Treatment for tobacco dependence: a potential application for stratified medicine? more

Review For reprint orders, please contact: reprints@futuremedicine.com Treatment for tobacco dependence: a potential application for stratified medicine? Tobacco addiction is a leading preventable cause of death worldwide and places a heavy social and financial burden on society. Therefore, ways of helping people to overcome nicotine dependence are a key element of strategies aimed at improving public health. Current treatments are only partially effective and there is a need to develop more efficient approaches to help smokers to stop. There exists a substantial genetic variability in smoking behavior and the likelihood of cessation – tailoring treatment according to an individual’s genetic profile is now technologically feasible and could lead to more successful cessation attempts. Here we review studies of the genetic effects on smoking cessation in randomized controlled trials of pharmacological therapy and discuss the potential value of a personalized approach to help people stop smoking. KEYWORDS: addiction n GWAS n nicotine n personalized medicine n pharmacogenetics n stratified medicine n tobacco There are currently over 1.4 billion smokers worldwide and this figure is expected to rise to 1.9 billion in 2025 [1–4] . Consequently the current annual global death toll from smoking is 5 million and if current trends persist, tobacco will be responsible for 8 million deaths a year by 2025 [5] . Thus, improvements in methods to combat nicotine dependence and alleviate the disease burden placed on society by tobacco are of major social and economic benefit. Smoking is the leading preventable cause of cardiovascular disease and cancer globally [5] . However, stopping smoking even in middle age is remarkably effective in reducing the risk of illness and death. Thus, whilst persistent smoking triples the risk of death in each decade of life, stopping smoking at age 50 years halves the risk, and a smoker who stops at age 30 years has the same life expectancy as someone who had never smoked [6] . There are currently three smoking cessation treatments commonly available: nicotine replacement therapy (NRT), bupropion and varenicline. NRT acts by replacing the blood nicotine levels normally achieved through smoking, which reduces cravings for tobacco and alleviates nicotine withdrawal symptoms. Bupropion is an antidepressant drug that inhibits reuptake of dopamine and norephinephrine, which are neurotransmitters involved in the brain. Varenicline is a partial nicotinic acetylcholine receptor (nAChR) agonist, which binds to nicotine receptors causing submaximal stimulation that eases withdrawal symptoms [7] . Varenicline 10.2217/PME.11.60 © 2011 Future Medicine Ltd may also block the stimulant effects of inhaled nicotine, thus blunting the pleasure derived from tobacco use. Nicotine from tobacco is rapidly absorbed through the lungs and buccal mucosa and then transported to the brain through the bloodstream. Nicotine crosses the blood–brain barrier triggering dopamine release in the nucleus accumbens, which is believed to be responsible for perception of the pleasurable effects of smoking. Bupropion and some other antidepressants may reduce the desire for nicotine by relieving a ‘dopamine-deficient state’ [8] . Without the aid of cessation treatments, the quit rate for smokers is approximately 10% at 1 month. If the smoker uses NRT, the most commonly used form of pharmacological treatment, quit rates of 53% at 4 weeks may be achieved, although this falls to only 15% at 1 year [9] . The long-term efficacy of bupropion is similar to NRT, with insufficient evidence to support the effectiveness of one treatment over the other [10] . Varenicline may be more effective than nicotine and bupropion, doubling quit rates at 12 months when compared with a placebo [7] . With the best possible quit rate using any cessation aid being in the region of 20% at 1 year, it is clear that there is both an opportunity and a pressing need to improve treatment for tobacco dependence. There exisits a high degree of genetic variability that contributes to individual differences in smoking behavior [11–16] . Since pharmacological treatments act on the same neurotransmitter pathways activated by nicotine, it is not surprising Personalized Medicine (2011) 8(5), 571–579 Alistair J Brock1,2, Andrea Takeda2, Caroline Brennan1 & Robert T Walton†2 School of Biological & Chemical Sciences, Queen Mary, University of London, UK 2 Centre for Primary Care & Public Health, Barts & the London Medical School, Blizard Institute, Queen Mary, University of London, UK † Author for correspondence: r.walton@qmul.ac.uk 1 ISSN 1741-0541 571 Review Brock, Takeda, Brennan & Walton that there is also a degree of genetic variability in how individuals respond to different pharmacological therapies. The same genes that predispose to nicotine addiction may also be involved in moderating the response to treatment. One