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Pharmacogenetics and nicotine addiction treatment
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for correspondence of Bristol, Department of Experimental Psychology, 8 Woodland Road, Bristol, BS8 ITN, UK Tel.: +44 117 9546841 Fax: +44 117 9288588 E-mail: marcus.munafo @bris.ac.uk 2Georgetown University, Health Policy Institute, Georgetown Public Policy Institute, 2233 Wisconsin Ave, NW, Suite 525, Washington DC 20007, USA 3University of Pennsylvania, Department of Psychiatry, Center for Neurobiology and Behavior, Room 111 Clinical Research Building, 415 Curie Bvd, PA 19104, USA 4University of Pennsylvania, Transdisciplinary Tobacco Use Research Center, Abramson Cancer Center, 3535 Market St, Suite 4100, PA 19104, USA
Cigarette smoking is the leading preventable cause of death worldwide, accounting for at least 30% of all cancer deaths and over three-quarters (87%) of lung cancer deaths in developed countries [1]. It is also an important risk factor for cardiovascular disease and pulmonary disease [2], and, therefore, represents a substantial economic and social burden. Despite almost two decades of intensive tobacco control efforts, and widespread knowledge of the health harms of tobacco use, a large proportion of men and women in developed countries continue to smoke [3]. Furthermore, tobacco use in developing countries is continuing to rise [3]. Clearly, to reduce tobacco-related morbidity and mortality, initiatives to both reduce smoking initiation and promote smoking cessation are required. This review focuses on the current status of, and future directions for, pharmacogenetic research on nicotine dependence and smoking cessation treatment. Following a brief overview of the current first-line pharmacological treatments for smoking cessation, the emerging and ongoing pharmacogenetic research that may provide insight into the causes of individual variation in response to smoking cessation pharmacotherapies will be reviewed. This is followed by a discussion of the strengths and limitations of pharmacogenetic investigations, including issues in study design, analysis, and interpretation. The paper concludes with the potential for such research to enable the future tailoring of a pharmacological treatment regimen to an individual’s genotype, and considers a range of policy and ethical concerns related to the clinical integration of such novel treatment approaches.
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This review focuses on the current status of, and future directions for, pharmacogenetic research on nicotine dependence and smoking cessation treatment. Pharmacological treatment involving nicotine replacement therapy and bupropion for nicotine addiction and smoking cessation has been shown to be efficacious when provided in combination with behavioral support. Cessation rates remain somewhat modest, however, and one possibility is that success rates may be enhanced by offering treatments tailored to an individual’s genotype. Nonetheless, research on this issue remains in its infancy, and although the scope for individualized treatment tailored to genotype is promising, there are substantial practical, ethical and social considerations that must be addressed before such research is translated into clinical practice.
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Marcus R Munafò1†, Alexandra E Shields2, Wade H Berrettini3, Freda Patterson4 & Caryn Lerman4
Keywords: bupropion, nicotine addiction, nicotine replacement therapy, smoking cessation
10.1517/14622416.6.3.xxx © 2005 Future Medicine Ltd ISSN 1462-2416
Brief overview of smoking cessation treatments Nicotine replacement therapy
Nicotine replacement therapies (NRTs), such as nicotine gum, patch, spray, inhaler and lozenge, are FDA-approved first-line pharmacological treatments for smoking cessation. Nicotine replacement provides the smoker with a potentially safer delivery mechanism for nicotine, with the goal of attenuating cravings and withdrawal symptoms [4] and, thereby, facilitating continued abstinence from smoking. A meta-analysis of 108 randomized clinical trials [5] that incorporated at least a 6-month follow-up assessment showed that participants using nicotine gum were over 1.5 times more likely to remain abstinent at 1-year follow up compared with those using placebo gum. Similarly, in a meta-analysis of 17 studies of the NRT patch [6], quit rates among active patch users were found to be more than twofold those for placebo patch users at the end of treatment and at 6-month follow up. Nicotine nasal spray has been documented in numerous randomized, controlled clinical trials to produce significantly higher abstinence rates than placebo spray [7–10]. However, aversive side effects, such as a burning sensation and watery eyes after spray use, have been reported to deter treatment adherence, particularly in the first week of a quit attempt [11]. To date, three randomized clinical trials have shown the nicotine inhaler to be more effective than placebo [12–14], and a relatively small body of literature has emerged documenting the efficacy of the new nicotine lozenge [15]. Thus, there is strong evidence that all forms of NRT are efficacious treatments for smoking cessation.
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dopaminergic regions in the human brain [31]. In addition, positron emission tomography (PET) studies have indicated that this allele is also associated with low receptor density [32,33]. Recent work shows that the Taq1A site is an amino-acidchanging single nucleotide polymorphism (SNP) in a previously undescribed protein kinase gene (ankyrin repeat and kinase domain containing 1 [ANKK1]) near the DRD2 locus [34]. The precise functional role of the Taq1A locus, however, still remains unknown. A common (although non-functional) polymorphism in the dopamine β-hydroxylase (DBH) gene was also examined, which codes for an enzyme involved in the conversion of dopamine to norepinephrine; lower levels of the DβH enzyme could result in higher levels of endogenous dopamine. The transdermal nicotine patch was found to be significantly more effective than placebo for carriers of the A1 allele of the DRD2 gene, but not those homozygous for the more common A2 allele [26]. The difference in odds ratios (ORs) for the treatment effect between the genotype groups was statistically significant after the first week of treatment, but not at the end of treatment. The patch was found to be highly effective (OR = 3.6, patch versus placebo effect on abstinence) among smokers with both the DRD2 A1 allele and the DBH A allele, and less effective for smokers with other genotypes (OR = 1.4). This genetic association with treatment response was significant both at 1 and 12 weeks of treatment, suggesting that the short-term efficacy of the transdermal nicotine patch may be modulated by DRD2 and DBH. A longer-term follow up of the same study sample supported the association of the DRD2 variant with abstinence at 6- and 12-month follow up, although this effect was observed only among women and the results for DBH were not reported [27]. This finding suggests that the efficacy of pharmacotherapy may be influenced by different genetic and biological factors in males and females. The second pharmacogenetic study of NRT was an open-label trial of transdermal nicotine versus nicotine nasal spray. This study examined the role of the µ-opioid receptor (OPRM1) gene [35]. The µ-opioid receptor is the primary site of action for the rewarding effects of the endogenous opioid peptide β-endorphin [77], which is released following acute and short-term nicotine administration [36,37]. Exon 1 of OPRM1 includes a common Asn40Asp (A118G) missense SNP. The Asp40 variant increases the binding affinity of β-endorphin for this receptor by
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The only other treatment approach currently approved by the FDA as a first-line treatment is bupropion, an atypical antidepressant medication approved in 1997 as the first non-nicotine pharmacological treatment for smoking cessation. Although bupropion’s precise mode of action is not yet fully understood, there is some evidence to suggest that it inhibits postsynaptic uptake of dopamine and norepinephrine [16–18], and may be a neuronal nicotinic receptor antagonist [19]. Sustained-release (SR) bupropion has emerged as an efficacious form of treatment for smoking cessation, outperforming both placebo [20,21] and, less consistently, transdermal nicotine [22]. Consistent with its antidepressant effects, bupropion has been reported to reduce depression symptoms [23] and abstinence-induced negative mood [24] among smokers during treatment. Despite progress made in the treatment of tobacco dependence, available FDA-approved treatments are effective for only a fraction of smokers. Although a few novel medications for tobacco dependence have been tested in controlled trials, effects on smoking cessation have been modest [25]. The wide individual variation in therapeutic response has prompted a growing interest in the study of the role of inherited factors in the efficacy of alternate pharmacotherapies [25].
