乙酰胆碱受体基因及其它因素与戒烟成功关系的研究

发布时间：2018-01-18 23:55

本文关键词： 戒烟成功乙酰胆碱受体基因基因分数贝叶斯网络优势分析　出处：《山东大学》2017年博士论文　论文类型：学位论文

【摘要】：研究背景虽然吸烟是一种可防可控的行为,世界各国也做了大量工作去控制烟草的流行,但是烟草在全球的流行趋势并不容乐观。2011年全球范围内15岁以上群体中,吸烟比例男性为36%、女性为8%。全球的统计结果显示,吸烟每年给人类社会造成了大约35000亿人民币的经济损失;每年因吸烟导致疾病所引起的死亡人数约有600万。在中国,2011年15岁以上人群中的吸烟比例男性为47%、女性为2%。在中国,有3亿个体正处于吸烟的状态中,处在二手烟危害中的非吸烟个体有7.4亿之多。然而在中国2年以上的成功戒烟率仅为11.70%。烟草烟雾中的化学物超过4000种,很多种化学物是有毒有害的,其中有69种化学物是被确定的致癌物。吸烟几乎可以危害到人的全部器官,导致一系列癌症的发病率升高,是支气管哮喘、脑卒中、动脉粥样硬化等非传染性慢性病的诱因。吸烟已成为全球前八位死亡原因中六种疾病的主要致病因子。戒烟是文献中可见到经证明过的降低、杜绝烟草损害的唯一方法。因此,探索戒烟成功的影响因素,为针对性制定戒烟干预措施提供理论支持,成了公共卫生工作者需要解决的一个问题。持续吸烟的主要原因是吸烟者产生了尼古丁依赖。尼古丁依赖是由烟草烟雾中的尼古丁造成的。烟草烟雾中的尼古丁被吸入人体经呼吸系统、循环系统到达脑部后,首先与烟碱型乙酰胆碱受体(nicotinic acetylcholine receptors,nAChRs)结合,然后刺激中脑边缘系统的多巴胺神经元合成多巴胺,最后导致伏隔核区的多巴胺释放增多,使人产生"愉悦感",完成物质奖赏过程。这是尼古丁依赖的生物学机制。尼古丁发挥作用的第一步是尼古丁与nAChRs的结合。烟碱型乙酰胆碱受体基因(nicotinic acetylcholine receptor gene,CHRN)起着调节烟碱型乙酰胆碱受体的作用。基因敲除模型研究表明,敲除了 CHRN的小鼠对尼古丁的某些反应发生了改变。戒烟与尼古丁依赖是相对立的:戒烟成功、放弃吸烟的关键一步就是要克服尼古丁依赖。因此我们推测CHRN可能对尼古丁依赖、戒烟成功有影响。人群研究表明,CHRN的单核苷酸多态性(singlenucleotide polymorphisms,SNP)突变可以降低戒烟成功的可能性、使安慰剂组戒烟率降低、使个体的主动戒烟次数出现差异。虽然现有的研究揭示了 CHRN与戒烟成功的某些关系,但这些研究尚存在着不足之处:第一,用单个SNP去研究基因变异与戒烟成功的关系有可能不能检测到基因变异对戒烟成功的全部影响;第二,当前的文献中,存在结果不一致或者结果相反的情况。第三,现有研究缺乏用整体基因信息从基因层面上去研究CHRN与戒烟成功关系的案例。研究表明,个体因素(如年龄、职业、教育、每天吸烟量、吸烟开始年龄、吸烟年数、戒烟动机等)与戒烟成功相关。尼古丁依赖不仅仅意味着躯体依赖也意味着心理依赖。诸多心理因素中,自我效能代表了人在一定的情景中解决问题的自信。Bandura的理论表明,具有较高自我效能的个体戒烟成功的机率相对较大。研究也显示,曾经吸烟者的拒烟自我效能(smoking abstinence self-efficacy,SASE)得分比现在吸烟者的SASE得分高。自我效能与尼古丁依赖之间存在着负向相关关联。据此推断SASE可能在成功戒烟中起着积极的作用。现有的戒烟成功影响因素的探讨大多数都是基于"单因素(基因)或多因素(基因)效应独立"的统计假设,数据分析采用的是基于变量间效应独立的统计方法。这种研究设计和统计分析适用于单因素或效应独立的多因素情况。就尼古丁依赖、成功戒烟这类多因子疾病而言,通常是由多个因素(基因)组成了一个复杂的交互网络系统。基于效应独立的统计方法,缺乏针对由多个因素(基因)所构成的交互网络的系统推断,因而难以从系统层面阐述戒烟成功的机理。现有研究中,多将个体因素、心理因素作为协变量纳入对遗传因素和戒烟关系的研究中。虽然这些研究揭示了遗传因素、个体因素、心理因素都对戒烟成功有影响,但未能揭示这三类因素对戒烟成功贡献的相对大小。根据目前研究的现状和不足,本研究拟进行社区为基础的病例对照研究,以成功戒烟者为病例组、以不成功戒烟者为对照组,采用综合基因变异整体信息的基因分数从基因层面去研究CHRN变异与戒烟成功之间的关系,并辨析遗传因素、个体因素、心理因素在戒烟成功中的作用。研究目的1.用综合了基因变异整体信息的基因分数研究遗传因素与戒烟成功的关系;2.探索遗传因素、个体因素、心理因素在戒烟成功中的相互作用;3.比较遗传因素、个体因素、心理因素对戒烟成功贡献的相对大小。研究方法1.采用社区为基础的病例对照研究,病例组由成功戒烟者组成、对照组由不成功戒烟者组成。调查对象来自于山东省3个县的17个村庄。采用调查问卷调查吸烟者的个体因素、心理因素资料。从调查对象的血液样品中提取DNA,并进行基因分型,获取吸烟者的遗传因素资料。2.采用T检验、秩和检验、卡方检验比较个体因素、心理因素在成功戒烟人群和不成功戒烟人群之间的分布差别。用单因素Logistic回归分析、多因素Logistic回归分析探索单个SNP位点、基因分数与戒烟成功的关系。用卡方检验探索单体型与戒烟成功的关系。3.用贝叶斯网络模型构建遗传因素、个体因素、心理因素对戒烟成功产生作用的交互网络,分析遗传因素、个体因素、心理因素对戒烟成功产生作用过程中的相互作用。4.采用Logistic回归预测为基础的优势分析比较遗传因素、个体因素、心理因素对戒烟成功的相对作用大小。研究结果1.年龄、戒烟时年龄、吸烟年数在成功戒烟人群和不成功戒烟人群之间的分布存在统计学差别(P0.05):成功戒烟人群的平均年龄高于不成功戒烟人群的平均年龄,成功戒烟人群戒烟时的平均年龄低于不成功戒烟人群戒烟时的平均年龄,成功戒烟人群的平均吸烟年数少于不成功戒烟人群平均吸烟年数。吸烟开始年龄、每天吸烟量、工作、教育水平、戒烟原因在成功戒烟人群与不成功戒烟人群之间的分布无差别(P0.05)。积极情境的拒烟自我效能(smoking abstinence self-efficacy in positive/social situation,SASEP)、消极情境的拒烟自我效能(smoking abstinence self-efficacy innegative/affective situation,SASEN)、习惯情境的拒烟自我效能(smoking abstinence self-efficacy in habit/addictive situation,SASEH)、拒烟自我效能总得分(smoking abstinence self-efficacy total score,SASET)都呈现出成功戒烟人群的平均分数高于不成功戒烟人群平均分数的趋势;SASEN、SASET在成功戒烟人群与不成功戒烟人群之间的分布存在统计学差别(P0.05)。多因素 Logistic 回归分析显示,位点 rs578776(CHRNA3)、rs660652(CHRNA3)、rs588765(CHRNA5)与戒烟成功存在显著性关系(P0.05)。位点rs578776的C等位基因(OR值为0.77)、位点rs660652的A等位基因(OR值为0.70)、位点rs588765的T等位基因(OR值为0.73)是戒烟成功的危险因素。单体型分析结果显示,CHRNA3、CHRNB4分别有一个单体型与戒烟成功相关(P0.05)。CHRNA3中的单体型ACC在成功戒烟人群中出现的频率低于它在不成功戒烟人群中出现的频率;而CHRNB4中的单体型GGG在成功戒烟人群中出现的频率高于它在不成功戒烟人群中出现的频率。多因素Logistic回归分析显示基因分数CHRNA3与戒烟成功存在显著性关系(P0.05)。基因分数CHRNA3为戒烟成功的危险因素(OR值为0.48)。2.本研究构建的贝叶斯网络的受试者工作特征曲线下面积为0.91,能够较好的预测结局变量。遗传因素、个体因素、心理因素在影响戒烟成功的过程中形成了5条主要的影响通路:①年龄→戒烟原因→戒烟成功,②年龄→戒烟时年龄→吸烟年数→戒烟成功,③吸烟开始年龄→吸烟年数→戒烟成功,④每天吸烟量→SASET→戒烟成功⑤CHRNA3→ CHRNA5→ CHRNB4→戒烟成功。