本文關(guān)鍵詞： 戒煙成功 多巴胺獎賞系統(tǒng)通路基因變異 尼古丁成癮 貝葉斯網(wǎng)絡 優(yōu)勢分析　出處：《山東大學》2017年博士論文　論文類型：學位論文

【摘要】：研究背景煙草使用一直是全球可預防死亡的首要原因,也是心腦血管系統(tǒng)疾病、惡性腫瘤等疾病的主要危險因素。吸煙對健康的危害不僅在于其對人民健康的直接危害,更在于其成癮性與依賴性。吸煙成癮的實質(zhì)是煙草依賴,而煙草依賴是一種慢性病,戒煙可有效減輕吸煙帶來的危害。近年來,我國已采取了許多煙草控制措施,但是當前我國的戒煙現(xiàn)狀仍不樂觀。研究顯示,我國總吸煙人群中的戒煙成功率非常低(16.9%),其中只有11.7%的人戒煙兩年或更長時間。在中國,農(nóng)村人口占大多數(shù)。與城市居民相比,我國農(nóng)村男性吸煙嚴重程度較高,戒煙成功率較低。因此在我國農(nóng)村地區(qū)研究戒煙成功的影響因素,以探討提高吸煙者的戒煙成功率的方法,意義重大。研究顯示,戒煙行為具有心理和生理兩方面的特征,受到個人因素、環(huán)境因素以及遺傳因素等各方面的共同影響。以前的研究表明,影響戒煙成功的個人因素和環(huán)境因素有許多,如年齡,受教育程度,婚姻狀況,吸煙量等。其中,尼古丁依賴程度是最主要的影響戒煙成功與否的因素之一。吸煙者的尼古丁依賴程度越高,則越不容易戒煙成功。另外,大量的研究表明吸煙者的拒煙自我效能越高,其戒煙成功的可能性越大,反之亦然。除上述環(huán)境因素外,戒煙成功與否也可能受到遺傳因素的影響。參與尼古丁成癮與依賴的基因主要包括兩個方面,一是藥代學方面的基因,即尼古丁代謝有關(guān)基因;二是藥效學方面的基因,主要包括中腦邊緣多巴胺獎賞通路系統(tǒng)基因和血清素(5-羥色胺)系統(tǒng)基因。中腦邊緣多巴胺系統(tǒng)是物質(zhì)成癮的神經(jīng)生物學基礎(chǔ),尼古丁進入人體后與尼古丁乙酰膽堿受體結(jié)合通過獎賞效應起作用。多巴胺獎賞通路有關(guān)基因,如多巴胺受體D2(DRD2)基因,多巴胺轉(zhuǎn)運載體基因(SLC6A3),多巴胺代謝酶有關(guān)基因如兒茶酚胺氧位甲基轉(zhuǎn)移酶(COMT)等,是目前戒煙行為遺傳學相關(guān)研究中關(guān)注最多的基因。但是當前關(guān)于戒煙成功影響因素的研究存在如下不足:1、很少有研究探討拒煙自我效能在尼古丁依賴程度對戒煙成功影響中的中介效應..目前的研究已表明,尼古丁依賴程度與戒煙成功有顯著關(guān)聯(lián),但其關(guān)聯(lián)的機制尚未清楚。而拒煙自我效能越高,其戒煙成功的可能性越大。此外,有研究表明,拒煙自我效能感與尼古丁依賴程度呈負相關(guān)關(guān)聯(lián)。然而,拒煙自我效能是否在尼古丁依賴程度對戒煙行為的作用中起到中介作用,目前鮮有研究。2、缺乏對多巴胺獎賞通路系統(tǒng)整體基因變異與戒煙成功關(guān)系的探討:國內(nèi)關(guān)于多巴胺獎賞通路系統(tǒng)單個基因變異與戒煙成功關(guān)系的遺傳學研究很少,而國外對于此方面的研究很多,但是研究結(jié)果并不一致,一個研究的結(jié)果很難得到重復。以往關(guān)于戒煙成功的遺傳學研究大都只針對單一基因的某個或某幾個位點,缺乏從通路系統(tǒng)層面研究基因變異與戒煙成功的關(guān)系;遺傳變異對戒煙成功作用的影響有限,缺乏對遺傳-環(huán)境交互作用的研究。3、缺乏從網(wǎng)絡系統(tǒng)層面探討各影響因素與戒煙成功關(guān)系的研究:戒煙成功與否受到個人因素、環(huán)境因素以及遺傳因素等各方面的共同影響,但是目前的多數(shù)研究,僅僅研究某一個或某幾個獨立因素,缺乏從網(wǎng)絡系統(tǒng)層面研究各個人因素、環(huán)境因素以及遺傳因素與戒煙成功關(guān)系的研究。另外,對于各因素對戒煙成功的影響作用大小也鮮有研究。針對上述研究現(xiàn)狀及存在的問題,本課題采用病例對照研究設(shè)計,以戒煙成功者為病例組,戒煙失敗者為對照組。