title: Smoking reduction, smoking cessation, and incidence of fatal and non-fatal myocardial infarction in Denmark 1976–1998: a pooled cohort study Genetic variation in mu-opioid-receptor-interacting proteins and smoking cessation in a nicotine replacement therapy trial. Gender Stratified Gene and Gene–Treatment Interactions in Smoking Cessation Association between nicotinic acetylcholine receptor single nucleotide polymorphisms and smoking cessation. Lack of association of DRD2 rs1800497 (Taq1A) polymorphism with smoking cessation in a nicotine replacement therapy randomized trial. Association of the mu-opioid receptor gene with smoking cessation Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation. Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR Association of COMT Val108/158Met Genotype with Smoking Cessation in a Nicotine Replacement Therapy Randomized Trial The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial Dopamine D4 Receptor Gene Variation Moderates the Efficacy of Bupropion for Smoking Cessation Prenatal Smoke Exposure and Genomic DNA Methylation in a Multiethnic Birth Cohort Nicotinic acetylcholine receptor β2 subunit gene implicated in a systems-based candidate gene study of smoking cessation Genome-Wide Association for Smoking Cessation Success in a Trial of Precessation Nicotine Replacement Identification of pharmacogenetic markers in smoking cessation therapy Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch Pharmacogenetic investigation of smoking cessation treatment. Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial. Catechol-O-Methyltransferase (COMT) Gene Variants Predict Response to Bupropion Therapy for Tobacco Dependence Role of Functional Genetic Variation in the Dopamine D2 Receptor (DRD2) in Response to Bupropion and Nicotine Replacement Therapy for Tobacco Dependence: Results of Two Randomized Clinical Trials Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: analysis of pooled data from two clinical trials. Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation. CYP2B6 Genotype Alters Abstinence Rates in a Bupropion Smoking Cessation Trial Convergent Evidence that Choline Acetyltransferase Gene Variation is Associated with Prospective Smoking Cessation and Nicotine Dependence The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: follow-up of a randomized controlled trial.
abstract: Objective : To analyse the effects of smoking reduction and smoking cessation on incidence of myocardial infa rct ion after adjustment for established cardiovascular risk factors . Design : Prospect i ve cohort study with record linkage to mortality and hospital registers . The association of individual change in smoking with myocardial infa rct ion was examined in Cox proportional hazard analyses with continuous heavy smokers ( ⩾5 cigarettes/day ) as reference . Setting : Pooled data from three population studies conducted in Copenhagen , Denmark . Participants : 10 956 men and 8467 women with complete information on smoking habits at two examinations five to ten years apart were followed up from the second examination for a first hospital admission or death from myocardial infa rct ion . Mean duration of follow up was 13.8 years . Main results : A total of 643 participants who were heavy smokers at baseline reduced their daily tobacco consumption by at least 50 % without quitting between first and second examination , and 1379 participants stopped smoking . During follow up 1658 men and 521 women experienced a fatal or non-fatal myocardial infa rct ion . After adjustment for cardiovascular risk factors , people who stopped smoking had a decreased risk of myocardial infa rct ion , hazard ratio 0.71 ( 95 % confidence intervals 0.59 to 0.85 ) . Smoking reduction was not associated with reduced risk of myocardial infa rct ion , hazard ratio 1.15 ( 95 % confidence intervals 0.94 to 1.40 ) . These associations remained unchanged after controlling for baseline illness in different ways . Conclusions : Smoking cessation in healthy people  reduces the risk of a subsequent myocardial infa rct ion , whereas this study provides no evidence of benefit from reduction in the amount smoked Extending a previous finding of an association between functional genetic variation in the mu-opioid receptor gene and response to nicotine replacement therapy , we explored the role of genetic variants in two genes encoding mu-opioid-receptor-interacting proteins , namely ARRB2 and HINT1 . Participants were 374 smokers treated for nicotine dependence with either transdermal nicotine or nicotine nasal spray for 8 weeks in an open-label r and omized trial . In a logistic regression model controlling for OPRM1 genotype , treatment type , and other covariates , we found no significant main effect of ARRB2 genotype on abstinence at either end of treatment or 6-month follow-up . Participants with the HINT1 TT genotype had significantly higher abstinence rates at 6-month follow-up , but this may not be a pharmacogenetic effect , given that the participants were drug free during this time . Haplotype analysis did not reveal any significant associations for either gene . We found an interaction of ARRB2 and OPRM1 genotype on abstinence at 6 months that approached significance ; however , interpretation of this finding is limited by the small number of participants with the minor alleles for both genes . Although these data do not provide support for the role of genetic variation in these mu-opioid-receptor-interacting proteins and smoking cessation , further exploration of opioid pathway genes in larger prospect i ve pharmacogenetic trials may be warranted We conducted gender-stratified analyses on a systems-based c and i date gene study of 53 regions involved in nicotinic response and the brain — reward pathway in two r and omized clinical trials of smoking  cessation treatments ( placebo , bupropion , transdermal and nasal spray nicotine replacement therapy ) . We adjusted P-values for multiple correlated tests , and used a Bonferroni-corrected α-level of 5 × 10−4 to determine system-wide significance . Four single-nucleotide polymorphisms ( rs12021667 , rs12027267 , rs6702335 , rs12039988 ; r2>0.98 ) in erythrocyte membrane protein b and 4.1 ( EPB41 ) had a significant male-specific marginal association with smoking abstinence ( odds ratio (OR)=0.5 ; 95 % confidence interval ( CI ) : 0.3–0.6 ) at end of treatment ( adjusted P<6 × 10−5 ) . rs806365 in cannabinoid receptor 1 ( CNR1 ) had a significant male-specific gene – treatment interaction at 6-month follow-up ( adjusted P=3.9 × 10−5 ) ; within males using nasal spray , rs806365 was associated with a decrease in odds of abstinence ( OR=0.04 ; 95 % CI : 0.01–0.2 ) . While the role of CNR1 in substance abuse has been well studied , we report EPB41 for the first time in the nicotine literature INTRODUCTION The α4β2 nicotinic receptor is of central importance in tobacco dependence , while the homomeric α7 receptor may also play a role . In this c and i date gene study , we examine the association between 8 single nucleotide polymorphisms ( SNPs ) in genes coding for nicotinic acetylcholine receptor subunits α4 ( rs1044396 , rs2273504 , rs2236196 , and rs2273502 ) , α7 ( rs2133965 and rs4779969 ) , and β2 ( rs2072660 and rs2072661 ) and smoking abstinence in a cohort of quitters enrolled in a clinical trial of behavioral support . METHODS Data were obtained from the " Patch in Practice " study , involving 925 smokers in the United Kingdom . All participants were given an 8-week course of 15 mg of transdermal nicotine replacement therapy and blood was taken for genotyping . RESULTS Logistic regression analyses assessed the association between each selected SNP and smoking abstinence at 4 , 12 , 26 , and 52 weeks . There were no statistically significant associations with smoking cessation success or nicotine intake assessed by plasma cotinine levels . However , rs2273502 was associated with a consistent ( though nonsignificant ) increase in the odds of abstinence . CONCLUSIONS There was no compelling evidence that these SNPs were associated with a reduced or higher chance of abstinence . However , rs2273502 may be worth investigating in future studies INTRODUCTION We previously reported evidence that the T allele of the dopamine type-2 receptor ( DRD2 ) rs1800497 polymorphism is associated with improved response to nicotine replacement therapy ( NRT ) relative to placebo and that this association may only be present in females . However , evidence of the poor replication validity of genetic association studies is growing , particularly among those that report subgroup analyses . We therefore attempted to replicate our previous finding of an association between the DRD2 rs1800497 genotype and response to NRT in a new , larger cohort , with greater statistical power . METHODS Participants were r and omly assigned to one of two levels of smoking cessation behavioral support ( usual care vs. weekly support ) . All participants received 8 weeks of 15-mg NRT transdermal patch . RESULTS The presence of one or more T alleles was associated with a slightly but not significantly lower likelihood of abstinence at 3 and 6 months . We found evidence of a genotype x sex interaction effect . However , stratified analyses indicated a main effect of genotype opposite to the effect reported previously , with females carrying one or more copies of the T allele less likely to be abstinent . DISCUSSION Our results do not support an association between the DRD2 rs1800497 ( Taq1A ) polymorphism and response to NRT , contrary to our previous study We investigated the association of the OPRM1 genotype with  long-term smoking cessation and  change