多巴胺奖赏通路系统基因变异及其他因素与戒烟成功关系的研究

发布时间：2018-01-22 22:08

  本文关键词： 戒烟成功 多巴胺奖赏系统通路基因变异 尼古丁成瘾 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】：研究背景烟草使用一直是全球可预防死亡的首要原因,也是心脑血管系统疾病、恶性肿瘤等疾病的主要危险因素。吸烟对健康的危害不仅在于其对人民健康的直接危害,更在于其成瘾性与依赖性。吸烟成瘾的实质是烟草依赖,而烟草依赖是一种慢性病,戒烟可有效减轻吸烟带来的危害。近年来,我国已采取了许多烟草控制措施,但是当前我国的戒烟现状仍不乐观。研究显示,我国总吸烟人群中的戒烟成功率非常低(16.9%),其中只有11.7%的人戒烟两年或更长时间。在中国,农村人口占大多数。与城市居民相比,我国农村男性吸烟严重程度较高,戒烟成功率较低。因此在我国农村地区研究戒烟成功的影响因素,以探讨提高吸烟者的戒烟成功率的方法,意义重大。研究显示,戒烟行为具有心理和生理两方面的特征,受到个人因素、环境因素以及遗传因素等各方面的共同影响。以前的研究表明,影响戒烟成功的个人因素和环境因素有许多,如年龄,受教育程度,婚姻状况,吸烟量等。其中,尼古丁依赖程度是最主要的影响戒烟成功与否的因素之一。吸烟者的尼古丁依赖程度越高,则越不容易戒烟成功。另外,大量的研究表明吸烟者的拒烟自我效能越高,其戒烟成功的可能性越大,反之亦然。除上述环境因素外,戒烟成功与否也可能受到遗传因素的影响。参与尼古丁成瘾与依赖的基因主要包括两个方面,一是药代学方面的基因,即尼古丁代谢有关基因;二是药效学方面的基因,主要包括中脑边缘多巴胺奖赏通路系统基因和血清素(5-羟色胺)系统基因。中脑边缘多巴胺系统是物质成瘾的神经生物学基础,尼古丁进入人体后与尼古丁乙酰胆碱受体结合通过奖赏效应起作用。多巴胺奖赏通路有关基因,如多巴胺受体D2(DRD2)基因,多巴胺转运载体基因(SLC6A3),多巴胺代谢酶有关基因如儿茶酚胺氧位甲基转移酶(COMT)等,是目前戒烟行为遗传学相关研究中关注最多的基因。但是当前关于戒烟成功影响因素的研究存在如下不足:1、很少有研究探讨拒烟自我效能在尼古丁依赖程度对戒烟成功影响中的中介效应..目前的研究已表明,尼古丁依赖程度与戒烟成功有显著关联,但其关联的机制尚未清楚。而拒烟自我效能越高,其戒烟成功的可能性越大。此外,有研究表明,拒烟自我效能感与尼古丁依赖程度呈负相关关联。然而,拒烟自我效能是否在尼古丁依赖程度对戒烟行为的作用中起到中介作用,目前鲜有研究。2、缺乏对多巴胺奖赏通路系统整体基因变异与戒烟成功关系的探讨:国内关于多巴胺奖赏通路系统单个基因变异与戒烟成功关系的遗传学研究很少,而国外对于此方面的研究很多,但是研究结果并不一致,一个研究的结果很难得到重复。以往关于戒烟成功的遗传学研究大都只针对单一基因的某个或某几个位点,缺乏从通路系统层面研究基因变异与戒烟成功的关系;遗传变异对戒烟成功作用的影响有限,缺乏对遗传-环境交互作用的研究。3、缺乏从网络系统层面探讨各影响因素与戒烟成功关系的研究:戒烟成功与否受到个人因素、环境因素以及遗传因素等各方面的共同影响,但是目前的多数研究,仅仅研究某一个或某几个独立因素,缺乏从网络系统层面研究各个人因素、环境因素以及遗传因素与戒烟成功关系的研究。另外,对于各因素对戒烟成功的影响作用大小也鲜有研究。针对上述研究现状及存在的问题,本课题采用病例对照研究设计,以戒烟成功者为病例组,戒烟失败者为对照组。运用中介效应分析方法,探讨尼古丁依赖程度与戒烟成功的关联,及拒烟自我效能在尼古丁依赖程度与戒烟成功的关联中的中介作用大小。利用加权基因分数反映多巴胺奖赏通路系统基因的整体基因信息,探讨多巴胺奖赏通路系统基因变异对戒烟成功发生的影响,并评价多巴胺奖赏通路系统基因与尼古丁依赖程度的交互效应对戒烟成功的影响。依托网络生物学的理论与技术,使用贝叶斯网络模型研究多巴胺奖赏通路系统基因、以及个体与环境因素对戒烟成功的影响;并利用优势分析方法探讨影响戒烟成功的个体因素、吸烟严重程度因素、心理因素以及遗传因素的相对重要性。研究目的1、探讨尼古丁依赖程度与戒烟成功的关系,并研究拒烟自我效能在尼古丁依赖程度对戒烟成功影响中的中介效应。2、探讨多巴胺奖赏通路系统整体基因变异与戒烟成功关系,及多巴胺奖赏通路系统基因变异与尼古丁依赖程度的交互作用对戒烟成功的影响。3、探讨个人因素、环境因素以及遗传因素对戒烟成功的影响及其影响的相对重要性。研究方法1、采用病例对照研究设计,采用基于logistic回归模型的KHB方法进行中介效应分析,运用倾向评分方法进行混杂因素的调整,探讨尼古丁依赖程度与戒烟成功的关联,及拒烟自我效能在尼古丁依赖程度与戒烟成功的关联中的中介作用大小。2、根据每个等位基因对戒烟成功的遗传效应大小来计算相应权重,通过计算加权等位基因的总数来反应计算每个基因的加权基因分数(weighted gene score)。利用加权基因分数反映多巴胺奖赏通路系统基因的整体基因信息,探讨多巴胺奖赏通路系统基因变异对戒烟成功发生的影响,并利用基于logistic回归的相乘模型交互作用分析来评价多巴胺奖赏通路系统基因与尼古丁依赖程度的交互效应对戒烟成功的影响。3、依托网络生物学的理论与技术,以研究对象的多巴胺奖赏通路系统基因变异、环境和个体因素为节点,以其对戒烟成功发生可能的影响为输出,采用基于搜索评分的爬山算法进行结构学习,运用贝叶斯估计法进行参数学习,构建由多巴胺奖赏通路系统基因、以及个体与环境因素所组成的贝叶斯网络模型;并利用贝叶斯信息准则-BIC准则选择网络,运用ROC曲线下面积AUC进行网络评价。采用因果推理方法对特定情境下吸烟者戒烟成功的概率进行估计。4、采用四个不同的logistic回归模型来产生4个不同的影响因素得分(个体因素得分、吸烟严重程度得分、心理因素得分以及基因分数),并利用的优势分析方法探讨戒烟成功影响因素的相对重要性。研究结果1、一般情况:本研究纳入研究对象1342名,其中戒烟成功者642名,戒烟失败者700名。对于用到基因信息的分析,在以上研究对象的基础上,排除了无血样或血样无法进行基因分型者,纳入415例基因分型成功的自发性戒烟成功者为病例组,404例基因分型成功的自发性戒烟失败者为对照组。与戒烟失败者相比,戒烟成功者的平均年龄更大。两组之间婚姻状态的分布差异有统计学意义,而职业的分布差异无统计学意义。2、中介效应分析:结果显示,调整年龄、开始吸烟年龄、职业、教育程度和婚姻状态等混杂因素后,拒烟自我效能总分在尼古丁依赖程度与戒烟成功的关系中的中介作用比例为32.90%。对于拒烟自我效能的三种情境得分(积极/社会情境,消极/情感情境和习惯/成瘾情境),其在尼古丁依赖程度与戒烟成功关系的作用中所起的中介效应大小分别12.14%,35.64%和83.03%。3、多巴胺奖赏通路系统基因分数与戒烟成功的关系..结果显示,在调整了年龄、职业、文化程度、婚姻状况、焦虑自评量表评分和疾病状态等混杂因素后多巴胺奖赏通路系统中,COMT和DRD2基因与戒烟成功存在显著负相关关系,而ANKK1、SLC6A3、DRD4与戒烟成功存在显著正相关关系。