possible approach to improving cessation rates could be to target treatment to specific subgroups of smokers. Individuals could be typed at an array of genetic loci related to these differing smoking behaviors and personalized treatments could be administered accordingly. This approach might stratify smokers into different groups according to fundamental biological mechanisms underlying the addictive process. A nosological advance of this kind could lead to the more effective use of therapies, reducing side effects and treatment costs while at the same time increasing cessation rates. people metabolize thiopurine drugs at a reduced rate [18] . This impaired metabolism causes build up of the drug and can lead to bone marrow toxicity. In fact approximately 5% of thiopurine therapies will prove dangerously toxic to the patient because of the individual’s impaired ability to metabolize the drug [19] . Patients are therefore typed for their TPMT activity before being given a course of treatment. Because of the diversity of genetic polymorphisms affecting enzymatic activity, biochemical rather than genetic methods of ascertaining the phenotype are usually used. n Anticoagulation Warfarin acts on the liver to reduce the production of key proteins responsible for blood clotting and is thus effective in preventing thrombosis and embolism [20] . Activity needs to be constantly monitored clinically through blood testing to ensure an adequate amount is used and to avoid overdose [21] . Polymorphisms in VKORC1, which explain 30% of dose variation between patients – and CYP2C9, which explain 10% of dose variation – are particularly important determinants of dose requirements [22–25] . Therefore, a stratified approach to warfarin dose, based on genetic variation at the VKORC1 and CYP2C9 loci, has been suggested as a possible way of improving dosage accuracy and reducing the occurrence of unwanted effects. Examples of stratified medicines The basis of stratified medicine is to identity genetic subgroups within a disease population that have differential responses to treatments. There have been numerous advances in this field, particularly in cancer treatment, although not all potential applications of personalized medicine have been widely adopted. n Breast cancer Herceptin (trastuzamab) is a monoclonal antibody that interferes with the HER2 receptor protein. HER2 receptor proteins are embedded in cell membranes and regulate vital cellular functions such as growth, differentiation, adhesion and migration. In some types of breast cancer, HER2 is overexpressed causing over-proliferation of the breast-tissue cells [17] . Herceptin binds to this protein and inhibits this uncontrolled cell growth. This makes herceptin effective only in cancers in which HER2 is overexpressed, and when it is administered to patients who do not exhibit this overexpression, the antibody can cause adverse effects. Routine clinical laboratory tests can identify patients with HER2-positive breast cancers who are likely to respond positively to treatment. n Hematological malignancy Thiopurine methyltransferase (TPMT) is an enzyme responsible for methylating thiopurine compounds. Thiopurine drugs, including 6-mercaptopurine, 6-thioguanine and azathioprine, are widely used in autoimmune disorders, organ transplant recipients and leukemia treatment. Genetic polymorphisms affect the enzymatic activity of TPMT and as a result, some 572 Personalized Medicine (2011) 8(5) Stratification of smokers using markers to identify specific subgroups Diagnostic classification techniques such as those used for HER2 and TPMT could potentially be applied in smokers to identify subgroups based on variation at key genetic loci in order to predict the best course of therapy to aid cessation. Several genes involved in nicotine-related pathways have been identified in recent genomewide association studies (GWAS) and are summarized in Table 1. The main genes implicated in these scans are those in the cholinergic receptor gene clusters, which affect the level of tobacco consumption, although the size of the effect is relatively small. A more detailed examination of these clusters has led to the identification of specific independent loci, which are responsible for these associations [26,27] , and haplotypes associated with the effects in Europeans [28] . Further research has demonstrated that markers in acetylcholine synthetic pathways may also contribute to nicotine dependence [29] . future science group Treatment for tobacco dependence: a potential application for stratified medicine? Review Table 1. Summary of recent genome-wide association studies. Gene Locus OxGSK [63] TAG [67] Thorgiersson et al. [64] Liu et al. [68] Caporaso et al. [69] rs4956302 p = 10 -6 rs6474412 p = 10 -8 rs3733829 p = 10 -8 rs1329650 p = 10 -10 rs1028936 p = 10 -9 rs55853698 p = 10 -16 rs6495308 p = 10 -5 rs12914385 p = 10 -4 rs1051730 p = 10 -4 rs4105144 p = 10 -12 rs2235186 p = 10 -5 rs6265 p = 10 -8 rs76905 p = 10 -7 rs13408379 p = 10 -7 rs3025343 p = 10 -8 rs4105144 p = 10 -3 Rs3025343 p = 10 -2 rs1051730 p = 10 -16 Thorgiersson et al. [70] Siedlinski et al. [71] Level of tobacco consumption IL15 CHRNA6 EGLN2 ? 