in body mass index ( BMI ) following a smoking cessation attempt among smokers who attempted to quit using the nicotine replacement therapy ( NRT ) patch or placebo in a r and omized controlled trial , and were followed-up over an 8-year period following their initial cessation attempt . We also investigated possible sex differences in these relationships , given evidence for sex differences in smoking cessation and central opioid mechanisms , as well as some evidence for sex differences in response to NRT . Our results indicate that OPRM1 genotype may moderate the effect of  transdermal nicotine patch compared to placebo during active treatment , with a benefit of active NRT treatment evident in the OPRM1 AA genotype group only and those carrying one or more copies of the G allele demonstrating no benefit of active NRT versus placebo patch . Our results also indicate a sex difference in change in BMI at 8-year follow-up following a smoking cessation attempt , with ex-smokers demonstrating an increase in BMI , and this increase being greater in female subjects than in male subjects . We did not observe any association of OPRM1 genotype with change in BMI , although there was a trend for genotype to influence the observed sex difference in change in BMI over time . Future studies should attempt to replicate these findings , and investigate the relationship between both short- and long-term weight gain and smoking cessation and investigate possible mechanisms that may underlie these processes . Future studies should also investigate the role of OPRM1 genotype and smoking cessation on other appetitive and reward behaviours such as alcohol consumption This r and omized , double-blinded , placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation . Smokers of European ancestry ( N = 291 ) , who were r and omized to receive bupropion or placebo ( 12 weeks ) plus counseling , were genotyped for the dopamine D2 receptor ( DRD2-Taq1A ) , dopamine transporter ( SLC6A3 3 ' VNTR ) , and cytochrome P450 2B6 ( CYP2B6 1459 CT ) polymorphisms . Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2- , 6- , and 12-month follow-ups post quit date . Using generalized estimating equations , we found that bupropion , compared with placebo , was associated with significantly greater odds of abstinence at all time points ( all p values<.01 ) . We found a significant DRD2 x bupropion interaction ( B = 1.49 , SE = 0.59 , p = .012 ) [ corrected ] and a three-way DRD2 x bupropion x craving interaction on 6-month smoking cessation outcomes ( B = -0.45 , SE = 0.22 , p = .038 ) , such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion . Furthermore , there was a significant DRD2 x CYP2B6 interaction ( B = 1.43 , SE = 0.56 , p = .01 ) , such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype . Because the sample size of this study was modest for pharmacogenetic investigations , the results should be interpreted with caution . Although these results require replication , the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and , further , that exploration of gene x gene and gene x craving interactions in future , larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion The A1 allele of the dopamine D2 receptor gene ( DRD2 ) is associated with a reduced number of dopamine binding sites in the brain and with the increased likelihood of substance abuse and addictive behavior . In a study of smokers enrolled in an open-label , r and omized effectiveness trial , we investigated whether variants in the DRD2 receptor gene are associated with smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling .  Adherence to treatment and point-prevalent smoking status were assessed at 3 and 12 months , respectively , following a target quit date . Compared to women who carry both A2 alleles , women with at least one A1 allele were more likely to report having stopped taking bupropion due to medication side effects ( odds ratio (OR)=1.91 , 95 % confidence interval (CI)=1.01–3.60 ; P<0.04 ) and at 12 months were somewhat more likely to report smoking ( OR=0.76 , 95 % CI=0.56–1.03 ; P<0.076 ) . Significant associations or trends were not observed in men . In women , individual variability in responsiveness to bupropion-based treatment may be partially due to differences in genetic variants influencing dopamine receptor function We investigated the association of catechol O-methyltransferase ( COMT ) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt . In addition , we examined the possible moderating influence of sex on any association . The genotype × treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met/Met genotype group ( 33 % versus 12 % ) , in comparison to the Met/Val + Val/Val group ( 22 % versus 16 % ) . Our results indicate that COMT genotype may moderate the effect of active transdermal nicotine