年龄可以通过戒烟原因、戒烟时年龄、吸烟年数等变量间接影响戒烟成功。吸烟年数是影响戒烟成功的一个关键节点。每天吸烟量可以通过影响SASET间接影响戒烟成功。CHRNA3对CHRNA5、CHRNB4在戒烟成功这一结局变量上有影响。3.优势分析显示,个体因素是戒烟成功的首要影响因素(标准化权重52.22%,重要性排序为1),其后依次为遗传因素(标准化权重28.85%,重要性排序为2)、心理因素(标准化权重18.93%,重要性排序为3)。主要结论1.个体因素是戒烟成功的影响因素,年龄、戒烟时年龄、吸烟年数在成功戒烟人群和不成功戒烟人群中的分布不同。心理因素是戒烟成功的影响因素,SASE水平越高的个体成功戒烟的机率就越大。遗传因素是戒烟成功的影响因素,CHRNA3是戒烟成功的危险因素,CHRNA3基因分数越高越难戒烟。2.个体因素之间、个体因素与心理因素之间、遗传因素之间在对戒烟成功的影响过程中存在依赖关系。在戒烟干预中,通过干预关键节点,来提高预定目标人群的戒烟率。3.个体因素是戒烟成功的首要影响因素,个体因素对戒烟成功的作用要大于遗传因素的作用。戒烟干预中,应加强对个体因素的关注,纠正吸烟者将戒烟不成功归结为遗传因素的错误观念。创新点1.本研究借助基因分数用整体基因信息反映基因效应,从基因层面上揭示了CHRNA3是戒烟成功的影响因素,避免了单个SNP研究的某些不足,提高了检验效能。2.以影响戒烟成功的乙酰胆碱受体基因为基础,借助贝叶斯网络模型,从系统层面上探索遗传因素、个体因素、心理因素对戒烟成功的影响以及各种因素之间的相互关系。3.通过优势分析,辨析遗传因素、个体因素、心理因素对戒烟成功作用的相对大小,确定了个体因素是戒烟成功的首要影响因素,为戒烟干预确定优先干预措施提供了理论基础。
[Abstract]:Background although smoking is a preventable and controllable behavior, all the countries in the world have also done a lot of work to control the epidemic of tobacco, but the tobacco is popular in the global trend is not optimistic.2011 worldwide over 15 years of age groups, the smoking rate was 36% for men and women for statistical 8%. Global results show that smoking every year caused about 35000 billion yuan of economic losses to human society; every year smoking causes the number of deaths caused by the disease is about 6 million. In China, people over 15 years in 2011 the smoking rate of the male was 47%, female was 2%. in China, there are 300 million individuals are smoking status, smoking in the individual second-hand smoke in 740 million. However, in 2 years China success rate was only 11.70%. chemical compounds in tobacco smoke more than 4000 kinds, many kinds of chemicals are toxic, of which there are 69 kinds of Chemicals are identified carcinogens. Almost all smoking harm to human organs, leading to a series of cancer incidence is increased, bronchial asthma, stroke, atherosclerosis and other causes of non infectious chronic disease. Smoking has become the main pathogenic factor of six kinds of diseases in the world's top eight causes of death in quitting smoking is. In the literature can be seen by reducing proven, the only way to prevent tobacco damage. Therefore, to explore the influence factors of successful smoking cessation, to develop targeted smoking cessation interventions and provide theoretical support for the public health workers need to solve a problem. The main reason is the continued smoking smokers had nicotine dependence and nicotine dependence. Is caused by nicotine in tobacco smoke. The nicotine in tobacco smoke is inhaled through the respiratory system, circulatory system reaches the brain, first with nicotinic acetylcholine Receptor (nicotinic acetylcholine receptors, nAChRs) combined, then stimulate the synthesis of dopamine mesolimbic dopamine neurons, resulting in nucleus accumbens dopamine release increased, make people have a "sense of pleasure", complete the material reward process. This is the biological mechanism of nicotine dependence. The first step is to play the role of nicotine and nicotine combined with nAChRs the nicotinic acetylcholine receptor gene (nicotinic acetylcholine receptor gene, CHRN) plays a regulatory role of nicotinic acetylcholine receptors. Gene knockout model study showed that addition changed some reaction of CHRN mice to nicotine. Smoking cessation and nicotine dependence is the opposite: quit smoking, quit smoking is the key step to to overcome nicotine dependence. So we speculate that CHRN may have effect on nicotine dependence, smoking cessation success. Study group showed that CHR The