4、交互作用分析:多巴胺奖赏通路基因分数与尼古丁依赖程度的交互作用分析结果显示,在调整了上述混杂因素后,SLC6A3基因与尼古丁依赖程度有显著的相乘模型交互作用(p=0.03)。5、贝叶斯网络分析:通过贝叶斯网络分析构建了一个包含10个节点(包括年龄、开始吸烟年龄、吸烟危害认知、每天吸烟量、吸烟年数、戒烟原因、戒烟年龄、拒烟自我效能、多巴胺奖赏通路系统基因分数和戒烟成功)的贝叶斯网络,其中包括影响戒烟成功的4个直接父节点,有6条不同的通路可影响戒烟成功。该模型的BIC值为-10013.26,采用五折交叉验证方法得出其ROC曲线,曲线下面积为0.78。贝叶斯网络推理结果显示,在每天吸烟量高、吸烟年数长、吸烟危害认知程度低、拒烟自我效能水平低的吸烟者中,只有37.9%成功戒烟。6、优势分析:戒烟成功影响因素的相对重要性(标准化优势权重)由大到小依次为吸烟严重程度因素(42%),其次是个体因素(40%)、遗传因素(10%)和心理因素(8%)。主要结论1、尼古丁依赖程度低的吸烟者更容易戒烟成功,拒烟自我效能在尼古丁依赖程度与戒烟成功的关联中起到部分中介作用。2、多巴胺奖赏通路系统整体基因变异与戒烟成功有显著关联,表明遗传因素可能对戒烟成功存在影响。并且多巴胺奖赏通路系统遗传变异与尼古丁依赖程度在对戒烟成功的影响中有显著的相乘模型交互作用,尼古丁依赖程度低且SLC6A3基因分数高的人更容易戒烟成功。3、遗传、个体、心理因素等共同影响戒烟成功与否。在实际控烟工作中,应根据不同吸烟者的情况,制定个性化的解决方案来帮助吸烟者戒烟。4、影响戒烟成功的首要因素是吸烟严重程度因素。虽然多巴胺奖赏通路基因变异与成功戒烟有关,但是吸烟的严重程度和个人因素比遗传因素对戒烟有更大的影响。帮助吸烟者降低吸烟严重程度,提高吸烟者的拒烟自我效能和吸烟危害认知,矫正吸烟者错误的遗传归因认知,可有利于促进吸烟者戒烟成功。研究意义上述研究结果不但为研究戒烟成功的影响因素提供了理论依据,为将来进行相关研究提供参考基础,而且为我国今后的控烟工作提供决策支持,具有重要的学术价值与应用价值。创新点1、以前的遗传学研究仅仅关注于单一基因的某个或某几个位点。本研究采用加权基因分数方法,探讨多巴胺奖赏通路系统整体基因变异与戒烟成功的关系,并研究遗传-环境交互作用。2、目前的多数研究,仅仅从单纯研究某一个或某几个独立因素。本研究采用贝叶斯网络方法,从网络系统层面研究个人因素、环境因素以及遗传因素等因素对戒烟成功的影响情况。3、以往很少有研究探讨戒烟成功各影响因素的相对重要性。本文采用优势分析方法,探讨个人因素、环境因素以及遗传因素等对戒烟成功影响的重要性。
[Abstract]:The research background of tobacco use is the leading cause of preventable death in the world, is also the main risk of cardiovascular and cerebrovascular diseases, malignant tumor and other diseases. The health hazards of smoking is not only the direct harm to people's health, but also in its addiction and dependence. Smoking addiction is the essence of tobacco dependence, and tobacco dependence is a kind of chronic disease, smoking can effectively reduce the hazards of smoking. In recent years, our country has taken many tobacco control measures, but the current smoking status in our country is still not optimistic. Research shows that China's total population in the smoking cessation success rate is very low (16.9%), only 11.7% of them quit smoking two years or longer. In China, the majority of the rural population. Compared with city residents, rural male smoking cessation severity is high, the success rate is low. So the study of smoking cessation in the rural area of our country into The impact of factors, methods, in order to increase the smoking cessation success rate is significant. Research shows that smoking behavior has the characteristics of the two aspects of physiology and psychology, by personal factors, influence of various environmental factors and genetic factors. On the table before Ming Dynasty, there are many individual factors and environmental factors smoking cessation success such as age, education level, marital status, smoking and so on. Among them, nicotine dependence is one of the most important factors influencing the success of quitting smoking. Nicotine dependence degree is high, it is not easy to quit smoking. In addition, a large number of studies show that smokers to smoke high self-efficacy and the possibility of successful smoking cessation is greater, and vice versa. In addition to the environmental factors, smoking