patch  compared with placebo , with reduced relative benefit of nicotine replacement therapy in individuals with Met/Val or Val/Val genotype . Our data follow an emerging pattern of results suggesting that genetic variation in the dopamine pathway may provide a future basis for tailored smoking cessation therapies , but indicate that different genes influencing various components of this pathway may have different effects on response to smoking cessation pharmacotherapy . ( Cancer Epidemiol Biomarkers Prev 2007;16(6):1065–9 ABSTRACT To determine whether the functional mu-opioid receptor ( OPRM1 ) Asn40Asp variant predicts the comparative efficacy of different forms of NRT , we conducted a clinical trial of transdermal nicotine ( TN ) vs nicotine nasal spray ( NS ) in 320 smokers of European ancestry . Smokers carrying the OPRM1 Asp40 variant ( n=82 ) were significantly more likely than those homozygous for the Asn40 variant ( n=238 ) to be abstinent at the end of treatment , and reported less mood disturbance and weight gain . The genotype effect on treatment outcome was most pronounced among smokers receiving TN , particularly during the 21 mg dose phase . Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose Smokers ( ⩾10 cigarettes per day , N=331 ) of European ancestry taking part in a double-blind placebo-controlled r and omized trial of 12 weeks of treatment with bupropion along with counseling for smoking cessation were genotyped for a variable number of t and em repeats polymorphism in exon III of the dopamine D4 receptor gene . Generalized estimating equations predicting point-prevalence abstinence at end of treatment and 2 , 6 and 12 months after the end of treatment indicated that bupropion ( vs placebo ) predicted increased odds of abstinence . The main effect of Genotype was not significant . A Genotype × Treatment interaction ( P=0.005 ) showed that bupropion predicted increased odds of abstinence in long-allele carriers ( odds ratios (OR)=1.31 , P<0.0001 ) , whereas bupropion was not associated with abstinence among short-allele homozygotes ( OR=1.06 , P=0.23 ) . The Genotype × Treatment interaction remained when controlling for demographic and clinical covariates ( P=0.01 ) and in analyses predicting continuous abstinence ( P's⩽0.054 ) . Bupropion may be more efficacious for smokers who carry the long allele , which is relevant to personalized pharmacogenetic treatment approaches Background : Exposure to prenatal tobacco smoke ( PTS )  has been associated with a number of health outcomes in the offspring , including some childhood cancers . Lower levels of genomic DNA methylation have also been associated with several types of cancers . We investigated whether PTS was associated with global DNA methylation levels in the offspring . Methods : Our sample was drawn from a birth cohort of women born between 1959 and 1963 in New York City ( n = 90 ) . We measured  methylation of repetitive elements ( Sat2 , Alu , LINE-1 )  from peripheral blood granulocytes . We combined prospect ively collected data on PTS with adult epidemiologic data and blood sample s collected in 2001 to 2007 ( mean age , 43 years ) . We used linear regression to assess the association between PTS and repetitive element methylation . Results : Thirty-six percent of mothers smoked during pregnancy . We observed an inverse association between PTS and Sat2 methylation . This inverse association remained even after adjustment for potential mediators including child environmental tobacco smoke exposure , birth size , postnatal weight and height changes , and adult smoking status and alcohol intake ( β = −0.22 , 95 % confidence interval = −0.40 to −0.03 for ever exposed to PTS vs. never exposed using models of log-transformed methylation levels ) . PTS exposure was not statistically significantly associated with LINE-1 or Alu methylation . Conclusions : PTS exposure , measured at the time of pregnancy and not retrospectively reported , was associated with a decrease in Sat2 methylation but not LINE-1 or Alu methylation . Impact : If replicated in larger studies , this study supports a persistent effect of PTS on DNA methylation levels , as measured by Sat2 , in adulthood . Cancer Epidemiol Biomarkers Prev ; 20(12 ) ; 2518–23 . © 2011 AACR Although the efficacy of pharmacotherapy for tobacco dependence has been previously demonstrated , there is substantial variability among individuals in treatment response . We performed a systems-based c and i date gene study of 1295 single nucleotide polymorphisms ( SNPs ) in 58 genes within the neuronal nicotinic receptor and dopamine systems to investigate their role in smoking cessation in a  bupropion placebo-controlled  r and omized clinical trial . Putative functional variants were supplemented with tagSNPs within each gene . We used global tests of main effects and treatment