polymorphism of N (singlenucleotide polymorphisms SNP) mutation can reduce the likelihood of successful smoking cessation, the placebo group smoking rate decreased, the active smoking individual differences occur frequently. Although the existing research reveals some relationship between CHRN and smoking cessation success, but these studies still exist shortcomings: first, using a single SNP to the relationship between gene variation and smoking cessation research success all influence is unable to detect the gene mutation on smoking cessation success possible; second, the current literature, there are inconsistent results or results to the contrary. Third, the lack of existing research to study CHRN and quit smoking from the relationship between the gene level with whole genome information case. The results show that individual factors (such as age, occupation, education, smoking, smoking age, years of smoking, smoking and smoking related work motivation). Nicotine dependence Not only means that the physical dependence also means psychological dependence. Many psychological factors, self-efficacy that represents people solve problems in certain Situational Confidence in.Bandura's theory, has a higher probability of successful smoking cessation self-efficacy individuals is relatively large. The research also showed that former smokers to smoke self-efficacy (smoking abstinence self-efficacy. SASE) scores than current smokers. The higher the SASE score between self-efficacy and nicotine dependence are negative related. Inferred that SASE may play a positive role in smoking cessation. Existing smoking cessation success factors influencing the majority are based on single factor (gene) or multi factor (gene) statistical hypothesis the effect of independent ", data were analyzed by statistical methods are based on independent variables effect. This research design and statistical analysis for single factor or effect Many independent factors. This kind of smoking cessation nicotine dependence, multi factor disease, which is usually caused by multiple factors (genes) formed a complex interaction network system. Statistical method based on independent effect, lack of response by a number of factors (genes) that constitute the system interactive network, thus it is difficult to explain the mechanism from the system level of successful smoking cessation. In the current study, the individual factors, psychological factors as a covariate in the research on genetic factors and smoking cessation relationships. Although these studies have revealed the genetic factors, individual factors, psychological factors have influence on quitting smoking, but failed to reveal the relative sizes of the three kinds of contribution the factors of successful smoking cessation. According to the present situation of the research and the lack of control of quasi community based on the case, to successfully quit smoking as the case group, to successfully quit smoking as control The comprehensive score group, gene mutation of the whole information to study the relationship between CHRN mutation and smoking cessation success from the gene level, and analysis of the genetic factors, individual factors, the role of psychological factors in smoking cessation success. Objective: 1. comprehensive relationship between gene fraction genetic factor gene mutation and overall information of successful smoking cessation; 2. to explore the genetic factors, individual factors, interaction of psychological factors in smoking cessation success; 3. compared