Relationship Of Variants In Nicotinic Acetylcholine Receptor Genes And Other Factors With Smoking Cessation

BackgroudAlthough smoking is a preventable problem and most countries in the world did a lot of wotk to control smoking,the prevalence of smoking is still unacceptable.In 2011,the prevalence of smoking in males and females aged 15 or more worldwide is 36%and 8%,respectively.In the world,smoking causes about 500 billion economical damage and about 6 million deaths should attibute to disease resulted from smoking every year.In China,the prevalence of smoking in males and females aged 15 or more is 47%and 2%in 2011,respectively.There are more than 300 million smokers and 740 million people who suffer from the secondhand smoking in China.But smoking cessation rate more than two years in China is just 11.7%.There are 4 thousand of chemical materials in the smoke of tabacco and most of these materials are poisonous.In smoke of tabacco,there are 69 categories of materials that can result in cancer.Smoking can damage nearly all organs of human being.It also boosts the incidence of many cancer.Smoking is the cause of many chronic diseases,such as bronchial asthma,stroke and artherosclerosis.Smoking has become the risk factor of six of the eight most important global deaths.Cessation is the confirmed method that can reduce or eliminate the damage of smoking.So,it is necessary to find the influenced factors of successful smoking cessation.Nicotine dependence is the reason for continuous smoking.Nicotine dependence is caused by the nicotine in tobacco smoke.After inhaled into body,nicotine is transported to brian through blood circulation,binded to nicotinic acetylcholine receptors in brian firstly,and then excite the dopaminergic neurons in mesolimbic system which results in more dopamine release in nucleus accumbens and self-administration.This is the mechanism of nicotine dependence.The first step of nicotine dependence is the binding between nicotine and nicotinic acetylcholine receptors.Nicotinic acetylcholine receptors are coded by nicotinic acetylcholine receptor genes(CHRN).Previous studies showed that some reactions of CHRN knocknout mice to nicotine have changed.Smoking cessation is opposite to nicotine dependence.The key step of smoking cessation is to overcome nicotine dependence.So,wepresume that CHRN may have taken part in nicotine dependence and smoking cessation.Human studies revealed that mutation in single nucleotide polymorphisms(SNP)may decrease the probability of successful smoking cessation,reduce the smoking cessation rate of placebo group and change the number of quitting.Although previous studies revealed some relationships between CHRN and smoking cessation,there are some shortages among these previous studies.Firstly,to explore the relationship between CHRN and smoking cessation with single SNP may not reveal the whole effect of CHRN on smoking cessation.Secondly,the effects of single SNP in CHRN on SC are inconsistent in intensity and direction.Thirdly,there is no study that use whole genetic mutation information to explore the association betweeen CHRN and smoking cessation.Previous studies showed that individual factors(such as age,occupation,education,ciggarete per day,age of smoking onset,years of smoking and reason for cessation)are related to smoking cessation.Nicotine dependence does not just mean physical dependence,it also means psychological dependence.Among psychological factors,self-efficacy represents the confidence of people to copy with a problem in a given condition.Bandura's theory showed that people with higher level of self-efficacy may be more probability to quit smoking successfully.Previous studies suggested the level of smoking abstinence self-efficacy(SASE)was significantly higher in ex-smokers than in current smokers.Additionally,self-efficacy was negtively related to nicotine dependence.Thus,self-efficacy may be an important psychological factor for smoking cessation.The previost studies about influencing factors of smoking cessation were most based on statistical hypothesis in which effect of univariate variable(single gene)or multiple variables(multiple genes)was independent.Methods in previous studies were also effect-independent statistical methods.These hypotheses and methods were suitable for univariate variable analysis and effect-independent multiple variables analysis.About multifactorial disease(such as nicotine dependence and smoking cessation),influencing factors constructed an interactive network in the influencing progress of outcome.Effect-independent statistical methods may not systematically infer the interactive network constructed by multiple factors.So,effect-independent statistical methods may not infer the mechanism of smoking cessation on systematically level.In previous studies,individual and psychological factors are treated as covariants in relationship between genetic factor and smoking cessation.Although these studies revealed that there were associations of genetic,individual and psychological factors with smoking cessation,prvious studies did not compare the relative contribution of these three kinds factos to smoking cessation.According to the shortages of previous studies,a community-based case-control study was carried out.In current case-control study,the case group referred to the successful smoking quitters and the control group referred to the unsuccessful smoking quitters.Genetic risk score that represtented the whole mutation information of gene was employed to explore the relationships between CHRN and smoking cessation and then the relative contributions of genetic,individual and psychological facoters on smoking cessation were compared.Objectives1.To explore the relationship between genetic factor and successful smkoing cessation with genetic risk score that represtented the whole mutation information of gene.2.To investigate the interaction among