cessation success may be influenced by genetic factors. Involved in nicotine addiction and dependence of gene. Includes two aspects, one is the pharmacokinetics of nicotine metabolism related gene, that gene; two is the pharmacodynamic of genes, including the mesolimbic dopamine reward pathway gene and serotonin (5- HT) gene. The mesolimbic dopamine system is the material into the neurobiological basis of addiction, through the role of rewarding effect nicotine into the human body and nicotinic acetylcholine receptors. Dopamine reward pathway genes, such as dopamine D2 receptor (DRD2) gene and the dopamine transporter gene (SLC6A3), dopamine metabolism enzyme related genes such as catechol-O-methyltransferase (COMT), is the current research focus of smoking cessation in genetics but gene. The study on the influencing factors of smoking cessation success exists the following problems: 1, there are few researches on the anti smoking self-efficacy in nicotine dependence on smoking cessation The present study. The mediating effect in the effects of success have shown that nicotine dependence and smoking cessation success has significant correlation, but the mechanism is not yet clear. But Association anti smoking self-efficacy is higher, the possibility of successful smoking cessation is greater. In addition, studies have shown that anti smoking self-efficacy level was negatively related with nicotine dependence. However, anti smoking self-efficacy plays an intermediary role or not depends on the extent of smoking cessation in nicotine, there are few studies on.2, the lack of overall gene mutation and dopamine reward pathway system quit relationship: a few dopamine reward pathway system of single gene mutation and genetic study of domestic successful quitting relationship however, for many foreign research in this area, but the results are not consistent, the results of a study is difficult to be repeated. Previous reports of successful smoking cessation genetics Study is only for a single gene or a few sites, the lack of success from the gene mutation and smoking cessation research system level pathway; genetic variation has limited effect on smoking cessation success effect, the lack of research on.3 gene environmental interactions, the lack of study on the factors and the influence relationship between smoking cessation success from the network level system quit smoking: success by personal factors, the common effects of various environmental factors and genetic factors, but most of the current study, only study one or several independent factors, lack of personal factors from each system level network system, research on environmental factors and genetic factors and smoking cessation success relationship. In addition, research the influence of various factors on smoking cessation for success. There are few studies aiming at the current situation and existing problems, a case-control study design of this subject, to quit The smoke of success as the case group, smoking