| BackgroundTobacco use continues to be the leading cause of preventable death worldwide,and it is also the major risk factor for most of the chronic diseases,such as cardiovascular disease and malignant tumors.The harm of smoking not only includes its direct harm for the health,but also includes its addiction and dependence.The essence of the tobacco dependence is nicotine dependence,which is a kind of chronic disease,and smoking cessation could help to reduce the harm caused by smoking.Despite of current tobacco control activities,the current status of the smoking cessation in China remains not optimistic.According to previous studies,among ever smokers,successful smoking cessation rate(16.9%)in China was very low and only 11.7%of them quit smoking successfully longer than two years.Additionally,in China,the rural population,whose smoking severity is higher and cessation rate is lower than the urban people,is in the majority.Thus,in China,especially in rural areas,studying the risk factors of smoking cessation,and developing effective tobacco control measures to increase successful smoking cessation rate is extremely important and imperative.Smoking and smoking cessation have both psychological and physiological traits,primarily induced by the rewarding effects of nicotine,and determined by a combination of genetic and environmental factors.Numerous studies suggested that there were a number of individual and environmental variables associated with successful smoking cessation,such as age,education,marital status,and smoking quantity.Among those,nicotine dependence was one of the major risks for successful smoking cessation.Smokers with lower level of nicotine dependence have a higher probability to quit smoking successfully.In addition,a solid body of evidence proved that smokers with higher level of smoking abstinence self-efficacy will be more likely to quit successfully,vice versa.On the other hand,genetic factors also influence the outcome of smoking cessation.The genes involved in the nicotine addiction and dependence includes two categories.The first category includes the drug metabolism genes,which are nicotine-metabolizing genes;and the other one is the drug effect genes,which are neurotransmitter genes,including the dopamine reward pathway system genes and the serotonin(5-HT)system genes.The mesolimbic dopamine system is the foundation of the neurobiology of the substance addiction.Previous studies related to genetics of smoking cessation mainly focus on the genes of the dopamine reward system,such as the dopamine D2 receptor(DRD2)gene,the dopamine transporter gene(SLC6A3),and catechol-o-methyltransferase(COMT),etc.The limitations of the current studies on the influence factors of smoking cessation include the following aspects:Firstly,there are few studies about the mediation effect of the smoking abstinence self-efficacy on the association of the nicotine dependence and smoking cessation.Current studies have already found that nicotine dependence might have a significant association with smoking cessation;however,the specific mechanism has not been clarified yet.Meanwhile,the smoking abstinence self-efficacy is also related to smoking cessation,and smokers with higher level of smoking abstinence self-efficacy,would be more likely to quit successfully.In addition,previous studies have also shown that smoking abstinence self-efficacy was negatively associated with nicotine dependence.To our knowledge,few data is now available about the mediation effect on the association of nicotine dependence and successful smoking cessation up to now.Secondly,the study about the whole gene effect of the Dopamine pathway gene on smoking cessation is rare.In China,there were few studies investigated on the DA pathway genetic factors of smoking cessation.Although some promising findings have reported DA pathway gene polymorphisms and smoking cessation in other countries,the effect size and direction from different studies are inconsistent,and the results of one study might be difficult to be confirmed in other studies.Generally,most studies only investigate single gene or single SNP(Single Nucleotide Polymorphisms)of one gene in the DA pathway,and there are few studies on the association of the whole gene variance of Dopamine pathway genes and the smoking cessation.Furthermore,the effect of genetic variation on smoking cessation is limited,and there is few study focus on the interaction effect of genetic factors and environmental factors.Thirdly,studies on the risk factors of smoking cessation from the network systems level are scarce.Smoking cessation success is influenced by individual factors,environmental factors,genetic factors,etc.However,most of the previous studies just focused on one or several independent factors,only few studies considered the risk factors of smoking cessation from the network systems level.In addition,the relative importance of the effect of different factors on smoking cessation is rarely studied.To deal with the above-mentioned issues,a community-based case-control study was performed with successful spontaneous smoking quitters as the cases,and failed spontaneous smoking quitters as the controls.The mediation analysis was conducted to investigate the mediation effect on the association of nicotine dependence and successful smoking cessation;the weighted gene score was used to investigate the whole gene effect of Dopamine pathway gene on the smoking cessation,and the interaction effect of the nicotine dependence and the weighted gene score on smoking cessation was also tested.Bayesian network analysis was used to study association of the individual factors,environmental factors,and genetic factors with smoking cessation,and dominance analysis was conducted to evaluate the relative importance of the risk factors on smoking cessation.ObjectivesFirstly,to investigate the mediation effect on the association of nicotine dependence and successful smoking cessation.Secondly,to investigate the whole gene effect of Dopamine pathway gene on the smoking cessation,and the interaction of the nicotine dependence and the weighted gene score on smoking cessation.Thirdly,to investigate the association and relative importance of individual-specific factors,heaviness of smoking factors,psychological factors and genetic factors with smoking cessation using Bayesian network analysis and dominance analysis.Materials and MethodsFirstly,a community-based case-control study was performed with successful spontaneous smoking quitters as the cases,and failed spontaneous smoking quitters as the controls.The mediation analysis based on logistic regression using KHB method was conducted to investigate the mediation effect on the association of nicotine dependence and successful smoking cessation.Propensity score as the covariate in the regression model was used to adjust for the potential confounders.Secondly,weighted gene score of each gene was calculated as the sum of weights for each allele corresponding to estimated genetic effect sizes.The weighted gene score was used to investigate the whole gene effect of Dopamine pathway gene on the smoking cessation,and the multiplicative model interaction of the nicotine dependence and