Marieke Quaak

Genetic variation as a predictor of smoking cessation success. A promising preventive and intervention tool for chronic respiratory diseases

Tobacco smoking continues to be the largest preventable cause of premature morbidity and mortality throughout the world, including chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease. Although most smokers are highly motivated to quit and many smoking cessation therapies are available, cessation rates remain very low. Recent research strongly suggests that variation in genetic background is an important determinant of smoking behaviour and addiction. Since these genetic variants might also influence the response to smoking cessation pharmacotherapies, it is likely that assessment of genetic background could be a promising tool to guide selection of the most effective cessation treatment for an individual smoker. Recently, it has been shown that genetic variants in the dopaminergic system, opioid receptors, the bupropion-metabolising enzyme CYP2B6 and the nicotine-metabolising enzyme CYP2A6 may play an important role in predicting smoking cessation responses to nicotine replacement therapy and bupropion treatment. Despite the progress that has been made, several challenges will still have to be overcome before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.

Effectiveness of testing for genetic susceptibility to smoking-related diseases on smoking cessation outcomes: a systematic review and meta-analysis

Objective To examine whether genetic testing for smoking-related diseases benefits smoking cessation. Data sources PubMed, EMBASE, ERIC, PsycINFO, PsychArticles, CiNAHL and socINDEX databases, the search engine Google Scholar, and key-author and reference list searches. Study selection Randomised controlled smoking cessation interventions using genetic testing for smoking-related diseases. Data extraction Consistent with the Cochrane guidelines, two reviewers completed the review process (initial n=139) in three phases, title selection (n=56), abstract selection (n=28) and whole paper selection (n=9). From these nine studies, each reviewer extracted information about outcome measures and statistical and methodological quality. Data synthesis Relevant data were abstracted from included papers and were subsequently subjected to meta-analysis. Results Interest in genetic testing was relatively high with 60-80% of smokers reporting to be interested. The authors observed positive short-term effects on risk perception, motivation to quit smoking and smoking cessation, but these effects fade at longer follow-ups. Importantly, the authors did not find any evidence of adverse effect of testing negative on the risk-predisposing gene. Conclusions This systematic review does not provide solid evidence for the proposed beneficial effects of genetic testing for smoking-related diseases on smoking cessation, but does suggest the presence of an immediate motivational effect, such that genetic testing resulted in higher risk perception and more motivation to quit smoking.

Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation

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 randomized, placebo-controlled efficacy trial of bupropion and nortriptyline for smoking cessation. SETTING Single-centre study, Maastricht University, the Netherlands. PARTICIPANTS A total of 214 of 255 (84%) current daily smokers participating in a randomized 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 resulted 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. Prospective studies have to assess if this can improve cessation rates when treatment is targeted at individuals based on their genotypes.

Implications of gene-drug interactions in smoking cessation for improving the prevention of chronic degenerative diseases.

Tobacco smoking continues to be the major preventable cause of premature morbidity and mortality throughout the world. Recent research strongly suggests that genetic background is associated with several aspects of smoking (e.g. initiation, maintenance, cessation, number of cigarettes smoked, indicators of nicotine dependence (ND) and nicotine withdrawal). Variations in two broad classes of genes have been shown to influence smoking: (1) genes that may influence the response to nicotine (e.g. nicotine metabolism, nicotinic receptors) and (2) genes that may predispose to addictive behaviour via their effects on key neurotransmitter pathways (e.g. dopamine, serotonin and opioid). Since these genetic variants might also influence the response to smoking cessation pharmacotherapies, smoking cessation rates might be increased by determining which treatment would be most effective based on the smokers genetic background. This is expected to result in a more efficient use of smoking cessation therapies, increased cessation rates and ultimately, in reduced deaths from smoking. Until now, most research on the influence of genetic variation on smoking cessation pharmacotherapy has been directed to the two most widely accepted and licensed forms of smoking cessation therapy: nicotine replacement therapy (NRT) and the antidepressant bupropion. Overall, genotypes associated with increased dopamine availability seem to predict a better response to bupropion, while smokers with genotypes associated with reduced dopamine levels probably achieve better quit rates with NRT. A decreased metabolism for the drug used (e.g. bupropion or NRT), results in increased cessation rates as well. Furthermore, smokers with reduced dopaminergic and nicotinic receptor activity variants may experience greater benefit from nicotine spray, while smokers with increased activity variants in the opioid receptor may have greater success with transdermal patches. Thus it seems that genetic information may give directions in determining which treatment would be most effective for an individual smoker. However, several challenges will still have to be overcome before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.

