| BackgroundKnown as the leading cause of preventable death around the world,tobacco use which brings noncommunicable diseases(NCDs),poverty and prematured death has become obvious hazards and heavier burdens on human health,social development and national progress.With more than 1.1 billion people currently smoking in the world,tobacco use kills more than 7 million people each year.Associated health costs and economic losses are over $140 million.China is reckoned to be the largest tobacco consumer of the world with the largest population of smokers,accounting for 28.73%of the global smokers and the worldwide highest per capita annual tobacco intake.China also suffers the most pain and loss from tobacco use.In 2014,smoking-related diseases killed 1.384 million people,causing economic losses equivalent to 0.55%of GDP in the same year.Severe damage brought by tobacco use has drawn strong attention by international community including China government.Since 2003,urgent actions such as "Framework Convention on Tobacco Control,FCTC" and MPOWER measures have been successively launched.With the support from over 180 countries including China,worldwide tobacco control has gained effective progress.In China,tobacco control and performance of FETC is promoted steadily alongside with Healthy China 2030 Program.However,the overlooked truth must be recognized clearly that in China people are far less acquaint with the damage to the health,on the other hand the entire society places fewer emphasis on the underlying dangers of tobacco use.Nowadays,there are 316 million smokers in China and 740 million Chinese people are exposed to second-hand smoke.There is a long way to accomplish the target set by Healthy China 2030 Planning Brief "By 2030,current smoking prevalence of people above the age of 15 will be under 20%".The work on tobacco control is complicated and arduous.Among various tobacco control measures,helping smokers to quit is the most direct and effective one to reduce tobacco-related diseases.Characteristics of smoking behavior is composed of physiological,psychological,and social factors.Factors influencing successful quitting include personal physiological characteristics,genetic characteristics,social intervention,living environment,cognitive level as well as mental activity.The success of smoking cessation is a result of the superposition and co-work of various aforementioned factors.Many studies have shown that the smoker's nicotine metabolism rate has an important influence on whether he can successfully quit smoking.This is mainly because a smoker keeps his nicotine level by continuously ingesting tobacco to prevent himself from torture of withdrawal symptoms.Therefore,to a certain extent,the smoker's own nicotine metabolism rate determines the smoking behavior.Compared with smokers which are slower nicotine metabolizers,faster nicotine metabolizers tend to smoke more cigarettes with higher frequency in order to restore and maintain the plasma nicotine concentration.Faster nicotine metabolizers are more likely to become nicotine dependent or have a higher nicotine dependence,meanwhile the thirst for tobacco is also increasing,which makes it more difficult to quit smoking.Genetic studies have shown that the heritability of smoking initiation(SI)is 47%-76%,the heritability of smoking maintenance(SM)is about 60%,and the heritability of successful smoking cessation(SC)is 50%-58%.The genetic factors affecting the success of smoking cessation mainly include two categories:one is pharmacodynamic genes,such as dopamine pathway-related genes,and serotonin pathway genes.The other is the pharmacokinetics gene that encode nicotine metabolizing enzymes in the body and of which the mutations may have influence on the nicotine metabolism rate of smokers.The enzymes taking part in nicotine metabolism in human body mainly consist of cytochrome P450 enzymes(CYPs)and UDP-glucuronosyltransferases(UGTs).Among them,the CYP2A6 enzyme is regarded as key enzyme that affects nicotine metabolism rate,and it plays a major role in the conversion of nicotine to cotinine,cotinine further to trans-3-hydroxycotinine(3HC).Its encoding gene CYP2A6 receives the most attention.In addition to genetic factors,successful smoking cessation is also affected by mixed factors including individual psychological factors(such as smoking motivation,self-efficacy,anxiety,stress,etc.),individual physiological characteristics(such as nicotine dependence,age,etc.),social and environmental factors(such as social support,cognitive level of smoking hazards,etc.).Therefore,in-depth research the influencing factors of successful smoking cessation in Chinese population,analysis of factors' internal interactions(such as genetic-environmental)and comparison of relative importance of various influencing factors,will provide theoretical proof to efficiently interventions,help