cessation failure as the control group. Using the analytical method to explore the mediating effect of nicotine dependence, associated with cessation success, the size of intermediary role Association and anti smoking self-efficacy in quitting smoking and nicotine dependence in successful. By using the weighted gene scores reflect the overall genetic information system of dopamine reward pathway genes. To investigate the effect of gene mutation on the dopamine reward pathway system quitting success occurred, and to evaluate the effect of nicotine gene and dopamine reward pathway system depends on the interaction effect of successful smoking cessation. Relying on the theory and technology of network biology, using Bayesian network model of dopamine reward pathway genes, and the influence of individual and environmental factors on smoking cessation success; and take advantage of analysis to explore the impact of individual factors of successful smoking cessation, smoking severity factor, The relative importance of psychological factors and genetic factors. The purpose of the study is to explore the relationship between the 1, the degree of nicotine dependence and smoking cessation success, and to study the anti smoking self-efficacy in nicotine dependence degree on the mediating effect of smoking cessation in the effects of.2 on the whole gene of dopamine reward pathway system variability and smoking cessation success,.3 gene mutation and effects of nicotine and dopamine the reward pathway system depends on the interaction degree of successful smoking cessation, to explore the relative importance of individual factors, environmental factors and genetic factors on smoking cessation success and impact. 1 research methods, a case-control study, the mediating effect analysis KHB method based on logistic regression model, using propensity score methods for confounding factors the adjustment of relationship between nicotine dependence and abstinence, and anti smoking self-efficacy in Nicholas Ding Yi The size of.2 mediated association degree and Lai of successful smoking cessation in, to calculate the corresponding weights according to the genetic effect of the size of each allele to quit smoking, the total weighted allele by reaction weighted score calculation of each gene gene (weighted gene score). By using the weighted gene scores reflect the overall genetic information of dopamine reward to investigate the effect of gene transduction, gene mutation of dopamine reward pathway system on smoking cessation success occurs, and the use of.3 analysis of the effect of interactions of multiplicative model based on logistic regression to evaluate the nicotine gene and the dopamine reward pathway system depends on the interaction degree of successful smoking cessation, relying on the theory and technology of network biology, the dopamine reward pathway system genetic variation of research object, environment and individual factors for the node, its possible to quit smoking For output, the