interactions , adjusting the P-values for multiple correlated tests . An SNP ( rs2072661 ) in the 3′ UTR region of the β2 nicotinic acetylcholine receptor subunit ( CHRNB2 ) has an impact on abstinence rates at the end of treatment ( adjusted P = 0.01 ) and after a 6-month follow-up period ( adjusted P = 0.0002 ) . This latter P-value is also significant with adjustment for the number of genes tested . Independent of treatment at 6-month follow-up , individuals carrying the minor allele have substantially decreased the odds of quitting ( OR = 0.31 ; 95 % CI 0.18–0.55 ) . Effect of estimates indicate that the treatment is more effective for individuals with the wild-type ( OR = 2.14 , 95 % CI 1.20–3.81 ) compared with individuals carrying the minor allele ( OR = 0.83 , 95 % CI 0.32–2.19 ) , although this difference is only suggestive ( P = 0.10 ) . Furthermore , this SNP demonstrated a role in the time to relapse ( P = 0.0002 ) and an impact on withdrawal symptoms at target quit date ( TQD ) ( P = 0.0009 ) . Overall , while our results indicate strong evidence for CHRNB2 in ability to quit smoking , these results require replication in an independent sample Abilities to successfully quit smoking display substantial evidence for heritability in classic and molecular genetic studies . Genomewide association ( GWA ) studies have demonstrated single-nucleotide polymorphisms ( SNPs ) and haplotypes that distinguish successful quitters from individuals who were unable to quit smoking in clinical trial participants and in community sample s. Many of the subjects in these clinical trial sample s were aided by nicotine replacement therapy ( NRT ) . We now report novel GWA results from participants in a clinical trial that sought dose/response relationships for “ precessation ” NRT . In this trial , 369 European-American smokers were r and omized to 21 or 42 mg NRT , initiated 2 wks before target quit date s. Ten-week continuous smoking abstinence  was assessed on the basis of self-reports and carbon monoxide levels . SNP genotyping used Affymetrix 6.0 arrays . GWA results for smoking cessation success provided no P value that reached “ genome-wide ” significance . Compared with chance , these results do identify ( a ) more clustering of nominally positive results within small genomic regions , ( b ) more overlap between these genomic regions and those identified in six prior successful smoking cessation GWA studies and ( c ) sets of genes that fall into gene ontology categories that appear to be biologically relevant . The 1,000 SNPs with the strongest associations form a plausible Bayesian network ; no such network is formed by r and omly selected sets of SNPs . The data provide independent support , based on individual genotyping , for many loci previously nominated on the basis of data from genotyping in pooled DNA sample s. These results provide further support for the idea that aid for smoking cessation may be personalized on the basis of genetic predictors of outcome Pharmacogenetic clinical trials seek to identify genetic modifiers of treatment effects . When a trial has collected data on many potential genetic markers , a first step in analysis is to screen for evidence of pharmacogenetic effects by testing for treatment‐by‐marker interactions in a statistical model for the outcome of interest . This approach is potentially problematic because ( i ) individual significance tests can be overly sensitive , particularly when sample sizes are large ; and ( ii ) st and ard significance tests fail to distinguish between markers that are likely , on biological grounds , to have an effect , and those that are not . One way to address these concerns is to perform Bayesian hypothesis tests [ Berger ( 1985 ) Statistical decision theory and Bayesian analysis . New York : Springer ; Kass and Raftery ( 1995 ) J Am Stat Assoc 90:773–795 ] , which are typically more conservative than st and ard uncorrected frequentist tests , less conservative than multiplicity‐corrected tests , and make explicit use of relevant biological information through specification of the prior distribution . In this article we use a Bayesian testing approach to screen a panel of genetic markers recorded in a r and omized clinical trial of bupropion versus placebo for smoking cessation . From a panel of 59 single‐nucleotide polymorphisms ( SNPs ) located on 11 c and i date genes , we identify four SNPs ( one each on CHRNA5 and CHRNA2 and two on CHAT ) that appear to have pharmacogenetic relevance . Of these , the SNP on CHRNA5 is most robust to specification of the prior . An unadjusted frequentist test identifies seven SNPs , including these four , none of which remains significant upon correction for multiplicity . In a panel of 43 r and omly selected control SNPs , none is significant by either the Bayesian or the corrected