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Pharmacogenetic investigations of smoking cessation Nicotine replacement therapy
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To date, two pharmacogenetic trials of NRT have been conducted (Table 1). The first of these investigations was a placebo-controlled trial of the transdermal nicotine patch conducted in a large general practice group in the UK [26,27]. Of over 1500 smokers participating in the original clinical trial (which was not explicitly designed as a pharmacogenetic study), 755 subsequently provided blood samples for DNA analysis when re-contacted. This analysis focused on genetic variation in the dopamine pathway, based on previous evidence that the rewarding effects of nicotine are mediated, in part, by dopaminergic mechanisms [28]. This included the Taq1A polymorphism of the dopamine D2 receptor (DRD2) gene (a C > T substitution located in a non-coding region of the DRD2 locus), which has been suggested to affect D2 receptor availability in postmortem striatal samples [29,30]. There is also evidence from in vivo studies for an association between the A1 (T) allele and a lower mean relative glucose metabolic rate in
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Table 1. Pharmacogenetic studies of smoking cessation. Country
Participants
Pharmacotherapy
Gene
Johnstone et al. (2004) [26]
UK
755 smokers of European ancestry enrolled in a placebo-controlled trial
Nicotine patch
DRD2, DBH
Yudkin et al. (2004) [27]
UK
755 smokers of European ancestry enrolled in a placebo-controlled trial
Nicotine patch
DRD2
Lerman et al. (2004) [35]
USA
320 smokers of European ancestry enrolled in an open-label, randomized trial
Nicotine patch or nasal spray
OPRM1
Lerman et al. (2002) [40]
USA
426 smokers of European ancestry enrolled in a placebo-controlled trial
Bupropion SR
CYP2B6
Lerman et al. (2003) [43]
USA
418 smokers of European ancestry enrolled in a placebo-controlled trial
Bupropion SR
DRD2, DAT1
Swan et al. (2005) [50]
USA
496 smokers of European ancestry enrolled in a randomized effectiveness trial
Bupropion SR
DRD2
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CYP: Cytochrome P450; DAT: Dopamine transporter; DBH: Dopamine β-hydroxylase; DRD2: Dopamine D2 receptor; OPRM: µ-Opioid receptor; SR: Sustained release.
bupropion placebo-controlled smoking cessation clinical trial [40]. The initial report from this trial focused on the cytochrome P450 (CYP) 2B6 gene (CYP2B6). The CYP2B6 enzyme has been implicated in bupropion kinetics [41] and is induced in the brain by nicotine [42]. In this trial, 426 smokers of European ancestry provided blood samples and received bupropion (300 mg/day for 10 weeks) or placebo, plus counseling. Smokers with a decreased activity variant of CYP2B6 (slower metabolizers) reported greater increases in cravings for cigarettes following the target quit date, and had significantly higher relapse rates. These effects were modified by a significant gender–genotype– treatment interaction, suggesting that bupropion attenuated the effects of genotype among female smokers. The finding of a significant association of the CYP2B6 genotype with smoking cessation in the placebo group and absence of a genotype association with bupropion side effects suggests that the genotype effect on treatment outcome is not attributable to bupropion pharmacokinetics. Rather, the greater relapse liability in the genetically slower metabolizers may be attributable to slower rates of inactivation of nicotine (by conversion to cotinine) in the central nervous system, and neuroadaptive changes that promote dependence and abstinence-induced craving. Additional trials are warranted to confirm these results, as are studies to explore the neurobiological mechanisms of the observed genetic effect. A second report from this clinical trial [43] examined genetic variation in the dopamine pathway, based on the premise that bupropion’s effects are attributable, in part, to inhibition of dopamine re-uptake [17]. The genetic analysis
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threefold, relative to the wild-type Asn40 OPRM1 [38]. The Asp40 variant in OPRM1 is found in approximately 25–30% of individuals of European ancestry [39] and is, therefore, sufficiently common to explain clinically significant differences in response to different forms of NRT. Among 320 individuals of European ancestry, smokers carrying the OPRM1 Asp40 variant were significantly more likely to be abstinent at the end of the treatment phase compared with Asn40 homozygotes. The differential treatment response was most pronounced among smokers receiving transdermal nicotine (quit rates of 52 versus 33% for the Asp40 and Asn40 groups, respectively; OR = 2.4); was modest and nonsignificant among smokers receiving nicotine nasal spray (OR = 1.28); and was nonsignificant in a group of 190 smokers treated with placebo in the bupropion clinical trial described below. A longitudinal analysis in the transdermal nicotine group revealed a dose-response effect of transdermal nicotine, such that the genotype effect in the Asp40 group was greatest during 21-mg patch treatment, reduced as treatment was tapered, and disappeared after treatment was discontinued. In addition, post-cessation weight gain was attenuated significantly in the Asp40 group. While these results must be validated in future research, the findings suggest a hypothesis that smokers with the OPRM1 Asp40 variant may be candidates for extended high-dose patch treatment, or even maintenance therapy, as an alternative to smoking. Bupropion
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Other studies
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Other studies have suggested mechanisms by which the genotype–treatment interactions reported above – if confirmed in subsequent replication studies – might operate. An association of the DRD2 polymorphism with the effects of bupropion on subjective withdrawal symptoms has also been reported in a small investigation [52]. In this study, 30 smokers were randomly assigned to bupropion or placebo and interviewed using the Minnesota Nicotine Withdrawal Scale on two occasions: prior to starting medication and after 14 days on bupropion or placebo. The individual symptoms of craving, irritability and anxiety were significantly reduced in the bupropion group, whereas no withdrawal symptoms were diminished in the placebo group. Within the bupropion group, subgroup analyses with stratification by genotype demonstrated that craving, irritability and anxiety were significantly attenuated only among subjects with DRD2 A2/A2 genotypes. In the DRD2 A1/A1 and A1/A2 groups, no significant reduction was seen in any individual symptom of the nicotine withdrawal syndrome. In another study, smokers carrying the DRD2 A1 allele exhibited greater increases in the rewarding value of food following smoking cessation, suggesting genetic influence on abstinence-induced weight gain [53]. The A1 allele of DRD2 has also been linked with smoking cessation and abstinence-induced negative mood symptoms following treatment with venlafaxine, a serotonin re-uptake inhibitor [54]. Participants were 134 smokers who took part in a larger clinical trial evaluating the effects of an antidepressant medication (venlafaxine or placebo) plus standard care (brief counseling and NRT). The results showed that smokers carrying the DRD2 A1 allele (i.e., A1/A1 and A1/A2) quit significantly less often than those homozygous for the A2 allele (OR = 1.54). No interaction with treatment was observed, but a significant pharmacogenetic effect of the drug on negative mood while quitting was also noted. Smokers homozygous for the A2 allele responded to the drug with a substantial reduction in negative affect, whereas those carrying the A1 allele showed no significant reduction in negative mood.
