Addiction to nicotine and ability to quit smoking are influenced by genetic factors. We used functional genomic approaches (chromatin immunoprecipitation (ChIP) and whole genome sequencing) to identify CREB targets following chronic nicotine administration and withdrawal in rodents. fWe found that chronic nicotine and withdrawal differentially modulate CREB binding to the gene for Neuregulin 3 (NRG3). Quantitative analysis of saline, nicotine, and nicotine withdrawal in two biological replicates corroborate this finding, with NRG3 increases in both mRNA and protein following withdrawal from chronic nicotine treatment. To translate these data for human relevance, single nucleotide polymorphisms (SNPs) across NRG3 were examined for association with prospective smoking cessation among smokers of European ancestry treated with transdermal nicotine in two independent cohorts. Individual SNP and haplotype analysis support association of NRG3 SNPs and smoking cessation success. NRG3 is a neural-enriched member of the EGF family, and a specific ligand for the receptor tyrosine kinase ErbB4, which is also up-regulated following nicotine treatment and withdrawal. Mice with significantly reduced levels of NRG3 or pharmacological inhibition of ErbB4 show similar reductions in anxiety following nicotine withdrawal compared to control animals, suggesting a role for NRG3 in nicotine dependence. While the function of the SNP in NRG3 in humans is not known, these data suggest that Nrg3/ErbB4 signaling may be an important factor in nicotine dependence.
mouse; human; single nucleotide polymorphism (SNP); ChIP-Seq; neuregulin 3 (NRG3); nicotine; smoking cessation
Anti-smoking public service announcements (PSAs) often include smoking-related cues; however, visual drug cues can trigger acute cravings that may impede cognitive processing of the anti-smoking message. This experiment evaluated effects of smoking cues in PSAs on smoking urges, immediate smoking behavior, and persuasion measures in daily smokers.
Three-hundred eighteen non-treatment seeking smokers completed a single laboratory session during which they viewed sets of PSAs differentiated by presence of smoking cues (central to the PSA’s argument, peripheral, or no cues) and argument strength (high versus low). After viewing the PSAs, participants completed self-report measures of smoking urges, attitudes toward quitting, self-efficacy, and intentions to quit smoking. Smoking behavior was recorded during a one-hour ad-libitum smoking period immediately following PSA viewing and assessment.
There was a significant positive effect of argument strength on attitudes toward quitting smoking (p = 0.012). There were no main effects of smoking cues or smoking cue by argument strength interactions on any of the outcome measures.
Visual smoking cues in PSAs do not increase urges to smoke, nor is there evidence that the inclusion of such cues impede the recall or persuasive effects of anti-smoking arguments.
smoking; tobacco; public service announcements; smoking cues; health communication
Anti-smoking public service announcements (PSAs) often use persuasive arguments to attempt to influence attitudes about smoking. The persuasiveness of a PSA has previously been associated with factors that influence the cognitive processing of its message. Genetic factors that influence cognitive processing might thus affect individuals' responses to the persuasive arguments presented in PSAs. In the current study, we examined polymorphisms in the genes encoding brain-derived neurotrophic factor (BDNF Val66Met) and catechol-O-methyltransferase (COMT Val158Met), which affect cognitive processing in the prefrontal cortex, to identify genetic factors associated with self-reported outcomes of message processing, perceived effectiveness, and quitting intentions among smokers viewing PSAs. 120 smokers viewed sets of 4 PSAs which varied with respect to features of argument strength and message sensation value. We observed significant associations of BDNF genotype with central processing, narrative processing, perceived effectiveness of the anti-smoking PSAs, and participant quitting intentions; the BDNF Met allele was associated with lower scores on all these measures. Central processing acted as a mediator of the association of genotype with quitting intentions and perceived effectiveness. There was a significant interaction of COMT genotype by argument strength in the model of narrative processing, such that individuals homozygous for the COMT Val allele reported higher narrative processing in the high argument strength condition, but not in the low argument strength condition. To our knowledge, this is the first study to identify genetic factors associated with cognitive processing of anti-smoking public service announcements.