frequentist test . © 2007 Wiley‐Liss , Smokers of European ancestry ( n=720 ) who participated in a double-blind , r and omised , placebo-controlled trial of transdermal nicotine replacement therapy  , were genotyped for two functional polymorphisms ( variable number of t and em repeats ( VNTR ) and a C to T transition at position –521 ( C-521 T ) ) in the dopamine D4 receptor gene ( DRD4 ) gene . Logistic regression models of abstinence at 12- and 26-week follow-ups were carried out separately for each polymorphism . For the DRD4 VNTR models , the main effect of treatment was significant at both 12-week ( P=0.001 ) and 26-week ( P=0.006 ) follow-ups , indicating an increased likelihood of successful cessation on active nicotine replacement therapy transdermal patch relative to placebo . The main effect of DRD4 VNTR genotype was associated with abstinence at 12-week follow-up ( P=0.034 ) , with possession of one or more copies of the long allele associated with reduced likelihood of cessation ( 17 vs 23 % ) , but this effect was not observed at 26-week follow-up . For the DRD4 C-521 T models , no main effect or interaction terms involving genotype were retained in the models at either 12- or 26-week follow-up . These data are consistent with observations from studies of the DRD2 gene that genetic variants related to relatively decreased dopaminergic tone in the mesocorticolimbic system are associated with increased risk for relapse to smoking following a cessation attempt Despite the efficacy of bupropion for smoking cessation , smokers exhibit variability in treatment outcome . The CYP2B6 gene has been implicated in bupropion kinetics and nicotine metabolism , and is a plausible c and i date for pharmacogenetic studies of treatment response . We investigated whether a functional genetic polymorphism in the CYP2B6 gene predicts smoking outcomes in a placebo-controlled r and omized trial . Four hundred and twenty-six smokers of European Caucasian ancestry provided blood sample s and received bupropion ( 300 mg/day for 10 weeks ) or placebo , plus counseling .  Smoking status , abstinence symptoms and side-effects were recorded weekly , and smoking status was verified at the end of treatment and at 6-month follow-up . Smokers with a decreased activity variant of CYP2B6 reported greater increases in cravings for cigarettes following the target quit date and had higher relapse rates . These effects were modified by a significant gender x genotype x treatment interaction , suggesting that bupropion attenuated the effects of genotype among female smokers . We conclude that smokers with the CYP2B6 variant may be more vulnerable to abstinence symptoms and relapse .  Bupropion may attenuate these effects , especially among females . Additional trials are warranted to confirm these results , as are studies to explore the neurobiological mechanisms . Such research could ultimately enable practitioners to select the optimal type and dose of medication for individual smokers This study examined the role of dopaminergic genes in prospect i ve smoking cessation and response to  bupropion treatment in a placebo-controlled clinical trial . Smokers of European ancestry ( N=418 ) provided blood sample s for genetic analysis and received either bupropion or placebo ( 10 weeks ) plus counseling . Assessment s included the dopamine D2 receptor ( DRD2 ) genotype , dopamine transporter ( SLC6A3 ) genotype , demographic factors , and nicotine dependence . Smoking status was verified at the end of treatment ( EOT ) and at 6-month follow-up . The results provided evidence for a significant DRD2 * SLC6A3 interaction effect on prolonged smoking abstinence and time to relapse at EOT , independent of treatment condition . Such effects were no longer significant at 6-month follow-up , however . These results provide the first evidence from a prospect i ve clinical trial that genes that alter dopamine function may influence smoking cessation and relapse during the treatment phase BACKGROUND Although bupropion is efficacious for smoking cessation , only a minority of smokers are able to quit . Pharmacogenetic research may improve treatment outcomes through discovery of DNA sequences predictive of successful pharmacotherapy for subgroups of smokers . We investigated variants in the catechol-O-methyltransferase ( COMT ) gene in a smoking cessation trial of bupropion . METHODS A double-blind , placebo-controlled , 10-week trial of bupropion and counseling ( with a 6-month follow-up period ) was conducted at two university-based smoking cessation research programs . Abstinence was biochemically verified at the end of treatment and at 6 months after the target quit date . RESULTS At the end of the treatment phase , statistically significant interaction effects indicated that COMT haplotypes of two SNPs ( rs737865 and rs165599 ) predicted the efficacy of bupropion compared with placebo . This interaction effect was attenuated at 6-month follow-up . CONCLUSIONS COMT haplotypes at rs737865 and rs165599 may predict a favorable outcome for bupropion treatment for smoking cessation . European-American smokers with a G allele at both SNPs may not benefit from bupropion treatment . Small numbers of some COMT haplotypes limit interpretation of response . If study findings are confirmed in additional large studies , COMT genotyping could be applied to identify likely responders to bupropion treatment for smoking cessation Although bupropion and nicotine replacement therapy ( NRT ) are efficacious tobacco dependence treatments , there is substantial interindividual variability in therapeutic response and most smokers relapse . Pharmacogenetics research may improve treatment outcomes by identifying genetic variants predictive of therapeutic response . We investigated the roles of two functional genetic variants in the dopamine D2 receptor ( DRD2 ) gene in response to pharmacotherapy for tobacco dependence among participants in two r and omized clinical trials with a 6-month follow-up period : a double-blind placebo-controlled  trial of  bupropion ( n=414 ) and an open label trial of transdermal nicotine vs nicotine nasal spray  ( n=368 ) . At the end of the treatment phase , a statistically significant ( p=0.01 ) interaction between the DRD2 − 141C Ins/Del genotype and treatment indicated a more favorable response to bupropion  among smokers homozygous for the Ins C allele compared to those carrying a Del C allele . By contrast , smokers carrying the Del C allele had statistically significantly ( p=0.006 ) higher quit rates on NRT compared to those homozygous for the Ins C allele , independent of NRT type . The C957 T variant was also associated ( p=0.03 ) with abstinence following NRT . These results suggest that bupropion may be the preferred pharmacologic treatment for smokers homozygous for the DRD2 − 141 Ins C allele , while NRT may be more beneficial for those who carry the Del C allele . Study findings require confirmation in additional larger sample s before they are applied in practice We analyzed pooled data from two comparable r and omized placebo-controlled clinical trials of bupropion pharmacotherapy for smoking cessation for which data on DRD2 Taq1A genotype were available . A total of 722 smokers across the two trials were r and omized to 10 weeks of sustained-release bupropion hydrochloride or placebo . General estimating equation analysis demonstrated a significant gene x drug interaction ( B = 0.87 , SE = 0.34 , p = .009 ) . Smokers with the A2/A2 genotype using bupropion were more than three times as likely , relative to placebo , to be abstinent at end of treatment ( 35.2 % vs. 15.1 % ; OR = 3.25 , 95 % CI 2.00 - 5.28 ) and at 6 months of follow-up ( 26.7 % vs. 12.2 % ; OR = 2.81 , 95 % CI 1.66 - 4.77 ) , which was attenuated by 12 months ( 16.3 % vs. 10.7 % ; OR = 1.70 , 95 % CI 0.95 - 3.05 ) . We found no significant benefit of bupropion relative to placebo on smoking cessation outcomes at any time point in participants with A1/A1 or A1/A2 genotypes . These data suggest that bupropion may be effective for smoking cessation only in a subgroup of smokers with the DRD2 Taq1 A2/A2 genotype AIMS We investigated whether variants in the serotonin transporter gene ( SLC6A4 ) influence  smoking cessation rates  using antidepressant therapy ( i.e. bupropion and nortriptyline ) . DESIGN Pharmacogenetic ( secondary ) analysis of a r and omized , placebo-controlled efficacy trial of bupropion and nortriptyline for smoking cessation . SETTING Single-centre study , Maastricht University , the Netherl and s. PARTICIPANTS A total of 214 of 255 ( 84 % ) current daily smokers participating in a r and omized controlled efficacy trial . MEASUREMENTS Subjects were genotyped for three functional variants in SLC6A4 ( 5-HTTLPR , STin2 , rs25531 ) . Primary outcome measures were prolonged abstinence from weeks 4 - 12 , 4 - 26 and 4 - 52 . Secondary outcome measures included 7-day point prevalence abstinence at weeks 4 , 12 , 26 and 52 . FINDINGS Carriers of the 5-HTTLPR high-activity L-variant had higher prolonged cessation rates with bupropion than placebo [ odds ratio ( OR ) = 1.44 , 95 % confidence interval ( CI ) = 1.01 - 2.05 , P = 0.04 ] . Combining the three variants result ed in increased prolonged cessation rates for both bupropion and nortriptyline among carriers of four to five high-activity variants ( bupropion : OR = 2.00 , 95 % CI = 1.21 - 3.29 , P = 0.01 ; nortriptyline : OR = 1.91 , 95 % CI = 1.02 - 3.56 , P = 0.04 ) . Similar results were found for point prevalence abstinence . CONCLUSIONS Bupropion and nortriptyline seem to be more effective in smoking cessation among SLC6A4 high-activity variant carriers , probably