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focused on common polymorphisms in the dopamine transporter (DAT1) and DRD2 genes, both of which had previously been associated with smoking behavior [44–47], as well as obesity [48,49]. Although the analysis did not support the hypothesis for genetic modulation of response to bupropion, the results revealed a significant gene–gene interaction effect on liability to relapse, mirroring results from a previous study of smoking status [43]. Specifically, among smokers with DRD2 A2A2 genotypes, those carrying the DAT1 9-repeat allele had significantly higher abstinence rates at the end of treatment (53 versus 39%), and a longer latency to relapse at the end of treatment (28 versus 21 days) and 6-month follow up (83 versus 65 days). By contrast, among smokers carrying the DRD2 A1 allele, the effect of DAT1 on abstinence rates and time to relapse was not significant. A recent study [50] investigated whether the Taq1A polymorphism is associated with smoking cessation outcomes following treatment with a combination of bupropion and behavioral counseling in smokers enrolled in an open-label, randomized effectiveness trial. Of 1524 participants assigned randomly to receive one of four combinations of bupropion and counseling (150 mg bupropion SR with less intensive counseling, or with more intensive counseling; or 300 mg bupropion SR with less intensive counseling, or with more intensive counseling), 496 subsequently provided buccal cell samples for DNA analysis when re-contacted. Adherence to treatment and point-prevalent smoking status were assessed at 3 and 12 months, respectively, following a target quit date. Compared to women homozygous for the A2 allele, women with at least one A1 allele were significantly more likely to report having stopped taking bupropion due to medication side effects (OR = 1.91), and were somewhat more likely to report smoking at 12 months (OR = 0.76), although this latter effect was not statistically significant and only constituted a trend. Significant associations or trends were not observed in men. In the same study, although not included in the published report, a significant DRD2–DAT1 interaction was observed for the nicotine dependence score as measured by the Fagerström Test for Nicotine Dependence [51], such that individuals with the DRD2 A2/A2 genotype and at least one DAT1 10 allele had a much higher mean score when compared with A2/A2 individuals without a DAT1 10 allele (GE Swan, personal communication, 6th December 2004).
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Study design issues Genetic association studies of smoking behavior and other complex neuropsychiatric conditions have provided valuable lessons about study design [55], many of which also apply to pharmacogenetic investigations of tobacco dependence Pharmacogenomics (2005) 6(3)
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Ascertainment of participants
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Pharmacogenetic studies of smoking cessation treatment conducted to date have utilized two general approaches. One approach has been to select participants for a pharmacogenetic analysis from an existing cohort of participants in an ongoing or completed pharmacotherapy trial. An advantage of this first approach is that genetic data may, in principle, be collected some time after the clinical trial has ended (assuming that participant contact details remain available), as genotype obviously remains unaltered over time. However, low response rates for retrospective DNA collection may introduce bias into the pharmacogenetic analysis, as individuals who provide DNA may differ from those who decline (e.g., willingness to provide DNA may be greater for participants who were successful in quitting smoking during the trial). Low response rates may also limit the generalizability of the pharmacogenetic findings, and the original study, having been designed for another explicit purpose, may not be ideally suited to a pharmacogenetic investigation. It is worth noting, for example, that all pharmacogenetic studies published to date have reported data on smokers of European ancestry only (Table 1), which obviously limits the generalizability of these findings to groups of different ancestry. An alternative, and preferable, approach is to explicitly design a pharmacogenetic trial in which DNA collection is part of study entry and the informed consent process. In this case, treatment can be stratified by genotype (based on likely drug targets and/or metabolic pathways), ensuring equal numbers of participants with variant alleles in each of the treatment groups. Participants who carry the minor alleles can be oversampled in order to provide greater statistical power for hypothesis testing. Given the sample sizes required (assuming small effects of individual loci), the potential for stratification of randomization by genotype may be limited to one or two key loci.
In designing a pharmacogenetic trial, one also needs to consider the ethnic composition of the study population. As with all case–control studies, the possibility of false positive results due to population stratification is a concern. Population stratification may occur when allele frequencies under investigation vary in different subpopulations with different ethnic ancestries and when the outcome varies similarly in these ethnic groups [56]. Methods are available to identify the presence of such subpopulations within the study sample, and typically involve genotyping markers across the genome [57]. Such techniques have been employed in one recent pharmacogenetic smoking cessation trial and did not provide evidence for bias due to ethnic admixture [35]. However, if one genotypes a functional variant to test the primary pharmacogenetic hypothesis, bias due to ethnic stratification would not be expected unless one supposes that the functional variant may act differently on distinct genetic backgrounds.
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treatment. Given the potential implications for patient treatment, pharmacogenetic studies require an exceptional degree of methodological rigor, particularly in participant ascertainment, phenotypic characterization of smoking cessation and relapse, and selection of genetic variants. Furthermore, a high degree of analytical and statistical stringency will be necessary to increase the likelihood of independent replication, a prerequisite for translation to practice.
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Selection of genetic variants
Pharmacogenetic investigations of smoking cessation treatment conducted to date have typically focused on one or two candidate genes of interest, and one or two polymorphisms within each gene. This approach may be most informative for investigations of medications with selective biological effects, those for which the pharmacokinetic pathways are well described, and in cases where functional genetic variants in drug targets and metabolizing enzymes have been characterized. However, these optimal conditions may not be met for many widely used medications for smoking cessation, such as bupropion. As genotyping technology develops, it will increasingly be possible to select an optimal subset of SNPs (commonly referred to as ‘haplotype tagging SNPs’ [htSNPs]), to capture efficiently the genetic variation within a candidate gene of interest. However, candidate gene approaches to pharmacogenetics require a priori knowledge about the biological mechanisms of medication effects, and important genetic influences may be missed. Clearly, therapeutic response is a complex trait influenced by multiple genes across multiple biological pathways, requiring a more comprehensive approach to genetic analysis. With anticipated reductions in the cost of genotyping, genome-wide association designs may emerge as a valuable approach for capturing the broad genetic variation associated with therapeutic response [58]. However, problems of multiple 5
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Phenotype definition
Even under the optimal circumstances when functional variants for selective biological targets of particular pharmacotherapies can be identified, the effect sizes in pharmacogenetic studies are likely to be modest. In addition, as therapeutic response is likely to be influenced by a complex interplay of multiple genes and environmental factors, pharmacogenetic investigations will need to be amply powered to detect gene–gene interactions, as well as the moderating effect of covariates (e.g., gender or racial heterogeneity in genetic effects). The determination of sample size for a pharmacogenetic study will depend not only on the number of markers and hypothesized covariates, but also on allele frequencies and the mode of genetic inheritance. Considering these factors, estimates of required sample size for pharmacogenetic investigations are very large (e.g., greater than 4000 participants) [68]. Although targeted investigations with smaller sample sizes may be informative, largerscale collaborative trials may ultimately be necessary to validate findings prior to translation to clinical practice.
