Variants in nicotine receptors and pharmacogenetics

描述（由申请人提供）：吸烟具有成瘾性，来自流行病学研究的数据表明，遗传因素在吸烟和尼古丁成瘾中起重要作用。最近的多项研究表明，染色体15q25上CHRNA5/CHRNA3/ CHRNB4位点的变异与重度吸烟和尼古丁依赖（ND）有关。其中一个变异，SNP rs16969968，将CHRNA5基因中的第398个氨基酸从天冬氨酸(D)改变为天冬酰胺(N) （D398N）。这一发现为我们提供了一个机会来测试D398N多态性和/或基因座的其他变异是否会改变人类对尼古丁的药理学和生理反应。我们假设这种D398N和/或CHRNA5/CHRNA3/CHRNB4基因的其他变异可能改变nachr的功能特性，最终改变对尼古丁的反应。为了验证这一假设，我们提出以下建议：测量400名不吸烟志愿者的尼古丁反应表型。在一个单独的实验中，每个参与者将按先后顺序接受0、2和4毫克尼古丁口香糖剂量。结果测量包括在给药前后对一系列问卷的回答，以及在给药前和给药期间测量的皮肤温度、心率和血压。这些问卷包括情绪与状态量表（POMS）、尼古丁直接影响量表（DENS）和积极与消极影响量表（PANAS）。2. 目的探讨D398N位点基因型和CHRNA5/CHRNA3/CHRNB4位点的其他多态性是否影响尼古丁口香糖给药的药理学和生理反应。我们将对所有受试者进行D398N多态性和位点上其他snp的基因分型，并使用unphase和PLINK程序来测试基因型是否与上述目的1中获得的表型相关。有证据表明，遗传因素影响人类对尼古丁的主观体验和生理反应。由于经常吸烟者会产生尼古丁耐受性，这会混淆人类对尼古丁的反应，我们建议在本应用中使用非吸烟者。人类的主观体验与吸烟行为相关，因此，了解遗传变异对主观体验的影响为了解吸烟和尼古丁成瘾的遗传机制提供了新的途径。

DESCRIPTION (provided by applicant): Tobacco smoking is addictive and data from epidemiological studies have suggested that genetic factors play an important role in smoking and nicotine addiction. Multiple recent studies indicate that variants in the CHRNA5/CHRNA3/ CHRNB4 locus on chromosome 15q25 are associated with heavy smoking and nicotine dependence (ND). One of the variants, SNP rs16969968, changes the 398th amino acid from aspartic acid (D) to asparagine (N) (D398N) in the CHRNA5 gene. This finding gives us an opportunity to test whether this functional D398N polymorphism and/or other variants in the locus change the pharmacological and physiological responses to nicotine administration in humans. We hypothesize that this D398N and/or other variants in the CHRNA5/CHRNA3/CHRNB4 genes may change the functional properties of nAChRs, ultimately altering the responses to nicotine administration. To test this hypothesis, we propose the following: 1. To measure the nicotine response phenotypes of 400 non-smoking volunteers. In a single laboratory session, each participant will receive 0, 2 and 4 mg of nicotine gum doses in ascending order. Outcome measures include responses to a battery of questionnaires administered before and after nicotine dosing, as well as skin temperature, heart rate and blood pressure measured before and during nicotine dosing. These questionnaires include the Profile of Mood and States (POMS), the Direct Effects of Nicotine Scale (DENS) and the Positive and Negative Affect Schedule (PANAS). 2. To evaluate whether genotypes at the D398N site and other polymorphisms in the CHRNA5/CHRNA3/CHRNB4 locus affect the pharmacological and physiological responses of nicotine gum administration. We will genotype all subjects for the D398N polymorphism and other SNPs in the locus and use the UNPHASED and PLINK programs to test whether genotypes are associated with the phenotypes obtained from aim 1 above. There is evidence that genetic factors influence humans' subjective experience and physiological responses to nicotine administration. Since regular smokers develop nicotine tolerance, which confounds human responses to nicotine, we propose to use non-smokers in this application. Humans' subjective experience is correlated to smoking behaviors, therefore, understanding the influence of genetic variants on subjective experience provides a new approach to understand the genetic mechanisms of smoking and nicotine addiction. PUBLIC HEALTH RELEVANCE: Multiple recent studies have shown that variants in the CHRNA5, CHRNA3 and CHRNB4 genes increase risks for tobacco smoking and nicotine dependence. In this application, we propose to test the hypothesis whether variants in these genes mediate humans' subjective experience and physiological responses to nicotine administration. The plan includes two specific aims. The first is to recruit 400 non- smokers to participate an experiment that measures their subjective and physiological responses to nicotine gum administration. The reason to use only non-smokers is to avoid nicotine tolerance and brain adaptation observed in regular smokers. The second aim is to analyze genetic variations at the CHRNA5, CHRNA3 and CHRNB4 genes and to correlate these variations with the response data obtained from the first aim. The overall goal is to evaluate whether and how genetic variants at particular genes affect humans' responses to nicotine administration. Knowledge obtained from this study can be used to guide future genetic studies of smoking and nicotine addiction and to help development of strategies for smoking cessation and prevention treatments.