Integrative genomic analysis identifies a role for intercellular adhesion molecule 1 in childhood asthma

Childhood asthma is characterized by chronic airway inflammation. Integrative genomic analysis of airway inflammation on genetic and protein level may help to unravel mechanisms of childhood asthma. We aimed to employ an integrative genomic approach investigating inflammation markers on DNA, mRNA, and protein level at preschool age in relationship to asthma development.

Are smokers interested in genetic testing for smoking addiction? A socio-cognitive approach

Genetic advances have made genetically tailored smoking cessation treatments possible. In this study, we examined whether smokers are interested in undergoing a genetic test to identify their genetic susceptibility to nicotine addiction. In addition, we aimed to identify socio-cognitive determinants of smokers’ intention to undergo genetic testing. Following the protection motivation theory (PMT), we assessed the following constructs using an online survey among 587 smokers: threat appraisal (i.e. susceptibility and severity), fear, coping appraisal (i.e. response efficacy and self-efficacy), response costs and intention. In addition, knowledge, social norms and information-seeking behaviour were measured. Mean intention rates were 2.57 on a 5-point scale. Intention was significantly associated with threat appraisal and coping appraisal, as predicted by the PMT. Fear of the outcome was negatively associated with the intention to undergo genetic testing, but response costs, knowledge and social influence were not. Intention to undergo genetic testing in turn was positively related to seeking information about genetic testing and genetically tailored smoking cessation treatments. Smokers seem ambivalent or ‘on the fence’ with regard to undergoing a genetic test for smoking addiction. Socio-cognitive concepts such as susceptibility, severity, response efficacy and self-efficacy may be used to inform or educate smokers about the value of genetically tailored smoking cessation treatments.

CD14/Toll-like receptors interact with bacteria and regulatory T-cells in the development of childhood asthma

To the Editor: The susceptibility to asthma development in childhood is influenced by genetic as well as environmental factors, and interactions between these factors [1–3]. However, at present, their exact role is still largely undetermined. Genetic variations in the innate immune system may lead to different adaptive immune responses to bacteria and may therefore vary the development of asthma [2, 4, 5]. We performed a prospective longitudinal study in preschool children, in which we determined polymorphisms in Toll-like receptors ( TLR s) and CD14 , the presence of bacteria, and the proportion of regulatory T-cells (Treg) all in relation to an asthma diagnosis at 6 years of age. We hypothesise that specific genetic variants in genes that affect the innate immune system influence the response to bacteria and the recruitment of Treg in preschool children, leading to an increased likelihood of asthma at 6 years of age. The Asthma DEtection and Monitoring (ADEM) study is a long-term prospective case–control study. A detailed protocol of this study has previously been published [6]. A total of 202 children who had experienced at least two wheezing episodes during their lifetime (International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire) [7] and 50 children without wheezing episodes were included at 2–4 years of age. The children were randomly selected from a random population sample in Limburg, the Netherlands, based on the presence or absence of recurrent wheeze [6]. During the initial visit, saliva or buccal cells (DNA), nasal and throat swabs (bacterial cultures), and blood (Treg) were collected. Participants were genotyped for six single nucleotide polymorphisms in TLR2 , TLR4 , TLR9 and CD14 (Sequenom …

Assessment of genetic variation as a predictor of smoking cessation succes: A review

of pharmacotherapy, especially when they have a different mechanism-ofaction. Conclusion Much progress has been made in unravelling the effects of genetic variants on smoking behaviour and smoking cessation treatment, but much research still remains to be done and prospective trials should be set up to fully confirm the effect of the variants before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.

Pharmacogenetics of smoking: how far to the clinic?

723 ISSN 1462-2416 10.2217/PGS.14.34