improve thesuccess rate of smoking cessation and help build healthy China.Objectives1.To investigate the association of genetic polymorphisms in nicotine metabolism pathway with successful smoking cessation.2.To explore the relationship between the genetic polymorphisms of hepatic cytochrome P450 oxidoreductase(POR)and successful smoking cessation.3.To research the influence of individual physiological factors,psychological factors,and social factors on successful smoking cessation,and compare the relative importance of various factors.4.To analyze the interaction of gene score and smoke abstinence self-efficacy(SASE)on successful smoking cessation.Materials and Methods1.A case-control study based on population in community was designed with cases referring to successful smoking quitters,and controls referring to failed smoking quitters.Characters of genetic factors were collected through collection of blood samples of the study subjects,extraction of DNA,and genotyping by Sequenom MassArray system and two-step PCR method.Psychological factors,social factors and other characteristics are collected and analyzed by the Russell Reason for Smoking Questionnaire(RRSQ),Smoking Abstinence Self-efficacy Scale(ASES-S),Trait Coping Style Questionnaire(TCSQ),Self-rating Anxiety Scale(SAS),Smoking Hazard Cognition Scale,Social Smoking Identifier Scale,Social Support Rating Scale,etc..2.Using the weighted gene score method,the gene score of the nicotine metabolic pathway gene was calculated based on the allele frequency in this study.Univariate logistic regression and multivariate logistic regression were used to analyze the association of genotype and gene scores with successful smoking cessation.Genotype association analysis was performed under the four genetic models:codominant,additive,dominant,and recessive.The Akaike Information Criterion(AIC)was used to determine the optimal genetic model for each polymorphic locus.The frequencies of haplotype distributions between cases and controls were compared by the Pearson's ?2 test.3.Joint effects of nicotine metabolism pathway gene score and smoking abstinence self-efficacy on successful smoking cessation was analyzed both on multiplicative and additive scale.Multiplicative interaction is evaluated by the cross product term(gene score-smoking abstinence self-efficacy)in logistic regression model.Additive interaction was evaluated by calculating the Relative Excess Risk Due to Interaction(RERI)and interactive effect of Attribution Percentage(AP).4.Scores of four influencing factors(psychological factors,genetic factors,social factors,and individual physiological characteristics)on successful smoking cessation was calculated applying logistic regression model.Furthermore,the relative importance of four factors on successful smoking cessation were compared with dominance analysis method.Results1.This study was conducted with 708 subjects in which 363 were successful smoking quitters as cases,and 345 were failed smoking quitters as controls.Compared with failed smoking quitters,successful smoking quitters are older and have more years of smoking.There was no statistically significant difference in occupation,educational level,daily smoking,and reasons for smoking cessation between cases and controls.-2.Genetic polymorphisms such as CYP2A6*4?rs11726322?rs12233719 and rs3100 played a positive role in successful smoking cessation.On the contrary,rs3760657 had a negative impact on successful smoking cessation.The nicotine metabolism pathway CYP2D6?FM03?UGT2810?UGT1A9?UGT2B7?CUGT2B15 weighted gene score and the nicotine metabolism pathway total gene score were positively correlated with successful smoking cessation.CYP2B6 gene score was negatively correlated with successful smoking cessation.3.POR rs3823884 and rs3898649 has positive impact on successful smoking cessation.SNPs of rs239953 and rs17685 in POR gene negatively impacts successful smoking cessation.No significant difference was found in the frequency distribution of POR haplotypes between successful smoking quitters group and failed smoking quitters group.4.It is statistically significant in distribution difference of FTND scores between successful smoking quitters group and failed smoking quitters group(?2= 7.612,P =0.022).Automatic scale scores,assistant scale scores and dependency scores in pharmacological dimensions of Russell Reason for Smoking Questionnaire(RRSQ)are related to the success of smoking cessation.Compared with failed smoking quitters,successful smoking quitters attained higher performances in Smoking abstinence self-efficacy total score and smoking hazard cognition score,while lower score on social recognition of smoking.There was no statistically significant difference in smokers' trait coping style and anxiety score between successful smoking quitters and failed smoking quitters.5.The multiplicative