4q31 8p11 9q13 10q25 CHRNA3/ 15q25 A5/B4 rs1051730 p = 10 -73 CYP2A6/ 19q13.2 B6 MAOA Xp11.3 Smoking initiation BDNF HLA ? 11p14.1 6p21 2q21.3 rs1051730 p = 10 -4 rs12461383 p = 10 -3 Smoking cessation DBH 9q34.2 CYP2A6/ 19q13.2 B6 Strongest associations are between level of tobacco consumption and markers in the cholinergic receptor gene cluster on chromosome 15. Replicated associations are also observed between the CYP450 gene that metabolizes nicotine and numbers of cigarettes smoked each day and also the dopamine-b hydroxylase gene and quitting. The lowest p-values have been highlighted in bold. OxGSK: Collaboration between Oxford and GlaxoSmithKline; TAG: The Tobacco and Genetics Consortium. One gene involved in dopamine metabolism and noradrenalin synthesis (dopamine-b hydroxylase) has been linked to spontaneous cessation in GWAS studies and interestingly this gene has also demonstrated effects on response to treatment with NRT in one randomized controlled trial [30,31] . Owing to the requirement for large numbers in GWAS, only genes involved in nicotine dependence have been identified in studies to date. Thus, this technique has not been applied to date to identify genetic determinants of response to treatment. In general, randomized trials of smoking cessation have fewer than 1000 future science group participants, half of whom will receive a placebo therefore, these trials provide insufficient numbers of participants for genome-wide analysis. As a consequence, conventional candidate gene studies undertaken within smoking cessation trials currently provide the best available evidence for pharmacogenetic effects on smoking cessation. Nicotine metabolism (CYP2A6) CYP2A6 is a member of the cytochrome P450 enzyme system and is involved in the metabolism of nicotine, oxidizing it to its inactive metabolite cotinine [32] . Furthermore, the breakdown of cotinine to trans-3´-hydroxycotinine www.futuremedicine.com 573 Review Brock, Takeda, Brennan & Walton is also mediated by CYP2A6 [33] . As a result, an individual’s ratio of blood cotinine and trans-3´-hydroxycotinine levels can be used as a simple biochemical indicator of their CYP2A6 status [33] . CYP2A6 is genetically polymorphic with certain alleles predicting altered metabolic activity [34] . CYP2A6*2, *4, *9 and *12 are common alleles conferring reduced enzymatic activity in Europeans [35] . As the primary enzyme for nicotine metabolism, variation in the metabolic activity of CYP2A6 has a significant effect on an individual’s level of tobacco consumption [34] . The reduced metabolism phenotype leads to higher blood/nicotine levels and smokers tend to compensate for this by smoking less [36] . Conversely, individuals with increased metabolic rate tend to smoke more [16,37] . Lower nicotine metabolism with CYP2A6 variants also has an effect on smoking cessation, with slow metabolizers demonstrating higher levels of cessation in transdermal nicotine therapy trials [38,39] . This may be owing to the higher therapeutic doses of nicotine that the slow metabolizer sub-group obtain from comparable levels of transdermal nicotine treatment [40] . Normal metabolizers have lower cessation rates probably as a result of current treatments failing to provide high enough levels of replacement blood nicotine [41] . These normal metabolizers may be candidates for higher-dose nicotine replacement, which might potentially give rise to adverse effects in those with impaired nicotine metabolism. Individuals could easily be typed for CYP2A6 status using either genetic tests or biochemical assays and a suitable dose of NRT could be given accordingly. CYP2B6 metabolizes nicotine to cotinine in the same way as CYP2A6, but at a much lower rate. This enzyme also metabolizes the antidepressant bupropion. Studies have examined the effect of CYP2B6 variants on smoking cessation but have found no influence on quit rates with NRT, although abstinence rates in bupropion trials were improved in those with the *6 allele [42,43] . receptors (nAChRs) thereby increasing dopamine levels in the nucleus accumbens and generating the sense of ‘wellbeing’ experienced by smokers [44] . As a result, variants in genes involved in the dopaminergic pathway may have effects on smoking behavior and response to treatment. n Dopamine receptors There are five known subtypes of dopamine receptors: DRD1, DRD5 (members of the DRD1-like family) and the DRD2, DRD3 and DRD4 receptors (D2-like family). Polymorphisms affecting the dopamine D2 receptor (DRD2) gene have been most studied in tobacco dependence and may have an effect on smoking behavior and response to treatment. Polymorphisms in DRD2 may confer reduced dopamine-receptor expression or function, and some studies have demonstrated that individuals with this genotype may have a higher