運用中介效應分析方法,探討尼古丁依賴程度與戒煙成功的關(guān)聯(lián),及拒煙自我效能在尼古丁依賴程度與戒煙成功的關(guān)聯(lián)中的中介作用大小。利用加權(quán)基因分數(shù)反映多巴胺獎賞通路系統(tǒng)基因的整體基因信息,探討多巴胺獎賞通路系統(tǒng)基因變異對戒煙成功發(fā)生的影響,并評價多巴胺獎賞通路系統(tǒng)基因與尼古丁依賴程度的交互效應對戒煙成功的影響。依托網(wǎng)絡生物學的理論與技術(shù),使用貝葉斯網(wǎng)絡模型研究多巴胺獎賞通路系統(tǒng)基因、以及個體與環(huán)境因素對戒煙成功的影響;并利用優(yōu)勢分析方法探討影響戒煙成功的個體因素、吸煙嚴重程度因素、心理因素以及遺傳因素的相對重要性。研究目的1、探討尼古丁依賴程度與戒煙成功的關(guān)系,并研究拒煙自我效能在尼古丁依賴程度對戒煙成功影響中的中介效應。2、探討多巴胺獎賞通路系統(tǒng)整體基因變異與戒煙成功關(guān)系,及多巴胺獎賞通路系統(tǒng)基因變異與尼古丁依賴程度的交互作用對戒煙成功的影響。3、探討個人因素、環(huán)境因素以及遺傳因素對戒煙成功的影響及其影響的相對重要性。研究方法1、采用病例對照研究設(shè)計,采用基于logistic回歸模型的KHB方法進行中介效應分析,運用傾向評分方法進行混雜因素的調(diào)整,探討尼古丁依賴程度與戒煙成功的關(guān)聯(lián),及拒煙自我效能在尼古丁依賴程度與戒煙成功的關(guān)聯(lián)中的中介作用大小。2、根據(jù)每個等位基因?qū)錈煶晒Φ倪z傳效應大小來計算相應權(quán)重,通過計算加權(quán)等位基因的總數(shù)來反應計算每個基因的加權(quán)基因分數(shù)(weighted gene score)。利用加權(quán)基因分數(shù)反映多巴胺獎賞通路系統(tǒng)基因的整體基因信息,探討多巴胺獎賞通路系統(tǒng)基因變異對戒煙成功發(fā)生的影響,并利用基于logistic回歸的相乘模型交互作用分析來評價多巴胺獎賞通路系統(tǒng)基因與尼古丁依賴程度的交互效應對戒煙成功的影響。3、依托網(wǎng)絡生物學的理論與技術(shù),以研究對象的多巴胺獎賞通路系統(tǒng)基因變異、環(huán)境和個體因素為節(jié)點,以其對戒煙成功發(fā)生可能的影響為輸出,采用基于搜索評分的爬山算法進行結(jié)構(gòu)學習,運用貝葉斯估計法進行參數(shù)學習,構(gòu)建由多巴胺獎賞通路系統(tǒng)基因、以及個體與環(huán)境因素所組成的貝葉斯網(wǎng)絡模型;并利用貝葉斯信息準則-BIC準則選擇網(wǎng)絡,運用ROC曲線下面積AUC進行網(wǎng)絡評價。采用因果推理方法對特定情境下吸煙者戒煙成功的概率進行估計。4、采用四個不同的logistic回歸模型來產(chǎn)生4個不同的影響因素得分(個體因素得分、吸煙嚴重程度得分、心理因素得分以及基因分數(shù)),并利用的優(yōu)勢分析方法探討戒煙成功影響因素的相對重要性。研究結(jié)果1、一般情況:本研究納入研究對象1342名,其中戒煙成功者642名,戒煙失敗者700名。對于用到基因信息的分析,在以上研究對象的基礎(chǔ)上,排除了無血樣或血樣無法進行基因分型者,納入415例基因分型成功的自發(fā)性戒煙成功者為病例組,404例基因分型成功的自發(fā)性戒煙失敗者為對照組。與戒煙失敗者相比,戒煙成功者的平均年齡更大。兩組之間婚姻狀態(tài)的分布差異有統(tǒng)計學意義,而職業(yè)的分布差異無統(tǒng)計學意義。2、中介效應分析:結(jié)果顯示,調(diào)整年齡、開始吸煙年齡、職業(yè)、教育程度和婚姻狀態(tài)等混雜因素后,拒煙自我效能總分在尼古丁依賴程度與戒煙成功的關(guān)系中的中介作用比例為32.90%。