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The definition of smoking persistence and relapse is considerably complex, and the currently utilized definitions of smoking abstinence mask a great deal of complexity. For example, the gold standard for evaluating the efficacy of a pharmacotherapy for smoking cessation is a biochemically verified abstinence at the end of treatment and at 6- or 12-months following the target quit date. However, such definitions do not account for the longitudinal trajectories of smoking cessation, including multiple lapses, relapses, and changes in smoking rates over time. Novel approaches to the analysis of smoking cessation outcomes, including analysis of recurrent events (e.g., transitions from abstinence to smoking and from smoking to abstinence) are under investigation [60,61], and may provide richer data for analysis of genetic effects on response to smoking treatment. In addition, pharmacogenetic studies of smoking cessation could also focus on harm reduction (via decreased numbers of cigarettes) as a valid end point. Some medications may be effective in reducing consumption, but not produce significant effects on abstinence. Another approach to elucidate the role of genetic variation in response to pharmacotherapy for smoking cessation is to study intermediate smoking-related phenotypes, also known as endophenotypes. These are phenotypes that are biologically more proximal to their genetic antecedents than the complex behavioral phenotypes described above, on the assumption that biological proximity affords a more homogeneous phenotype and a stronger genetic signal. Biobehavioral endophenotypes can also be measured in the context of human behavioral pharmacology studies in order to gauge the potential effects of genotype on medication response before proceeding to a large-scale clinical trial. In the smoking area, relevant measures include the acoustic startle response (including prepulse inhibition and affective modulation of the acoustic startle) [63], measures of the relative reinforcing value of nicotine in a behavioral choice paradigm [64], various cue reactivity and cue-induced craving paradigms [65], and measures of attentional bias, such as the modified Stroop task [66] and the dotprobe task [67]. The list of candidate endophenotypes is growing rapidly, and these may offer powerful measures for pharmacogenetic analysis.
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testing and the need for very large sample sizes will provide challenges to this approach in the pharmacogenetics context [59].
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Social and ethical implications While the potential for increasing quit rates by individually tailoring smoking treatment by genotype is promising, there are practical, policy and ethical considerations that will have to be addressed in the course of determining if, when, how and under what circumstances such genetically tailored treatment should be incorporated into clinical practice (Table 2) [69,70]. In many cases, ensuring that policy makers have adequate data to make fully informed decisions regarding clinical integration will require additional research, which ideally should be undertaken concomitantly with the genetics research currently underway. Many of the lessons learned from disease genetics (where the underlying genetic architecture is, in some cases, relatively simple) will need to be revised in the light of the more complex genetic influences on behaviors, such as cigarette smoking and cessation, and gene–treatment interactions. Assessing clinical utility
Even if clinical trials underway confirm the efficacy of genetically tailored treatment, additional data will be needed to evaluate the clinical utility of such an approach in the general clinical population. A careful assessment of the potential benefits and harms associated with the adoption of Pharmacogenomics (2005) 6(3)
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Table 2. Ethical and social implications. Potential obstacle
Clinical utility
Improvement in outcomes based on genetic information and the costeffectiveness of potential interventions, remain to be determined.
Physician preparedness
Primary care physicians and other healthcare providers who may deliver genetically tailored treatment will require appropriate training and support.
Patient willingness
Little is known regarding patient attitudes toward the use of genetic tests to tailor smoking cessation treatment or the potential psychosocial effects of genetic test disclosure.
Privacy and discrimination
Genotypes used to tailor treatment may also provide information on risk of other outcomes, and the risk for social stigma and discrimination will need to be considered.
Racial differences
Allele frequencies in genotypes used to tailor treatment may differ across racial groups, which may raise further risks for social stigma and discrimination, and exacerbate disparities in healthcare.
have little formal training and limited knowledge of clinical genetics [79], and fewer than 5% consider themselves ‘very prepared’ to counsel patients considering genetic testing [78]. Physicians have expressed concerns regarding the potential for their patients to experience genetic discrimination, problematic family dynamics, confusion, or other adverse consequences resulting from genetic testing [79]. There is recent evidence that such concerns are greater in the context of new genetic tests relative to new nongenetic tests [78], thus posing an additional barrier to adoption. Despite lack of preparedness to directly provide genetic counseling, physicians report low rates of referral to genetic specialists [78] and are frequently unaware of the genetic resources available to them [78]. Furthermore, once their patients undergo genetic testing, physicians often have difficulty interpreting genetic test results [78]. Resource constraints within the practice setting pose additional challenges. Primary care physicians are expected to provide an increasing scope of care without support of a specialist, and more than 25% believe that the scope of care they are expected to provide is greater than it should be [80]. The average time a physician spends with patients is currently about 16 min per visit [81], making it difficult to take additional time needed to discuss complex genetics issues with patients. Coverage and financing decisions by policy makers and plan administrators will greatly affect the resources available to support the integration of genetic testing at the level of the individual primary care practice [82]. Although numerous initiatives have been launched to enhance physicians’ knowledge of clinical genetics [83], far more work will be
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any new genetic technology, guided by the normative principles of medical ethics [71,72], must necessarily include a rigorous analysis of the specificity and validity of the test, as well as evidence regarding the efficacy of genetically tailored treatments compared to outcomes associated with currently available treatment strategies [73]. In particular, an important distinction to be made will be between the statistical significance of any observed improvement in treatment response and the clinical significance of the improvement in outcome when genetic testing is performed. Analyses of the cost-effectiveness of genetic testing to tailor treatment are essential, and such models should compare the utility of multiple approaches, including:
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• offering the standard treatment to all smokers • offering standard treatment to all smokers and then an alternative (possibly more intensive) stepped-care approach for those who fail to stop smoking on the standard treatment • selecting the type and intensity of treatment based upon genotype
Preparedness of primary care physicians
Given that primary care physicians are the first contact for patients who want to quit smoking, and in light of the current shortage of trained medical geneticists [74], it is likely that counseling patients about undergoing genetic testing in this context will fall to primary care physicians [75]. Patients have difficulty understanding the meaning of genetic test results for complex traits [76] and must rely on medical personnel to facilitate this knowledge [77]. Yet several studies indicate that primary care physicians may not have the knowledge, willingness or training to take on this role [78]. Primary care physicians, in particular, www.futuremedicine.com
