNA 以及具有互补优势的大量信息样本的效率来识别 22q12 上对 HoS 做出贡献的一个或多个基因，这些样本是从获得原始连锁信号的相同群体中抽取的。这一目标将通过 (i) 进行遗传关联研究，对 1000 名不相关的芬兰男性重度吸烟者（吸烟 40 岁的 ATBC 化学预防试验参与者）的主要连锁区域内的 1-LOD 支持区间内的 1436 个 SNP 进行高通量基因分型。 + 每天吸烟）和 1000 名芬兰男性人口对照（Health2000 参与者）（目标 1：“芬兰系列 I”； “第一阶段基因分型”）； (ii) 对两个独立系列中在第一阶段发现名义上显着的 SNP 进行后续基因分型：(a) 另外 2000 名不相关的重度吸烟者（每天吸 30 支以上香烟）和 2000 名人口对照（“芬兰系列 II”） ; (b) 以家庭为基础的系列，由 4429 名吸烟兄弟姐妹组成（55% 为女性），来自以社区为基础的澳大利亚大型同胞系列（“BIGSIB”样本），仅根据澳大利亚双胞胎小组的大型同胞规模来确定，来自与澳大利亚连锁家族相同的队列（目标 2：“第 2 阶段基因分型”）。结合芬兰系列 I 和 II 将确保有足够的功效来检测相当适度的 QTL 效应大小；澳大利亚系列中名义上第一阶段关联的确认将确保我们能够检测到遗传效应，这种效应在男性长期吸烟者中可能只是适度的，但在女性吸烟者中更有效。对于已确认与 HoS 相关的 SNP 基因，我们将对选自原始芬兰和澳大利亚连锁家族的高风险和低风险单倍型个体进行 DNA 测序，以尝试识别可能具有功能的变异（目标 3）），并将使用基于家庭的关联方法来表征由此确定的遗传变异（或单倍型）对吸烟和相关行为（包括相关物质使用和其他精神疾病）的影响，使用原始数据芬兰 NAG 家庭和澳大利亚 BIGSIB 样本（目标 4）。多年来，人们已经知道遗传因素对成为长期重度吸烟者风险的重要性。了解某些个体风险增加的遗传机制最终应该会导致改进辅助戒烟的疗法。