search score climbing algorithm based on structure learning, using Bayesian estimation of parameter learning, constructed by dopamine reward pathway gene system, Bayesian network model composition and individual and environmental factors; and the selection of the network using the Bayesian information criterion -BIC criterion, using the area under the ROC curve of AUC network by evaluation. Causal reasoning method is used to estimate the probability of successful smoking cessation.4 specific context, using four different logistic regression model to generate 4 different influencing factors (score, individual factors of smoking severity score, psychological factor score and gene fraction) advantage analysis method, and to investigate the relative importance of smoking cessation effect the results of the 1 factors. In general, this study included 1342 subjects, including 642 patients to quit smoking, quit smoking loss Loser 700. Genetic information used for the analysis, based on the above research object, no blood or blood cannot exclude the genotype, genotype included 415 cases of successful spontaneous successful smoking cessation as the case group, 404 cases of spontaneous gene Xingjie smoke successful losers as control group. The average age of smoking and smoking cessation failure, success is greater. There were statistically significant differences in the distribution of marital status between the two groups, but the difference was not statistically significant.2 occupation distribution, mediating effect analysis: the results showed that, adjusted for age, smoking age, occupation, marital status and education degree of confounding factors such as, to the intermediary role the relationship between self efficacy score in the proportion of tobacco nicotine dependence and smoking cessation success in 32.90%. for resisting the three situations of self-efficacy score smoke (positive / negative / social situation, emotion situation and learning Inertial / situation), addiction mediating effect size dependence and the relationship between smoking cessation success in the role of nicotine in respectively 12.14%, 35.64% and 83.03%.3, dopamine reward pathway system. Relationship between gene fraction and successful smoking cessation results showed that after adjusting for age, occupation, education level, marital status, self rating Anxiety Scale confounding factors score and disease status after the dopamine reward pathway system, success has significant negative correlation, COMT and DRD2 genes and quit ANKK1, SLC6A3, DRD4 and quit there was a positive correlation between the.4 and the interaction analysis: dopamine reward pathway gene fraction and interaction degree of nicotine dependence analysis results show that in the adjustment for confounding factors, SLC6A3 gene and nicotine dependence have multiplicative significant interaction degree (p=0.03) of.5, a Bayesian network analysis by Bayesian network 鍒嗘瀽鏋勫缓浜嗕竴涓�鍖呭悾�

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