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Patients’ willingness to undergo testing
Concerns about privacy issues and the potential for genetic discrimination are not only a concern affecting physician and patient behavior, but also reflect the policy context that shapes risk of harm and thus decisions regarding clinical integration. In the USA, despite some modest protections provided by the privacy regulations promulgated by the Department of Health and Human Services under the Health Insurance Portability and Accountability Act of 1996 (HIPAA), current privacy law fails to protect patients from misuses of genetic information. With respect to genetic discrimination statutes, the 1990 Americans with Disabilities Act (ADA) prohibits certain uses of genetic information, yet no US federal law currently bans genetic discrimination in the general population. State laws remain the primary source of protection, yet only 41 states currently ban genetic discrimination in group health insurance and only 31 states have passed laws that ban the misuse of genetic information by employers [91,92]. Nearly a quarter (22%) of respondents from a national survey in the USA with a known genetic condition in the family report being refused health insurance coverage, whether they were symptomatic or not, and 13% reported that they or a family member had been fired or denied a job due to a genetic condition in the family [93]. Some insurers have already increased premiums or denied insurance coverage on the basis of genetic susceptibility test results for breast and ovarian cancer and for Alzheimer’s disease [94], despite the low penetrance of relevant genotypes. There is also limited evidence that employers might use genetic information to bar certain persons from being hired or to abdicate responsibility for work-related injuries [95]. While cases of genetic discrimination have not been systematically documented, the gaping holes in current privacy and antidiscrimination protections generate tremendous concern. These concerns are exacerbated in the context of smoking due to the pleiotropic nature of many of the genotypes that would be tested for and used to tailor treatment. Many of the genotypes associated with smoking behavior or response to treatment actually exacerbate the potential for social stigma and discrimination against persons identified as testing positive for these genotypes. The same genotypes that would be used to tailor smoking treatment have not only been implicated in risk of becoming addicted to nicotine in the first place, but have also been associated with
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The willingness of patients to undergo genetic testing in the context of smoking treatment will need to be considered. Research is required to understand patient attitudes about genetic testing, to evaluate the psychological sequelae of testing, and to identify the most appropriate strategies for counseling patients and communicating test results in this context. The results of such research should factor prominently in the decision-making process of policy makers as they evaluate the potential benefits and harms of integrating genetic-based smoking treatments into clinical practice. We have learned from research on genetic testing for cancer that whereas as many as 70% of individuals in the general population [85] and 80% of respondents with family histories of cancer were highly interested in receiving testing [86], only about half of the highrisk individuals who are expected to benefit from such testing opted to be tested once testing was made available [87]. Uptake rates among smokers may be even less encouraging. Research in other areas has identified several barriers to genetic testing, including the uncertainty of patients about the meaning of test results, psychological distress, concerns about family stress, lack of health insurance, and concerns regarding potential discrimination [87]. Those in the USA are particularly concerned about the potential for genetic test results to be used to deny coverage or increase the costs of health insurance. Nearly two-thirds of Americans say they would refuse a genetic test if employers or health insurers could access the results [88] (as many can do legally at present), and many reportly do not seek medical care because they do not want to harm their job prospects or other life opportunities [89]. Providing an adequate process of informed consent in which a patient can make informed autonomous decisions [90] will not only require the education of providers, but also anticipating the concerns of patients and identifying optimal strategies for presenting complex genetic information to patients.
Privacy, genetic discrimination, and social stigma
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needed to adequately prepare primary care physicians for clinical integration of new treatment strategies that involve genetic testing. The development of guidelines for genetic testing, for example, has been identified as a critical need [84]. New models of staffing may also need to be developed to ensure effective and appropriate delivery of genetic services.
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• Cigarette smoking is the leading preventable cause of death worldwide, accounting for at least 30% of all cancer deaths and over three-quarters (87%) of lung cancer deaths in developed countries. • Effective, first-line pharmacological treatments for nicotine dependence and smoking cessation include a variety of nicotine replacement therapies (NRTs) and bupropion, an atypical antidepressant. Long-term cessation rates, however, remain modest. • Pharmacogenetic research may advance the effectiveness of pharmacological smoking cessation interventions by providing a greater understanding of the role of genetic factors in contributing to individual differences in treatment outcome. • Pharmacogenetic trials of NRT conducted to date have implicated the dopamine D2 receptor (DRD2), dopamine β-hydroxylase (DBH) and µ-opioid receptor 1 (OPRM1) genes in smoking cessation outcome, whereas trials of bupropion have implicated the DRD2, dopamine transporter 1 (DAT1) and cytochrome P450 2B6 (CYP2B6) genes. • There are numerous practical, policy and ethical considerations that will have to be addressed in the course of determining if, when, how and under what circumstances such genetically tailored treatment should be incorporated into clinical practice.
ancestry [103]. But the framing of genetic data in terms of self-identified racial categories, which have far more saliency as social constructs than as proxy measures for capturing underlying biological human diversity, is highly problematic and a matter of intense public debate [104]. Once a particular socially defined group is identified as having a higher prevalence of riskconferring genotypes, there are increased concerns regarding discrimination and stigmatization of individuals and their particular communities [105], as well as the quality of clinical care. Early screening efforts for sickle cell hemoglobin, for example, resulted in substantial racial stigmatization and discrimination against African–Americans in both insurance and employment settings, despite the fact that other subpopulations had a similarly high prevalence of sickle cell traits [106]. Meanwhile, those of European ancestry and other groups not associated with sickle cell disease often went undiagnosed. Similar misunderstandings of the meaning of a higher frequency of addiction-related ‘susceptibility’ genotypes among identified racial and ethnic subpopulations could be equally destructive. A full discussion of these concerns is beyond the scope of this paper. A comprehensive consideration of the use of race variables in genetic studies of complex traits and implications for clinical integration of new genetic-based treatments, public policy and health disparities is available in a recent review [104]. In the anticipated future of ‘individualized medicine’, each patient would be matched to optimal treatment based on genetic make-up and other factors. Until that time, great care must be taken in reporting racial and ethnic differences in risk-conferring mutations. Given the long history of empirically documented racial disparities in access to and quality of care [107], these issues raised in the clinical integration of genetic testing to tailor treatment by genotype should be considered simultaneously with pharmacogenetic research.