with genetic factors, individual factors, the relative contribution of psychological factors on smoking cessation success. Methods 1. community-based case-control study cases by smokers, the control group is composed of former smokers. Survey from 3 counties in Shandong Province in 17 villages. Individual factors by questionnaire survey of smokers, psychological factors. The blood samples from the data surveyed in the DNA extraction and genotyping data, genetic factors.2. for smokers with T test, rank sum test, chi square test to compare individual factors, psychological factors in distribution between people and successfully quit smoking successfully quit smoking population difference. Using single factor Logistic regression analysis, Logistic regression analysis to explore the individual SNP sites. The relationship between gene fraction and successful smoking cessation. To explore the relationship between haplotype and.3. quit successfully used Bayesian network model to construct the genetic factors, individual factors by chi square test, interactive network psychological factors have an effect on smoking cessation, analysis of genetic factors, individual factors, psychological factors on quitting smoking interaction effect in the process of using.4. Logistic regression prediction based comparative advantage analysis of genetic factors, individual factors, psychological factors on the relative contributions of successful smoking cessation. Results 1. age, When you stop smoking age, there was statistical difference in distribution between the years of smoking and quit smoking cessation among populations (P0.05): the average age of the population is higher than the average age of smoking cessation did not quit the crowd, mean age of smoking cessation quit when populations are less successful quitting smoking cessation of smoking, average smoking cessation in the number of years not less than the average number of years of smoking people quit smoking. Age, level of daily smoking, work, education, distribution in the crowd and the reasons for quitting smoking cessation among people not quit no difference (P0.05). The positive situation of anti smoking self-efficacy (smoking abstinence self-efficacy in positive/social situation, SASEP), negative situation of anti smoking self-efficacy (smoking abstinence self-efficacy innegative/affective situation, SASEN), the anti smoking habits situation since I (smoking abstinence self-efficacy in habit/addictive performance situation, SASEH), anti smoking self-efficacy score (smoking abstinence self-efficacy total score, SASET) are showing the average score was higher than that of people successfully quit smoking successfully quit smoking population average trend; SASEN, there was statistical difference between the distribution of SASET in the crowd and not quit smoking cessation success the crowd (P0.05). Logistic regression analysis showed that rs578776 locus (CHRNA3), rs660652 (CHRNA3), rs588765 (CHRNA5) and quit smoking significantly (P0.05). The relationship between the loci of rs578776 C allele (OR = 0.77), the site of rs660652 A allele (OR 0.70), the site of rs588765 T allele (OR = 0.73) were risk factors of successful smoking cessation. Haplotype analysis showed that CHRNA3 and CHRNB4 have a haplotype and smoking cessation success (P0.05) The.CHRNA3 haplotype of ACC in the quit crowd appear less frequently than it appears in the quit in the crowd and haplotype frequency; GGG in CHRNB4 successfully quit smoking crowd appear frequency is higher than it is in the