BDNF; COMT; genetics; cognitive processing; public service announcements
Little is known about the impact of knowledge of CDKN2A and MC1R genotype on melanoma prevention behaviors like sun avoidance and skin examination in the context of familial melanoma.
73 adults with a family history of melanoma were randomly assigned to be offered individualized CDKN2A and MC1R genotyping results in the context of a genetic counseling session, or the standard practice of not being offered counseling or disclosure of genotyping results. Mixed effects or longitudinal logistic models were used to determine whether the intervention affected change in sun protection habits, skin examinations and perception and beliefs related to melanoma risk, prevention, and genetic counseling.
All participants in the intervention group who attended genetic counseling sessions chose to receive their test results. From baseline to follow-up, participants in the intervention group reported an increase in the frequency of skin self-examinations compared to a slight decrease in the control group (p=0.002). Participants in the intervention group reported a smaller decrease in frequency of wearing a shirt with long sleeves than did participants in the control group (p =0.047). No effect of the intervention was noted for other outcomes.
Feedback of CDKN2A and MC1R genotype among families without known pathogenic CDKN2A mutations does not appear to decrease sun protection behaviors.
While disclosure of CDKN2A and MC1R genotype did not have negative effects on prevention, the benefits of communicating this information remain unclear. The small number of families who tested positive for CDKN2A mutations in this study is a limitation.
skin cancer; genetic testing; sun exposure; sun protection; surveys
Genome-wide association studies have linked single-nucleotide polymorphisms (SNPs) in the CHRNA5/A3/B4 gene cluster with heaviness of smoking. The nicotine metabolite ratio (NMR), a measure of the rate of nicotine metabolism, is associated with the number of cigarettes per day (CPD) and likelihood of cessation. We tested the potential interacting effects of these two risk factors on CPD.
Pretreatment data from three prior clinical trials were pooled for analysis. One thousand and thirty treatment seekers of European ancestry with genotype data for the CHRNA5/A3/B4 SNPs rs578776 and rs1051730 and complete data for NMR and CPD at pretreatment were included. Data for the third SNP, rs16969968, were available for 677 individuals. Linear regression models estimated the main and interacting effects of genotype and NMR on CPD.
We confirmed independent associations between the NMR and CPD as well as between the SNPs rs16969968 and rs1051730 and CPD. We did not detect a significant interaction between NMR and any of the SNPs examined.
This study demonstrates the additive and independent association of the NMR and SNPs in the CHRNA5/A3/B4 gene cluster with smoking rate in treatment-seeking smokers.
To explore public attitudes toward the incorporation of cost-effectiveness analysis into clinical decisions.
The authors presented 781 jurors with a survey describing 1 of 6 clinical encounters in which a physician has to choose between cancer screening tests. They provided cost-effectiveness data for all tests, and in each scenario, the most effective test was more expensive. They instructed respondents to imagine that he or she was the physician in the scenario and asked them to choose which test to recommend and then explain their choice in an open-ended manner. The authors then qualitatively analyzed the responses by identifying themes and developed a coding scheme. Two authors separately coded the statements with high overall agreement (kappa = 0.76). Categories were not mutually exclusive.
Overall, 410 respondents (55%) chose the most expensive option, and 332 respondents (45%) choose a less expensive option. Explanatory comments were given by 82% respondents. Respondents who chose the most expensive test focused on the increased benefit (without directly acknowledging the additional cost) (39%), a general belief that life is more important than money (22%), the significance of cancer risk for the patient in the scenario (20%), the belief that the benefit of the test was worth the additional cost (8%), and personal anecdotes/preferences (6%). Of the respondents who chose the less expensive test, 40% indicated that they did not believe that the patient in the scenario was at significant risk for cancer, 13% indicated that they thought the less expensive test was adequate or not meaningfully different from the more expensive test, 12% thought the cost of the test was not worth the additional benefit, 9% indicated that the test was too expensive (without mention of additional benefit), and 7% responded that resources were limited.