chance of becoming addicted to nicotine [45] . There are two main DRD2 polymorphisms which have been extensively studied for their effect on smoking cessation treatments: Taq1A and -141C ins/del. The DRD2 Taq1A polymorphism is located approximately 10 kb downstream of the DRD2 coding sequence in the closely linked ankyrin repeat and kinase domain containing the ANKK1 gene [46] . Carriers of the A1 allele have a higher quit rate on NRT [30,47] . Those homozygous for the A2 genotype demonstrate greater response to bupropion treatment and display fewer of the withdrawal symptoms normally associated with the drug [48,49] . The -141C ins/del variant affects transcription of the DRD2 gene. Individuals with at least one copy of delC have a better response to NRT than those without, and those with the InsC allele respond more favorably to bupropion [50] . A study investigating the effects of variants in DRD4 on NRT has also been conducted. The variants were variable number nontandem repeats (VNTRs) which confer lower receptor activity in those with the long allele, and also a -521C/T polymorphism which confers lower transcription levels in those with the T allele. Alleles at the DRD4 locus had no effect on cessation in NRT trials [45,51] . Typing people for ANKK1/DRD2 markers could therefore potentially lead to more effective bupropion treatment, and minimize the occurrence of side effects. The benefits of using DRD2 gene variants to guide selection of nicotine replacement or bupropion therapy have not yet been examined in prospective trials. future science group Dopaminergic genes The mesolimbic pathway in the brain transmits dopamine from the ventral tegmental area to the nucleus accumbens. Since the mesolimbic pathway is associated with feelings of reward and pleasure, this pathway is heavily implicated in most neurobiological theories of addiction [8] . Nicotine activates the dopamine reward pathway through nicotinic acetylcholine 574 Personalized Medicine (2011) 8(5) Treatment for tobacco dependence: a potential application for stratified medicine? Review n Dopamine metabolism & synthesis Variants in genes involved in dopamine synthesis also have an effect on response to drug therapy in smoking cessation. A polymorphism (1368A/G) in the promoter region of the dopamine-b hydroxylase (DBH) gene which confers lower enzyme activity and is more frequent in heavy smokers [52] . In one NRT trial, individuals carrying at least one A allele demonstrated significantly higher quit rates [30] . Catechol-O-methyltransferase (COMT) is responsible for degrading dopamine. A functional valine to methionine mutation at position 158 (Val158Met) leads to a reduction in enzymatic activity [53] . Individuals homozygous at this locus have an increased likelihood of abstinence in NRT trials [54,55] . The same Val158Met polymorphism has been demonstrated not to influence the efficacy of bupropion treatment [56] . However, the same study identified two additional COMT polymorphisms (rs165599 and rs737865), which demonstrated a significant associations with abstinence [56] . patches [54,59] . Another study has investigated two further genes involved in the opioid pathway, the MOR-interacting proteins b-arrestin 2 (ARBB2) and histidine triad nucleotide binding protein 1 (HINT1). However at the end of NRT treatment, neither HINT1 nor ARRB2 were found to be significantly associated with abstinence [60] . n Nicotinic acetylcholine receptors Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels of which nicotine is an agonist [61] . Neuronal subtypes of nicotinic receptors consist of subunits ranging from a2–a10 and b2–b4. Since nicotine is an agonist for these receptors, which in turn modulate mesolimbic dopamine function, these receptors act as one of the primary mechanisms underlying the development of nicotine dependence [62] . Several genome scans indicate that genetic variations in these receptors may influence nicotine dependence [31,63,64] . As yet however, only one study has examined two polymorphisms in the a4 subunit coded by the CHRNA4 gene and their effect on abstinence with NRT [65] . Individuals with a polymorphism which affected mRNA stability were more likely to maintain abstinence on NRT nasal spray but not with the transdermal nicotine patch [65] . Other genes affecting smoking cessation n Serotonin & opioid neurotransmitter pathways In addition to dopamine, nicotine also causes both serotonin and opioid peptide release as a consequence of stimulating cholinergic receptors. Many symptoms of nicotine withdrawal can be associated with reduced serotonergic neurotransmission [45] . It therefore appears possible that variation in genes involved in the serotonin pathway could influence individual response to smoking cessation treatment. So far studies have centered on one variant in the serotonin transporter gene (5-HTT ) and examined its effect on abstinence in NRT trials. The 5-HTTLPR variant regulates transcription of the serotonin transporter with the