對于拒煙自我效能的三種情境得分(積極/社會情境,消極/情感情境和習慣/成癮情境),其在尼古丁依賴程度與戒煙成功關(guān)系的作用中所起的中介效應大小分別12.14%,35.64%和83.03%。3、多巴胺獎賞通路系統(tǒng)基因分數(shù)與戒煙成功的關(guān)系..結(jié)果顯示,在調(diào)整了年齡、職業(yè)、文化程度、婚姻狀況、焦慮自評量表評分和疾病狀態(tài)等混雜因素后多巴胺獎賞通路系統(tǒng)中,COMT和DRD2基因與戒煙成功存在顯著負相關(guān)關(guān)系,而ANKK1、SLC6A3、DRD4與戒煙成功存在顯著正相關(guān)關(guān)系。4、交互作用分析:多巴胺獎賞通路基因分數(shù)與尼古丁依賴程度的交互作用分析結(jié)果顯示,在調(diào)整了上述混雜因素后,SLC6A3基因與尼古丁依賴程度有顯著的相乘模型交互作用(p=0.03)。5、貝葉斯網(wǎng)絡分析:通過貝葉斯網(wǎng)絡分析構(gòu)建了一個包含10個節(jié)點(包括年齡、開始吸煙年齡、吸煙危害認知、每天吸煙量、吸煙年數(shù)、戒煙原因、戒煙年齡、拒煙自我效能、多巴胺獎賞通路系統(tǒng)基因分數(shù)和戒煙成功)的貝葉斯網(wǎng)絡,其中包括影響戒煙成功的4個直接父節(jié)點,有6條不同的通路可影響戒煙成功。該模型的BIC值為-10013.26,采用五折交叉驗證方法得出其ROC曲線,曲線下面積為0.78。貝葉斯網(wǎng)絡推理結(jié)果顯示,在每天吸煙量高、吸煙年數(shù)長、吸煙危害認知程度低、拒煙自我效能水平低的吸煙者中,只有37.9%成功戒煙。6、優(yōu)勢分析:戒煙成功影響因素的相對重要性(標準化優(yōu)勢權(quán)重)由大到小依次為吸煙嚴重程度因素(42%),其次是個體因素(40%)、遺傳因素(10%)和心理因素(8%)。主要結(jié)論1、尼古丁依賴程度低的吸煙者更容易戒煙成功,拒煙自我效能在尼古丁依賴程度與戒煙成功的關(guān)聯(lián)中起到部分中介作用。2、多巴胺獎賞通路系統(tǒng)整體基因變異與戒煙成功有顯著關(guān)聯(lián),表明遺傳因素可能對戒煙成功存在影響。并且多巴胺獎賞通路系統(tǒng)遺傳變異與尼古丁依賴程度在對戒煙成功的影響中有顯著的相乘模型交互作用,尼古丁依賴程度低且SLC6A3基因分數(shù)高的人更容易戒煙成功。3、遺傳、個體、心理因素等共同影響戒煙成功與否。在實際控煙工作中,應根據(jù)不同吸煙者的情況,制定個性化的解決方案來幫助吸煙者戒煙。4、影響戒煙成功的首要因素是吸煙嚴重程度因素。雖然多巴胺獎賞通路基因變異與成功戒煙有關(guān),但是吸煙的嚴重程度和個人因素比遺傳因素對戒煙有更大的影響。幫助吸煙者降低吸煙嚴重程度,提高吸煙者的拒煙自我效能和吸煙危害認知,矯正吸煙者錯誤的遺傳歸因認知,可有利于促進吸煙者戒煙成功。研究意義上述研究結(jié)果不但為研究戒煙成功的影響因素提供了理論依據(jù),為將來進行相關(guān)研究提供參考基礎(chǔ),而且為我國今后的控煙工作提供決策支持,具有重要的學術(shù)價值與應用價值。創(chuàng)新點1、以前的遺傳學研究僅僅關(guān)注于單一基因的某個或某幾個位點。本研究采用加權(quán)基因分數(shù)方法,探討多巴胺獎賞通路系統(tǒng)整體基因變異與戒煙成功的關(guān)系,并研究遺傳-環(huán)境交互作用。2、目前的多數(shù)研究,僅僅從單純研究某一個或某幾個獨立因素。本研究采用貝葉斯網(wǎng)絡方法,從網(wǎng)絡系統(tǒng)層面研究個人因素、環(huán)境因素以及遺傳因素等因素對戒煙成功的影響情況。3、以往很少有研究探討戒煙成功各影響因素的相對重要性。本文采用優(yōu)勢分析方法,探討個人因素、環(huán)境因素以及遺傳因素等對戒煙成功影響的重要性。
[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 鍒嗘瀽鏋勫緩浜嗕竴涓寘鍚，

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