by blocking the increased serotonin transporter activity , thereby increasing serotonin levels . Prospect i ve studies have to assess if this can improve cessation rates when treatment is targeted at individuals based on their genotypes BACKGROUND CYP2B6 is the primary enzyme involved in bupropion ( Zyban ; GlaxoSmithKline , Research Triangle Park , North Carolina ) metabolism . Genetic polymorphisms in CYP2B6 , such as CYP2B6 * 6 , can alter bupropion metabolism and may affect bupropion treatment outcome . METHODS Subjects participated in a smoking cessation clinical trial of bupropion versus placebo . The main outcome was a 7-day point prevalence abstinence rate measured 10 weeks after the start of treatment ( i.e. , end of treatment ) and at the 6-month follow-up ; secondary outcomes were severity of adverse effects , withdrawal , and urge to smoke . Subjects were haplotyped for the CYP2B6 * 6 variants . RESULTS Among smokers in the CYP2B6 * 6 group ( CYP2B6 * 1/*6 or CYP2B6 * 6/*6 genotype , n = 147 , 45 % of the population ) , bupropion produced significantly higher abstinence rates than placebo at the end of treatment ( 32.5 % vs. 14.3 % , p = .01 ) and at the 6-month follow-up ( 31.2 % vs. 12.9 % , p = .008 ) . In contrast ,  bupropion  was no more effective than placebo for smokers in the CYP2B6 * 1 group ( CYP2B6 * 1/*1 , n = 179 ) at the end of treatment ( 31.0 % vs. 31.6 % , p = .93 ) or at the 6-month follow-up ( 22.0 % vs. 21.5 % , p = .94 ) . There was a significant genotype by treatment interaction at the end of treatment ( odds ratio [ OR ] = 2.97 , confidence interval [ CI ] = 1.05 - 8.40 , p = .04 ) , which was similar at 6-month follow-up ( OR = 2.98 , CI = .98 - 9.06 , p = .05 ) . CONCLUSIONS These data suggest that smokers with the CYP2B6 * 6 genotype have a higher liability to relapse on placebo and that they may be good c and i date s for bupropion treatment for smoking cessation The ability to quit smoking is heritable , yet few genetic studies have investigated prospect i ve smoking cessation . We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation . The genotyping panel included 169 single-nucleotide polymorphisms ( SNPs ) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system . The primary outcome was smoking cessation ( biochemically confirmed ) at the end of treatment . SNPs clustered in the choline acetyltransferase ( ChAT ) gene were individually identified as nominally significant , and a 5-SNP haplotype ( block 6 ) in ChAT was found to be significantly associated with quitting success . Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort . To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort , we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry . Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence . Although the effect sizes in both cohorts are modest , converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking . Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation In this follow-up of a r and omized placebo-controlled clinical trial of nicotine replacement transdermal patch for smoking cessation , 741 smokers of European ancestry who were r and omized to receive active patch or placebo patch  were genotyped for the serotonin transporter gene-linked polymorphic region . The study setting was a primary care research network in Oxfordshire , United Kingdom . The primary outcome measures were biochemically verified sustained abstinence from cigarette smoking at end of treatment and 24-week follow-up . The main effect of genotype was not associated with sustained abstinence from smoking at either end of treatment ( SL : p=.33 ; SS : p=.81 ) or 24-week follow-up ( SL : p=.05 ; SS : p=.21 ) , and we found no evidence for a genotypextreatment interaction effect . In summary , despite the theoretically important contribution of serotonin neurotransmission to smoking cessation , the serotonin transporter gene was not associated with treatment response to nicotine patch for smoking cessation in this primary care-based trial
target: Results : We confirmed the importance of the 4 main factors influencing SC : ( 1 ) environmental factors , ( 2 ) genomic factors , ( 3 ) gene-environment interactions , and ( 4 ) evidence -based interventions .
  The model demonstrates the complex network of factors influencing SC .
background: Background : Smoking behaviour is a major public health problem worldwide .
  Several sources have confirmed the implication of genomic factors in smoking behaviour .
  These factors interact both with environmental factors and interventions to develop a certain behaviour .
  Objectives : Describing the environmental and genomic factors as well as the interventions influencing smoking cessation  ( SC ) and developing a working model incorporating the different factors influencing SC were our main objectives .