genetic,individual and psychological factors on smoking cessation.3.To compare the relative contribution of genetic,individual and psychological factors on smoking cessation,Matetials and Methods1.A community-based case-control study was carried out.In current case-control study,the case group referred to the successful smoking quitters and the control group referred to the unsuccessful smoking quitters.Pareicipants were recruited from 17 villages of 3 counties in Shandong province,China.Informatin of individual and psychological factors was acquired by by questionnaire.DNA was extracted from the blood samples and genotyped in order to get the genetic information.2.Student t-test,Wilcoxon rand sum test or Pearson's ?2 test was explored to compare the distributon of individual and psychological factors between case group and control group.Univariate and multiple logistic regression were performed to explore the relationships of single SNP and genetic risk score with smoking cessation.Pearson's ?2 test was used to compare the distribution of haplotype between case group and control group.3.Bayesian network was carried out to constructed the network of genetic,individual and psychological factors about smoking cessation and then preformed to analyse the interaction effect of genetic,individual and psychological factors on smoking cessation.4.Dominance analysis based on logistic regression estimation was carried out to assess the relatiove importance of genetic,individual and psychological factors for smoking cessation.Results1.Compared with the unsuccessful smoking quitters,the successful smoking quitters had significant higher age,smoking abstinence self-efficacy in negative/affective situation score(SASEN),smoking abstinence self-efficacy total score(SASET),but lower age of smoking cessation and fewer years for smoking(P<0.05).There was no difference between the case and control group in age of smoking onset,cigarettes per day,smoking abstinence self-efficacy in positive/social situation score(SASEP)and smoking abstinence self-efficacy in habit/addictive situation score(SASEH)(P>0.05).Although the association of SASEP and SASEH with smoking cessation did not reach significant level,they represented the same trend as SASEN and SASET score.The distribution of education and reason for cessation between the case and control group was no significantly different(P>0.05).Moltiple logistic regression showed that there were significant associations of rs578776(CHRNA3),rs660652(CHRNA3)and rs588765(CHRNA5)with smoking cessation(P<0,05),The C allele of rs578776(OR:0.77),A allele of rs660652(OR:0.70)and T allele of rs588765(OR:0.73)were risk factors of smoking cessation.There were two haplotypes(one in CHRNA3 and one in CHRNB4)signigicantly related to smoking cessation(P<0.05).The frequency of haplotype ACC(in CHRNA3)in case group was lower than that in control group.The frequency of haplotype GGG(in CHRINB4)in case group was higher than that in control group.CHRNA3 genetic risk score was significantly related to smoking cessation(P<0.05)and was risk factor of smoking cessation(OR:0.48).2.The area under the concentration-time of receiver operator characteristic curve was 0.91,which meant the Bayesian network may predict the smoking cessation acceptably.There were five main passway in basesian network which reflected the progress of genetic,individual and psychological factors influencing smoking cessation:?age?reason for cessation?successful smoking cessation,? age?age of smoing quitting?years of smoking?successful smoking cessation,? age of smoking onset?years of smoking?sucessful smoking cessation,? cigarette per day?SASET?sucessful smoking cessation,? CHRNA3?CHRNA5?CHRNB4?sucessful smoking cessation.Age influenced smoking cessation through reason for quitting,age of smoking quitting and years of smoking indirectly.Years of smoking was a key node in our Bayesian network.Cigarette per day may influence smoking cessatin through SASET.CHRNA3 may influence smoking cessatin through CHRNA5 and CHRNB4.3.Dominance analysis showed that individual factor(standardized weight:52.22%,ranking:1)was the most important predictor for smoking cessation,followed by genetic factor(standardized weight:28.85%,ranking:2)and psychological factor(standardized weight:18.93%,ranking:3).Conclusions1.Individual factor influenced smoking cessation.Age,age of smoking quitting and years of smoking distributed between case and control group differently.Psychological factor influenced smoking cessation.Compare with smokers with lower SASE,smokers with higher SASE were more probable to quit.Genetic factor influenced smoking cessation.CHRNA3 was risk factor for smoking cessation.Smokers with higer CHRNA3 genetic risk score had less probability to quit than smokers with lower CHRNA3 genetic risk score.2.There were dependence among individual factors,among individual and psychological factors,and among genetic factor in the progress of influencing smoking cessation.In the intervene of smoking cessation,actions aimed at key nodes can be taken in order to heighten the rate of moking cessation in population.3.Individual factor was the most impotant predictor for smoking cessation.Compared with genetic factor,individual factor had more contribution to smoking cessation.It is necessary to pay more attention to individual factor in the intervene of smoking cessation and correct the idea of smokers that genetic factor resulted in unsuccessful smoking cessation.Innovations1.Using genetic risk score to explore the relationship between genetic mutation and smoking cessaton on gene level.2.Using Bayesian network to reflect the effect of genetic,individual and psychological factors on smoking cessation and interacton of these factors in the progress of influencing smoking cessation.3.Using dominance analysis to comparing the relative contribution of genetic,individual and psychological factors to smoking cessation.