model indicated that there is negatively multiplicative interaction between UGT1A9 gene score and smoking abstinence self-efficacy.The additive model showed that UGT1A9 gene score,CYP2D6 gene score and POR gene score positively interact with smoking abstinence self-efficacy.6.Results of dominant analysis showed that individual physiology characteristic was the predictor accounting for 64.7%of all predictors for smoking cessation.Genetic factor,social factor and psychological factor accounted for 20.8%,13.0%and 1.5%,respectively.Conclusion1.Genetic polymorphisms of nicotine metabolism pathway is associated withsuccessful smoking cessation.Not only genetic variations of Phase ? metabolizing enzymes,but also the genetic variations of Phase ? metabolizing enzymes were found influence smoking cessation.2.To our knowledge,it is the first study to investigate the relationship between the genetic polymorphisms of hepatic cytochrome P450 oxidoreductase(POR)and successful smoking cessation.It is found that four SNPs have impacts on the genetic susceptibility to successful smoking cessation,and POR mutations were associated with smoking behavior.3.Successful smoking cessation was affected by individual physiological factors,psychological factors as well as social factors.Nicotine dependence of smokers is related with successful smoking cessation.The higher degree of nicotine dependence the smoker has,the more difficult he will feel to cease smoking.Smokers with higher levels of smoking abstinence self-efficacy are more likely to quit smoking,especially in positive/social situations and negative/affective situations.Besides,smokers who have higher level cognition of smoking hazards and who have lower levels of social recognition of smoking behavior are more likely to quit smoking.4.There was negative multiplicative interaction and positive additive interaction between UGT1A9 gene score and smoking abstinence self-efficacy(SASE).It indicated that the effect when the two factors combines together is greater than the sum of the two alone effects,and less than the product of the two alone effects.Analysis results also found positive additive interactions between CYP2D6 gene score,POR gene score and smoking abstinence self-efficacy.5.The results of dominant analysis showed that the individual physiological characteristics were the most significant factors on successful smoking cessation,followed by genetic factors,social factors and psychological factors.Significance and Innovations1.In this study;not only the analysis of the gene encoding phase ? metabolizing enzymes was performed,but also the relationship between the genetic variations of phase ? metabolic enzyme-encoding genes and smoking cessation was analyzed.Most of previous studies always focused on the gene encoding phase ? metabolic enzymes,particularly CYP2A6.There have been almost no reports about the effect of polymorphisms in the gene encoding phase ? metabolic enzymes on smoking behaviors.This study provides new ideas for the future exploration of genetic factors which affect smoking behaviors.2.In this study,not only the effect of single polymorphic loci on the successful smoking cessation was analyzed,but also the overall role of nicotine metabolic pathway genes was evaluated by weighted gene score.3.To our knowledge,it was the first study to investigate the relationship between the genetic polymorphisms of hepatic cytochrome P450 oxidoreductase(POR)and successful smoking cessation.Four SNPs were found to have impacts on the genetic susceptibility to successful smoking cessation,in which variations of POR rs3823884 and rs3898649 were positively associated with successful smoking cessation and variations of POR rs239953 and rs17685 have negative impact on smoking cessation.4.This study found that there were joint effects between genetic factors and psychological factors on the smoking cessation.In the tobacco control work,the interaction between various factors should be applied to formulate more effective smoking cessation measures.5.This study showed that the individual physiological characteristics were the most significant factors on successful smoking cessation.This suggests that for smokers who have a willingness to quit smoking,especially those who are highly dependent on nicotine,they should be advised to go to quit-smoking clinics and get cured under the guidance of a doctor.At the same time,a positive social environment for smoking quitters should be created by increasing education and propaganda,establishment of smoke-free communities and promotion of prohibition of smoking in public.As to some smokers trying quitting,strengthen psychological counseling and psychological interventions should be used to help them establish confidence in smoking cessation and promote the success in quitting smoking. |
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