THE GENETICS OF VULNERABILITY TO NICOTINE ADDICTIONS

尼古丁成瘾易感性的遗传学

• 批准号: 7618164
• 负责人: Pamela Ann Madden
• 金额: $ 89.35万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-25 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618164
• 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; 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; case control; cigarette smoking; cohort; density; 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

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，预计本世纪全球与吸烟有关的死亡人数约为10亿人。这是一项基因流行病学合作的重新修订（A2）竞争延续，以确定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内，使用10cM微卫星标记基因组扫描数据进行的QTL连锁分析发现，澳大利亚和芬兰兄弟姐妹的主要吸烟重度（HoS）表型在Chr 22q12上存在强烈的连锁信号（在更新的分析中，多点lod分别为3.05和3.21）。在芬兰和澳大利亚的基因组扫描样本中，对连锁峰两侧的另外两个微卫星标记进行基因分型，在25cM处获得了5.21的多点LOD（全基因组显著性p= 0.006）。这一竞争的延续旨在利用现有数据和dna的效率，以及从获得原始连锁信号的同一种群中提取的具有互补优势的大量信息样本，确定22q12上对HoS有贡献的基因或基因。这一目标将通过(i)开展一项遗传关联研究，对1000名无亲缘关系的芬兰男性重度吸烟者（每天吸烟40支以上的ATBC化学预防试验参与者）和1000名芬兰男性人群对照（Health2000参与者）进行1- lod支持区间内的1436个snp进行高通量基因分型（目标1：“芬兰系列i”；“1期基因分型”）；（ii）在两个独立的系列中对第一阶段发现的名义上显著的snp进行后续基因分型：(a)另外2000名不相关的重度吸烟者（每天吸烟30支以上）和2000名人口对照（“芬兰系列ii”）；(b)基于家庭的4429名吸烟的兄弟姐妹（55%为女性），来自基于社区的澳大利亚大兄弟姐妹系列（“BIGSIB”样本），仅根据来自澳大利亚双胞胎小组的大兄弟姐妹规模确定，来自与澳大利亚连锁家族相同的队列（目标2：“2期基因分型”）。结合芬兰系列I和II将确保足够的功率检测相当适度的QTL效应量；在澳大利亚的一系列研究中，对第一阶段关联的确认将确保我们能够发现基因效应，这种效应在男性长期吸烟者中可能只是适度的，但在女性吸烟者中则更为强烈。对于证实与HoS相关的snp基因，我们将从芬兰和澳大利亚的原始连锁家族中选择具有高风险和低风险单倍型的个体进行DNA测序，以试图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，使用原始芬兰NAG家族和澳大利亚BIGSIB样本（目标4）。基因对成为长期重度吸烟者的风险的影响的重要性已经为人所知很多年了。了解某些个体风险增加的遗传机制，最终将有助于改进戒烟疗法。