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cocaine and alcohol addiction [96], compulsive gambling [96], sexual activity [97], novelty seeking [98], and various psychiatric conditions [99]. A genetic test to tailor smoking treatment would thus simultaneously generate information about an individual’s genetic risk with respect to many other traits associated with significant stigmatization, thereby intensifying the potential for stigma and discrimination among those identified as carrying these genetic variants. Racial differences in allele frequencies
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Finally, additional ethical issues are raised by racial differences in the frequency of specific relevant alleles. Existing racial discrimination may be compounded by reported racial differences in the frequency of certain putative alleles associated with risk of addiction and response to treatment. Some smoking risk alleles, for example, have been reported to be more common among African–Americans relative to those of European ancestry. For example, key variants in dopaminergic genes related to smoking behavior have been found at a higher frequency in African– Americans [46,100]. Other genetic studies have identified biological differences in nicotine metabolism between those of European ancestry and (self-identified) African–Americans [101], which may be attributable to specific genetic factors [101]. Such studies may offer some insight into why African-American smokers inhale more deeply [102], have higher overall nicotine intake per cigarette [101] or are less likely to quit smoking when compared with smokers of European
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Outlook The potential for improving the outcomes of smoking cessation treatment by individually tailoring treatment to genotype is promising. However, in addition to replicating the existing findings reviewed here, future studies will need to be explicitly designed to address the question of whether prospective treatment tailoring by genotype enhances smoking cessation rates. Such studies are already in preparation and, in some cases, 9
REVIEW – Munafò, Shields, Berrettini, Patterson & Lerman
underway, and may provide powerful evidence for the potential benefits of genetically tailored treatment. In parallel to the pharmacogenetic research effort, there will need to be an investigation of the psychosocial, ethical and health policy issues raised in the translation of research to clinical practice. Importantly, intellectual and practical input from scientists from a diverse range of disciplines, such as physicians, psychologists, molecular geneticists, statistical geneticists, and so on, will be necessary. Such a transdisciplinary
Hurt R, Dale L, Croghan G, Croghan IT, Gomez-Dahl LC, Offord KP: Nicotine nasal spray for smoking cessation: pattern of use, side effects, relief of withdrawal symptoms, and cotinine levels. Mayo Clin. Proc. 73, 118–125 (1998). Tonnesen P, Norregaard J, Mikkelsen K, Jorgensen S, Nilsson F: A double-blind trial of a nicotine inhaler for smoking cessation. JAMA 269, 1268–1271 (1993). Schneider NG, Olmstead R, Nilsson F, Mody FV, Franzon M, Doan K: Efficacy of a nicotine inhaler in smoking cessation: a double-blind, placebo-controlled trial. Addiction 91, 1293–1306 (1996). Hjalmarson A, Nilsson F, Sjostrom L, Wiklund O: The nicotine inhaler in smoking cessation. Arch. Intern. Med. 157, 1721–1728 (1997). Shiffman S, Dresler CM, Hajek P, Gilburt SJ, Targett DA, Strahs KR: Efficacy of a nicotine lozenge for smoking cessation. Arch. Intern. Med. 162, 1267–1276 (2002). Cooper BR, Wang CM, Cox RF, Norton R, Shea V, Ferris RM: Evidence that the acute behavioral and electrophysiological effects of bupropion (Wellbutrin) are mediated by a noradrenergic mechanism. Neuropsychopharmacology 11, 133–141 (1994). Ascher JA, Cole JO, Colin JN et al.: Bupropion: a review of its mechanism of antidepressant activity. J. Clin. Psychiatry 56, 395–401 (1995). Sanchez C, Hyttel J: Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell. Mol. Neurobiol. 19, 467–489 (1999). Slemmer JE, Martin BR, Damaj MI: Bupropion is a nicotinic antagonist. J. Pharmacol. Exp. Ther. 295, 321–327 (2000). Tonnesen P, Tonstad S, Hjalmarson A et al.: A multicentre, randomized, double-blind, placebo-controlled, 1-year study of
bupropion SR for smoking cessation. J. Intern. Med. 254, 184–192 (2003). Dalsgareth OJ, Hansen NC, Soes-Petersen U et al.: A multicenter, randomized, double-blind, placebocontrolled, 6-month trial of bupropion hydrochloride sustained-release tablets as an aid to smoking cessation in hospital employees. Nicotine Tob. Res. 6, 55–61 (2004). Jamerson BD, Nides M, Jorenby DE et al.: Late-term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo. Clin. Ther. 23, 744–752 (2001). Ahluwalia JS, Harris KJ, Catley D, Okuyemi KS, Mayo MS: Sustained-release bupropion for smoking cessation in African Americans: a randomized controlled trial. JAMA 288, 468–474 (2002). Lerman C, Roth D, Kaufmann V et al.: Mediating mechanisms for the impact of bupropion in smoking cessation treatment. Drug Alcohol Depend. 67, 219–223 (2002). Lerman C, Patterson F, Berrettini W: Treating tobacco dependence: state of the science and new directions. J. Clin. Oncol. 23, 311–23 (2005). Comprehensive review of current treatments for nicotine addiction and smoking cessation. Johnstone EC, Yudkin PL, Hey K et al.: Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch. Pharmacogenetics 14, 83–90 (2004). Describes the effect of DRD2–DBH. Yudkin PL, Munafò M, Hey K et al.: Effectiveness of nicotine patches in relation to genotype in women versus men: randomised controlled trial. Br. Med. J. 328, 989–990 (2004). Describes the effect of DRD2.. Balfour DJ: Neuroplasticity within the mesoaccumbens dopamine system and its role in tobacco dependence. Curr. Drug
13.
ho
14.
ut
15.
16.
17.
18.
19.
20.
21.
ro
12.
A
10
Acknowledgements This work was supported in part by Transdisciplinary Tobacco Use Research Center Grant P5084718 (CL), a UICC American Cancer Society International Fellowship for Beginning Investigators (MRM) and a grant from the Robert Wood Johnson Foundation (AES).
of
11.
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. American Cancer Society: Cancer Facts and Figures 2004. American Cancer Society, Atlanta, USA (2004). 2. Munafò MR, Drury M, Chambers R, Wakley G: Smoking Cessation in Primary Care. Radcliffe Medical Press, Oxford, UK (2002). 3. Hopper JA, Gallagher RE: Tobacco cessation: new challenges, new opportunities. J. Cancer Educ. 18, 128–133 (2003). 4. Hughes JR: Pharmacotherapy for smoking cessation: unvalidated assumptions, anomalies, and suggestions for future research. J. Consult. Clin. Psychol. 61, 751–760 (1993). 5. Silagy C, Lancaster T, Stead L, Mant D, Fowler G: Nicotine replacement therapy for smoking cessation. Cochrane Database Syst. Rev. (2002). 6. Fiore MC, Smith SS, Jorenby DE, Baker TB: The effectiveness of the nicotine patch for smoking cessation. A metaanalysis. JAMA 271, 1940–1947 (1994). 7. Schneider NG, Olmstead R, Mody FV et al.: Efficacy of a nicotine nasal spray in smoking cessation: a placebo-controlled, double-blind trial. Addiction 90, 1671–1682 (1995). 8. Sutherland G, Stapleton JA, Russell MA et al.: Randomised controlled trial of nasal nicotine spray in smoking cessation. Lancet 340, 324–9 (1992). 9. Hjalmarson A, Franzon M, Westin A, Wiklund O: Effect of nicotine nasal spray on smoking cessation. A randomized, placebo-controlled, double-blind study. Arch. Intern. Med. 154, 2567–2572 (1994). 10. Blondal T, Franzon M, Westin A: A doubleblind randomized trial of nicotine nasal spray as an aid in smoking cessation. Eur. Respir. J. 10, 1585–1590 (1997).
rP
Bibliography
approach can be challenging, requiring the acquisition of common vocabularies and sharing of conceptual models; however, the outcomes of this process can be highly rewarding [108].
22.
23.
24.
25.
•
26.
•• 27.
•• 28.
Pharmacogenomics (2005) 6(3)
Pharmacogenetics and nicotine addiction treatment – REVIEW
33.
34.
43.
•• 44.
45.
46.
•• 36.
37.
38.
A
ut
35.
42.
www.futuremedicine.com
47.
48.
49.
50.
•• 51.
53.
54.