short form conferring higher transcriptional activity [57] . As a result, this might be expected to govern the availability of serotonin released by nicotine [45] . A recent study has demonstrtaed individuals with the high-activity variant are more likely to quit in a bupropion trial [58] . Nicotine triggers the release of b-endorphin, which targets the µ-opioid receptor (MOR), evoking feelings of pleasure. The Asp40 variant of OPRM1 confers increased activity owing to an increased binding affinity for b-endorphin. Studies have demonstrated an association between the Asp40 genotype and increased quit rates when using transdermal nicotine future science group Conclusion Whilst there is existing evidence that polymorphisms at various loci affect smoking behavior and response to therapies, large-scale prospective studies with treatment allocation according to genotype are yet to be conducted. Such studies will be necessary to examine the effectiveness of this approach and to gather conclusive data on economic outcomes. The key to improving cessation rates using stratified medicine most likely lies in typing individuals for a variety of markers and thus identifying a specific course of treatment or the most appropriate dose. Genetic or biochemical markers of nicotine metabolism would seem the most promising candidates for further research at present, with the aim of achieving a more accurate dose of nicotine replacement at the time of the cessation attempt. It is surprising that nicotinic receptor genes have not been studied more in randomized controlled trials of NRT, and this could be a fruitful area for future research. Ideally such studies should be conducted on a large scale which would require the pooling together of resources from several different trials of smoking cessation pharmacotherapies. www.futuremedicine.com 575 Review Brock, Takeda, Brennan & Walton Future perspective Previous studies have demonstrated a significant genetic contribution to susceptibility to nicotine dependence and have identified a number of alleles that could be used to stratify smokers according to the underlying mechanism for their addiction. However, currently identified individual genes only explain a very small proportion of variation in smoking behavior. In one study for example the A5/A3/B4 gene cluster only explained 1% variation in reported levels of tobacco consumption [64] , although another study relating variation in the same gene cluster to cotinine levels demonstrated a much stronger association [66] . The use of more refined phenotypes to classify smokers more accurately may provide better answers and unearth more genotypic variants in future GWAS studies. n Possible clinical use of biomarkers in pharmacotherapies There are two distinct ways of employing stratified medicine techniques to improve clinical treatment of those seeking to give up use of tobacco (Figure 1) . First smokers could be typed for a number of genetic loci and these could then be used to select the most effective treatment with fewest side effects (Figure 1a) . Whilst this is potentially attractive and there are suggestions from previous studies that existing markers could be used to identify those likely to quit with bupropion and with nicotine replacement, it seems likely that additional markers would be needed to improve the predictive value of current tests. From the limited number of studies available, it would appear that biomarkers predicting success with nicotine replacement will predict failure with bupropion and vice versa. This effect could be linked to the opposite modes of action of the two drugs, and if this is the case, markers discovered in the future may also fall into the same two mutually exclusive categories. While this would be convenient for the development of personalized medicine there is no guarantee that this will be the case and the situation will become complicated as more drugs with different mechanisms of action enter the market. As yet, there are no genetic studies of varenicline, which is becoming increasingly used in smoking cessation clinics. The alternative approach would be to use genotype to guide appropriate dosing of treatment (Figure 1b) . Since the effects of cytochromes on nicotine metabolism are well studied, this could be most easily achieved with NRT. Currently there is relatively little data available on the genetic effects on pharmacokinetics of bupropion and varenicline. In the case of nicotine metabolism, biochemical markers (such as cotinine and trans3´-hydroxycotinine metabolite ratio) could be used to identify smokers with differing rates of nicotine metabolism, so that an appropriate dose of drug could be used. This would be similar in principle to the way biochemical markers are used to assess TPMT activity when prescribing thiopurine drugs. This may lead to more accurate stratification when compared with current genetic technologies. Diagnostic techniques are being developed which will run both genetic and biochemical