the weighted gene score on smoking cessation was also conducted.Multiplicative model interaction was assessed through a cross-product interaction term in a multivariate logistic regression model.Thirdly,based on the theory and technology of network biology,Bayesian network analysis was used to study association of the individual factors,environmental factors,and genetic factors with smoking cessation.The Dopamine pathway gene score,individual and environmental variables were treated as the nodes of the Bayesian network,and the smoking cessation variable was regarded as the outcome node.The hill-climbing algorithm based on search scoring method was used for the structure learning of the Bayesian network,and Bayesian estimation method was employed for parameter learning.Bayesian Information Criterion(BIC)criteria were used to select network,and ROC area under the curve AUC was used to evaluate the network.Causal inference method is used to estimate the probability of successful smoking cessation under specific situations.Fourthly,four scores(individual score,heaviness of smoking score,psychological score,and genetic score)were predicted by four different logistic models.Dominance analysis was conducted to evaluate the relative importance of the risk factors on smoking cessation.Results1.Sample characteristics.In this study,the total number of the sample size is 1342.642 successful spontaneous smoking quitters were regarded as the cases,and 700 failed spontaneous smoking quitters as the controls.As for the analysis which using the genetic information,the participants without blood sample or was excluded,and 415 successful spontaneous smoking quitters with genotyping results were regarded as the cases,and 404 failed spontaneous smoking quitters as the controls.Compared with the failed spontaneous smoking quitters,the successful spontaneous smoking quitters had significant higher age.The distribution of marital status between the case and control groups was significantly different,while the distribution difference of profession was not significant.2.Mediation analysis.After adjusting for the potential confounders of age,age of smoking initiation,occupation,educational level,and marital status,the mediating effect(indirect effect)of the smoking abstinence self-efficacy total score was 32.90%among the total effect of nicotine dependence on successful spontaneous smoking cessation.As for the three context-specific scores of smoking abstinence self-efficacy,the mediating effects on the association of nicotine dependence with successful spontaneous smoking cessation were 12.14%,35.64%and 83.03%for the positive/social situation,negative/affective situation,and habit/addictive situation,respectively.3.Association of gene score and smoking cessation.We observed significant negative associations of catechol-O-methyltransferase(COMT),dopamine receptor D2(DRD2)gene score and smoking cessation,as well as significant positive associations between ankyrin repeat and kinase domain containing 1(ANKK1),dopamine transporter(SLC6A3),dopamine receptor D4(DRD4)gene score and smoking cessation.The results remained significant after adjusting for age,occupation,education,marital status,self-rating anxiety score,and disease status.4.Interaction of gene score and nicotine dependence on smoking cessation.A significant interaction between FTND and the SLC6A3 gene score was observed(p=0.03),and the results remained significant after adjusting for the above-mentioned confounding(p=0.03).5.Bayesian network analysis.Bayesian network with ten ancestor nodes(including age,age of smoking onset,awareness of smoking hazard,cigarette per day,years of smoking,reasons for smoking cessation,age of smoking cessation,smoking abstinence self-efficacy,Dopamine pathway gene score and smoking cessation)that influenced successful smoking cessation was built.There were four parent nodes in the network,and 6 different pathways influenced the outcome of smoking cessation.The BIC value for the model was-10013.26.The cross-validation method was used to conduct the ROC curve.and the area under the curve to 0.78.Bayesian network inference results showed that smokers with higher daily cigarette consumption,longer of years of smoking,lower level of smoking hazard awareness,and lower level of smoking abstinence self-efficacy,only have a probability of 37.9%to quit smoking successfully.6.Dominance analysis.The most important predictor for smoking cessation was heaviness of smoking score(42%).following by individual(40%).genetic(10%)and psychological score(8%).Conclusions1.The smokers with lower level of nicotine dependence have a higher probability to quit smoking successfully.Smoking abstinence self-efficacy has a partial mediating effect on the association of nicotine dependence with successful spontaneous smoking cessation.2.The Dopamine pathway gene score has a significant association with smoking cessation,which means that the genetic factor might play a role in the outcome of smoking cessation.Multiplicative model interaction analysis revealed those with lower level of nicotine dependence and higher SLC6A3 gene score were associated with a higher possibility to quit smoking successfully.3.Bayesian network analysis shows genetic,environmental and individual factors jointly influence the outcome of smoking cessation.Different measures should be developed in practical tobacco control intervention according to different situations.4.The most important factors influencing the outcome of smoking cessation are heaviness of smoking factors.The effect of genetic variation is minor for the successful smoking cessation,compared with the other involved factors.Helping smokers reduce the heaviness of smoking with nicotine replacement therapy and persuading them to quit smoking as early as possible,could help them quit smoking successfully.It is also necessary to help the smokers who attribute smoking to genetic reasons to set up right perception about smoking.Research SignificanceThe findings provide basic but essential information for future studies on the risk factors of smoking cessation;it could provide evidence for the future practical tobacco control measures as well.Innovations1.Most of the previous studies only focus on single gene or single SNP of one gene in the DA pathway.In this study,the weighted gene score was used to investigate the whole gene effect of Dopamine pathway gene on the smoking cessation,and the interaction of the nicotine dependence and the weighted gene score on smoking cessation was also conducted.2.Most of the previous studies on the risk factors of smoking cessation just focused on one or several independent factors,and few studies focused on the risk factors of smoking cessation from the network systems level.In the study,Bayesian network analysis was used to study association of the individual factors,environmental factors,and genetic factors with smoking cessation.3.There were few studies investigate the relative importance of the effect of different factors on smoking cessation.Dominance analysis was conducted to evaluate the relative importance of the risk factors on smoking cessation in the study. |
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