Fagerström Tolerance Questionnaire. Br J Addict. 86, 1119–1127 (1991). David SP, Niaura R, Papandonatos GD et al.: Does the DRD2-Taq1 A polymorphism influence treatment response to bupropion hydrochloride for reduction of the nicotine withdrawal syndrome? Nicotine Tob. Res. 5, 935–942 (2003). Lerman C, Berrettini W, Pinto A et al.: Changes in food reward following smoking cessation: a pharmacogenetic investigation. Psychopharmacology (Berl.) 174, 571–577 (2004). Cinciripini P, Wetter D, Tomlinson G et al.: The effects of the DRD2 polymorphism on smoking cessation and negative affect: Evidence for a pharmacogenetic effect on mood. Nicotine Tob. Res. 6, 229–239 (2004). Sullivan P, Eaves L, Kendler K, Neale M: Genetic case-control association studies in neuropsychiatry. Arch. Gen. Psychiatry 58, 1015–1024 (2001). Cardon LR, Palmer LJ: Population stratification and spurious allelic association. Lancet 361, 598–604 (2003). Pritchard J, Rosenberg N: Use of unlinked genetic markers to detect population stratification in association studies. Am. J. Hum. Genet. 65, 220–228 (1999). Hirschhorn JN, Daly MJ: Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95–108 (2005). Wang WY, Barratt BJ, Clayton DG, Todd JA: Genome-wide association studies: theoretical and practical concerns. Nat. Rev. Genet. 6, 109–118 (2005). Wileyto EP, Patterson F, Niaura R et al.: Do small lapses predict relapse to smoking behavior under bupropion treatment? Nicotine Tob. Res. 6, 357–366 (2004). Wileyto EP, Patterson F, Niaura R et al.: Recurrent event analysis of lapse and recovery in a smoking cessation clinical trial utilizing bupropion. Nicotine Tob. Res. (In press). Jarvis MJ, Boreham R, Primatesta P, Feyerabend C, Bryant A: Nicotine yield from machine-smoked cigarettes and nicotine intakes in smokers: evidence from a representative population survey. J. Natl Cancer Inst. 93, 134–138 (2001). Hutchison KE, Niaura R, Swift R: The effects of smoking high nicotine cigarettes on prepulse inhibition, startle latency, and subjective responses. Psychopharmacology (Berl) 150, 244–252 (2000). Blendy JA, Strasser A, Waters CL et al.: Reduced nicotine reward in obesity: cross-
of
32.
•• 41.
52.
55.
ro
31.
40.
Crowley JJ, Oslin DW, Patkar AA et al.: A genetic association study of the mu opioid receptor and severe opioid dependence. Psychiatr. Genet. 13, 169–173 (2003). Lerman C, Shields P, Wileyto E et al.: Pharmacogenetic investigation of smoking cessation treatment. Pharmacogenetics 12, 627–634 (2002). Describes the effect of CYP2B6. Kirchheiner J, Klein C, Meineke I et al.: Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 13, 619–626 (2003). Miksys S, Lerman C, Shields PG, Mash DC, Tyndale RF: Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology 45, 122–132 (2003). Lerman C, Shields PG, Wileyto EP et al.: Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial. Health Psychol. 22, 541–548 (2003). Describes the effect of DRD2–DAT1. Comings DE, Muhleman D, Gysin R: Dopamine D2 receptor (DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication. Biol. Psychiatr. 40, 368–372 (1996). Spitz M, Shi H, Yang F et al.: Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients. J. Natl Cancer Inst. 90, 358–363 (1998). Lerman C, Caporaso NE, Audrain J et al.: Evidence suggesting the role of specific genetic factors in cigarette smoking. Health Psychol. 18, 14–20 (1999). Sabol, S. and D. Hamer: An improved assay shows no association between the CYP2A6 gene and cigarette smoking behavior. Behav. Genet. 29, 257–261 (1999). Epstein LH, Jaroni JL, Paluch RA et al.: Dopamine transporter genotype as a risk factor for obesity in African-American smokers. Obes. Res. 10, 1232–1240 (2002). Noble EP: D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am. J. Med. Genet. 116, 103–125 (2003). Swan GE, Valdes AM, Ring HZ et al.: Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR. Pharmacogenomics J. 5, 21–29 (2005). Describes the effect of DRD2.. Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO: The Fagerström Test for Nicotine Dependence: a revision of the
rP
30.
39.
ho
29.
Target CNS Neurol. Disord. 1, 13–421 (2002). Noble EP, Blum K, Ritchie T, Montgomery A, Sheridan PJ: Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch. Gen. Psych. 48, 648–654 (1991). Thompson J, Thomas N, Singleton A et al.: D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 7, 479–484 (1997). Noble EP, Gottschalk LA, Fallon JH, Ritchie TL, Wu JC: D2 dopamine receptor polymorphism and brain regional glucose metabolism. Am. J. Med. Genet. 74, 162–166 (1997). Pohjalainen T, Rinnie JO, Nagren KI: The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol. Psychiatr. 3, 256–260 (1998). Jönsson EG, Nothen MM, Grunhage F et al.: Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol. Psychiatr. 4, 290–296 (1999). Neville MJ, Johnstone EC, Walton RT: Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum. Mutat. 23, 540–545 (2004). Lerman C, Wileyto EP, Patterson F et al.: The functional µ opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial. Pharmacogenomics J. 4, 184–192 (2004). Describes the effect of OPRM1. Davenport KE, Houdi AA, Van Loon GR: Nicotine protects against µ-opioid receptor antagonism by β-funaltrexamine: evidence for nicotine-induced release of endogenous opioids in brain. Neurosci. Lett. 113, 40–46 (1990). Boyadjieva NI, Sarkar DK: The secretory response of hypothalamic β-endorphin neurons to acute and chronic nicotine treatments and following nicotine withdrawal. Life Sci. 61, 59–66 (1997). Bond C, LaForge KS, Tian M et al.: Singlenucleotide polymorphism in the human µ opioid receptor gene alters β-endorphin binding and activity: possible implications for opiate addiction. Proc. Natl Acad. Sci. USA 95, 9608–9613 (1998).
56.
57.
58.
59.
60.
61.
62.
63.
64.
11
REVIEW – Munafò, Shields, Berrettini, Patterson & Lerman
70.
71.
72.
73.
74.
75.
76.
77.
12
81.
82.
83.
84.
85.
86.
87.
88.
89. 90.
92.
93.
94. 95.