crowd not successfully quit smoking frequency. Logistic regression analysis showed that there was a significant relationship between the success of the gene score CHRNA3 and smoking cessation (P0.05). The gene fraction CHRNA3 as a risk factor of successful smoking cessation (OR = 0.48) Bayesian network.2. constructed in the study of the subject area under the curve is 0.91, can better predict the outcome variable. Genetic factors, individual factors, psychological factors formed 5 main the effects of impact pathway in the process of successful smoking cessation: age, smoking causes to quit smoking and age, smoking age, years of smoking, quit smoking, smoking, smoking and age years The number to quit smoking and the daily smoking amount to SASET and CHRNA3 to CHRNA5 and quit smoking, smoking cessation success. CHRNB4 age can quit smoking, age, years of smoking and other variables indirectly to quit smoking. Smoking is a key point of successful smoking cessation. Smoking can affect every day.CHRNA3 CHRNA5 to successfully quit smoking by affecting SASET, CHRNB4 in the smoking cessation success outcome variables on Impact Analysis of.3. advantage display, individual factors are primary factors of successful smoking cessation (standard weight of 52.22%, ranking 1), followed by genetic factors (standard weight of 28.85%, ranking 2), psychological factors (standard weight of 18.93%, the importance of the order of 3). The main conclusions 1. individual factors, effects of smoking cessation success age, smoking age, years of smoking in the crowd and not quit successfully The distribution of smoking in the crowd. Different psychological factors are the factors affecting the probability of successful smoking cessation, the higher the SASE level of the individual to successfully quit smoking more. Genetic factors are smoking cessation success, CHRNA3 is a risk factor for smoking cessation success, CHRNA3 gene, higher scores are difficult to quit.2. individual factors, individual factors and psychological factors, genetic factors in process of successful smoking cessation in dependence. In the smoking cessation intervention, through the intervention of the key nodes, to improve the target population.3. quit rate of individual factors is the first smoking cessation success factors, individual factors of successful smoking cessation effect is greater than the role of genetic factors in smoking cessation intervention. That should strengthen the individual factors of concern, correct smokers will quit smoking is not successful due to genetic factors misconceptions. This study uses 1. innovation points in the whole body based gene Because the gene effect information reflected from the gene level revealed that CHRNA3 is the influence factors of successful smoking cessation, to avoid some shortcomings of single SNP research, improve the effectiveness of.2. based on acetylcholine receptor gene effects of smoking cessation success, using Bayesian network model to explore the genetic factors, from the system level between the individual factors, psychological impact the factors of successful smoking cessation and various factors of the relationship between.3. through the analysis of the advantages of genetic factors, individual factors, the relative size of psychological factors on quitting smoking effect, determine the individual factor is the primary influence factor of successful smoking cessation, quit smoking

【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R163

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