tests side by side, quickly and accurately at the point-of-care, which could combine the benefits of both approaches in a clinically appropriate setting. n Future research in personalized treatment for smoking cessation There is a need for larger prospective trials to be undertaken which have more power to detect genetic effects on response to treatment and to examine interactions between genes. Such studies will be difficult to fund as sample sizes need to be at least an order of magnitude greater than those necessary to test the efficacy of a particular drug. Therefore, pharmaceutical companies are unlikely to fund such studies and the diagnostic industry in its infancy will struggle to secure the necessary financial backing. Public funding seems the most likely way forward, although the sums involved will be large. One way of mitigating the costs would be for researchers with existing sample repositories from randomized trials to form consortia for studies on pharmacogenetic effects. This future science group Varenicline Genotype NRT Bupropion Varenicline Genotype Dosage adjustment NRT Bupropion Figure 1. Schematic of two possible methods for determining personalized treatment. (A) A diagnostic test is performed that guides treatment selection; (B) Markers of metabolic rate for the drug are used to inform dose level and treatment regimen. NRT: Nicotine replacement therapy. 576 Personalized Medicine (2011) 8(5) Treatment for tobacco dependence: a potential application for stratified medicine? Review might allow for a more detailed examination of the effects of candidate genes on cessation outcomes, for example those in the cholinergic receptor clusters, and enable the use of genome-wide association techniques to identify novel targets. Financial & competing interests disclosure Alistair J Brock is funded by the Medical Research Council on a CASE PhD studentship. Robert T Walton has performed consultancy work for diagnostics companies (Third Wave Technologies, Sciona and g-Nostics) and holds shares in TTS Ltd, a company making nicotine replacement patches. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Executive summary Examples of stratified medicines ƒ A stratified approach to treatment is gaining ground in the management of particular diseases. Examples include breast cancer (HER2) and hematological malignancy (TPMT). ƒ There is a high degree of genetic variability in smoking behavior between individuals, which may predict response to pharmacotherapy; thus, a stratified approach to treatment may also be possible for tobacco dependence. Nicotine metabolism (CYP2A6) ƒ CYP2A6 is the enzyme responsible for metabolizing nicotine into cotinine. Variation at the CYP2A6 genetic locus affects enzymatic activity and therefore blood nicotine levels. ƒ Individuals could be typed for CYP2A6 status and given an appropriate dose of nicotine replacement (e.g., nicotine patch, chewing gum or lozenge) to achieve more accurate levels of replacement at the time of attempted quitting. Dopaminergic genes ƒ Genetic analyses in randomized controlled trials tend to suggest that smokers with the DRD2 Taq1A1 allele (ANKK1) respond to nicotine replacement therapy and the DRD2 Taq1A2 to bupropion. ƒ The DRD2 -141C ins/del variant results in lower transcription of the DRD2 gene with the DelC allele. Individuals with at least one copy of delC may have a better response to nicotine replacement therapy than those without. Conclusion & future perspective ƒ It seems unlikely that the full repetoire of genes affecting the pharmacodynamic actions of nicotine have been identified. ƒ Genome-wide association studies demonstrate significant effects from the acetylcholine nicotinic receptor genes on smoking behavior and these genes should be investigated further for effects on response to treatment. ƒ Much larger studies than are currently feasible are required to apply genome-wide association study techniques to study effects on cessation. Sufficient power for these studies to examine candidate genes in complex regions such as the nicotinic receptor gene clusters could be achieved by a consortium approach to maximize the use of existing genetic material. ƒ There is a need for prospective studies in which smokers are allocated to treatments according to results of biomarker analyses. ƒ The most promising markers are those indicating nicotine metabolic rate. Either genetic or biochemical indicators could be used to allocate the most appropriate nicotine replacement dose. Bibliography Papers of special note have been highlighted as: n of interest 1 development of an evidence based global public health treaty. BMJ 327(7407), 154–157 (2003). 5 8 Curbing the epidemic: governments and the economics of tobacco control. The World Bank. Tob. Control 8(2), 196–201 (1999). Steptoe A, Wardle J, Cui W et al. An international comparison of tobacco smoking, beliefs and risk awareness in university students from 23 countries. 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