National Human Genome Research Institute: Genetic Information and the Workplace. National Human Genome Research Institute, Bethesda, USA (1998). National Human Genome Research Institute: Genetic Information and Health Insurance. National Human Genome Research Institute, Bethesda, USA (1998). Hudson KL, Rothenberg KH, Andrews LB, Kahn MJ, Collins FS: Genetic discrimination and health insurance: an urgent need for reform. Science 270, 391–393 (1995). Kite M: Insurance firm admits using genetic screening. The Times (February 8, 2001). Lewin T: Commission sues railroad to end genetic testing in work injury cases. New York Times (February 10, 2001). Comings DE, Muhleman D, Ahn C, Gysin R, Flanagan SD: The dopamine D2 receptor gene: a genetic risk factor in substance abuse. Drug Alcohol Depend. 34, 175–180 (1994). Miller WB, Pasta DJ, MacMurray J, Chiu C, Wu H, Comings DE: Dopamine receptor genes are associated with age at first sexual intercourse. J. Biosoc. Sci. 31, 43–54 (1999). Noble EP, Ozkaragoz TZ, Ritchie TL et al.: D2 and D4 dopamine receptor polymorphisms and personality. Am. J. Med. Genet. 81, 257–267 (1998). Comings DE, Comings BG, Muhleman D et al.: The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA 266, 1793–1800 (1991). Shields PG, Lerman C, Audrain J et al.: Dopamine D4 receptors and the risk of cigarette smoking in African-Americans and Caucasians. Cancer Epidemiol. Biomarkers Prev. 7, 453–458 (1998). Perez-Stable EJ, Herrera B, Jacob P 3rd, Benowitz NL: Nicotine metabolism and intake in black and white smokers. JAMA 280, 152–156 (1998). Clark PI, Gautam S, Gerson LW: Effect of menthol cigarettes on biochemical markers of smoke exposure among black and white smokers. Chest 110, 1194–1198 (1996). Novotny TE, Warner KE, Kendrick JS, Remington PL: Smoking by blacks and whites: socioeconomic and demographic differences. Am J Pub Health 78, 1187–1189 (1988). Shields AE, Fortun M, Hammonds E et al.: The use of race variables in genetic studies of complex traits and the goal of reducing health disparities: a transdisciplinary review. Am. Psychol. 60, 70–73 (2005).
of
80.
91.
96.
ro
69.
79.
rP
68.
•
Shields AE, Blumenthal D, Weiss KB et al.: Barriers to translating emerging genetic research on smoking into clinical practice: perspectives of primary care physicians. J. Gen. Intern. Med. (2005) (In press). Reviews the potential difficulties in translating pharmacogenetic research of nicotine addiction and smoking cessation into clinical practice. Freedman AN, Wideroff L, Olson L et al.: US physicians' attitudes toward genetic testing for cancer susceptibility. Am. J. Med. Genet. 120A: 63–71 (2003). St Peter RF, Reed MC, Kemper P, Blumenthal D: Changes in the scope of care provided by primary care physicians. New Eng J. Med. 341, 1980–1985 (1999). Blumenthal D, Causino N, Chang YC et al.: The duration of ambulatory visits to physicians. J. Fam. Prac. 48, 264–271 (1999). Schoonmaker MM, Bernhardt BA, Holtzman NA: Factors influencing health insurers' decisions to cover new genetic technologies. Int. J. Technol. Assess. Health Care 16, 178–189 (2000). Emery J, Walton R, Murphy M et al.: Computer support for interpreting family histories of breast and ovarian cancer in primary care: comparative study with simulated cases. Br. Med. J. 321, 28–32 (2000). Watson EK, Shickle D, Qureshi N, Emery J, Austoker J: The 'new genetics' and primary care: GPs' views on their role and their educational needs. Fam Prac 16, 420–425 (1999). Tambor ES, Rimer BK, Strigo TS: Genetic testing for breast cancer susceptibility: awareness and interest among women in the general population. Am. J. Med. Genet. 68, 43–49 (1997). Berth H, Balck F, Dinkel A: Attitudes toward genetic testing in patients at risk for HNPCC/FAP and the German population. Genetic Testing 6, 273–280 (2002). Hadley DW, Jenkins J, Dimond E et al.: Genetic counseling and testing in families with hereditary nonpolyposis colorectal cancer. Arch. Intern. Med. 163, 573–582 (2003). Department of Labor: Genetic Information and the Workplace. Department of Labor, Washington DC, USA (1998). Goldman J: Protecting privacy to improve health care. Health Aff. 17, 47–60 (1998). Elwyn G, Gray J, Clarke A: Shared decision making and non-directiveness in genetic counseling. J. Med. Genet. 37, 135–138 (2000).
ho
67.
78.
ut
66.
A
65.
comparison in human and mouse. Psychopharmacology (In press). Tiffany ST, Cox LS, Elash CA: Effects of transdermal nicotine patches on abstinenceinduced and cue-elicited craving in cigarette smokers. J. Consult. Clin. Psychol. 68, 233–240 (2000). Munafò MR, Mogg K, Roberts S, Bradley BP, Murphy M: Selective processing of smoking-related cues in current smokers, ex-smokers and never-smokers on the modified Stroop task. J. Psychopharmacol. 17, 311–317 (2003). Waters AJ, Shiffman S, Bradley BP, Mogg K: Attentional shifts to smoking cues in smokers. Addiction 98, 1409–1417 (2003). Cardon LR, Idury RM, Harris TJ, Witte JS, Elston RC: Testing drug response in the presence of genetic information: sampling issues for clinical trials. Pharmacogenetics 10, 503–510 (2000). Shields AE, Lerman C, Sullivan PF: Integrating genetics into smoking treatment: emerging ethical, social and legal issues. Nicotine Tob. Res. 6, 675–688 (2004). Lerman C, Shields AE: Genetic testing for cancer susceptibility: the promise and the pitfalls. Nat. Rev. Cancer 4, 235–241 (2004). Beauchamp TL, Walters L: Contemporary Issues in Bioethics. (4e.) Wadsworth, Belmont, USA (1994). World Health Organization: Proposed International Guidelines on Ethical Issues in Medical Genetics and Genetic Services. World Health Organization, Geneva (1998). National Institutes of Health: Enhancing the Oversight of Genetic Tests: Recommendations of the Secretary's Advisory Committee on Genetic Testing. National Institutes of Health, Washington DC (2000). Emery J, Hayflick S: The challenge of integrating genetic medicine into primary care. Br. Med. J. 322, 1027–1030 (2001). Whittaker L: Clinical applications of genetic testing: implications for the family physician. Am. Fam. Physician 53, 2077–2084 (1996). Aktan-Collan K, Haukkala A, Mecklin JP, Uutela A, Kaariainen H: Comprehension of cancer risk one and 12 months after predictive genetic testing for hereditary nonpolyposis colorectal cancer. J. Med. Genet. 38, 787–792 (2001). Hallowell N, Foster C, Eeles R, ArdernJones A, Murday V, Watson M: Balancing autonomy and responsibility: the ethics of generating and disclosing genetic information. J. Med. Ethics 29, 74–79 (2003).
97.
98.
99.
100.
101.
102.
103.
104.
Pharmacogenomics (2005) 6(3)
Pharmacogenetics and nicotine addiction treatment – REVIEW
105. Foster MW, Bernsten D, Carter TH: A
Johns Hopkins University Press, Baltimore, USA (1990). 107. Smith DB: Health Care Divided: Race and Healing a Nation. University of Michigan Press, Ann Arbor, USA (1999).
108. Morgan GD, Kobus K, Gerlach KK et al.:
Facilitating transdisciplinary research: the experience of the transdisciplinary tobacco use research centers. Nicotine Tob. Res. (Suppl. 1), S11–S19 (2003).
A
ut
ho
rP
ro
of
model agreement for genetic research in socially identifiable populations. Am. J. Hum. Genet. 63, 696–702 (1998). 106. Bowman J, Murray Jr RF: Genetic Variation and Disorders in Peoples of African Origin.
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