Public response to cost-quality tradeoffs is mixed. Although some respondents justified their decision based on the cost-effectiveness information provided, many focused instead on specific features of the scenario or on general beliefs about whether cost should be incorporated into clinical decisions.
decision making; public opinion; cost-benefit analysis; health care rationing
Nicotine alters auditory event-related potentials (ERPs) in rodents and humans and is an effective treatment for smoking cessation. Less is known about the effects of the partial nicotine agonist varenicline on ERPs.
We measured the effects of varenicline and nicotine on the mouse P20 and varenicline and smoking on the human P50 in a paired-click task. Eighteen mice were tested following nicotine, varenicline, and their combination. One hundred and fourteen current smokers enrolled in a placebo-controlled within-subject crossover study to test the effects of varenicline during smoking and abstinence. Thirty-two subjects participated in the ERP study, with half receiving placebo first and half varenicline first (VP).
Nicotine and varenicline enhanced mouse P20 amplitude, while nicotine improved P20 habituation by selectively increasing the first-click response. Similar to mice, abstinence reduced P50 habituation relative to smoking by reducing the first-click response. There was no effect of varenicline on P50 amplitude during abstinence across subjects. However, there was a significant effect of medication order on P50 amplitude during abstinence. Subjects in the PV group displayed reduced P50 during abstinence, which was blocked by varenicline. However, subjects in the VP group did not display abstinence-induced P50 reduction.
Data suggest that smoking improves sensory processing. Varenicline mimics amplitude changes associated with nicotine and smoking but fails to alter habituation. The effect of medication order suggests a possible carryover effect from the previous arm. This study supports the predictive validity of ERPs in mice as a marker of drug effects in human studies.
The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.
nicotine; smoking cessation; choline acetyltransferase ChAT; pharmacogenetics; addiction; Pharmacogenetics/Pharmacogenomics; Addiction & Substance Abuse; Clinical Pharmacology/Trials; Psychiatry & Behavioral Sciences; Nicotine; Smoking Cessation; choline acetyltransferase ChAT
As many as one-half of smokers relapse in the first week following a quit attempt, and subjective reports of cognitive deficits in early abstinence are associated with increased relapse risk. This study examined whether objective cognitive performance after three days of abstinence predicts smoking resumption in a 7-day simulated quit attempt. Sixty-seven treatment-seeking smokers received either varenicline or placebo (randomized double-blind) for 21 days. Following medication run-up (days 1-10), there was a 3-day mandatory (biochemically confirmed) abstinence period (days 11-13) during which working memory (Letter-N-Back Task) and sustained attention (Continuous Performance Task) were assessed (day 13). Participants were then exposed to a scheduled smoking lapse and instructed to try to remain abstinent for the next 7 days (days 15-21). Poorer cognitive performance (slower correct reaction time on Letter-N-Back task) during abstinence predicted more rapid smoking resumption among those receiving placebo (p=.038) but not among those receiving varenicline. These data lend further support for the growing recognition that cognitive deficits involving working memory are a core symptom of nicotine withdrawal and a potential target for the development of pharmacological and behavioral treatments.
nicotine; addiction; withdrawal; smoking relapse; cognition
The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry following eight weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 SNPs in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pre-treatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non treatment-seeking cohort, we utilized data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.
nicotine; smoking cessation; choline acetyltransferase ChAT; pharmacogenetics; addiction
Antitobacco media campaigns using public service announcements (PSAs) have shown promise in reducing smoking initiation and increasing intentions to quit. Research on what makes an effective PSA has had mixed outcomes. The present study tested the effects of specific message features in antitobacco PSAs, using theory-based physiological and self-report outcomes.
PSAs were categorized as high or low in message sensation value (MSV) and strength of argument and presented to 200 current smokers in a 2 × 2 factorial design. Physiological responses—specifically, heart rate, skin conductance, zygomaticus major, and corrugator supercilii—were assessed while participants viewed the PSAs. Beliefs, attitudes, efficacy, norms, and intentions to quit were assessed immediately following viewing.
Corrugator activity was significantly greater in the high MSV condition. Among those low in sensation seeking, low MSV PSAs elicited higher self-efficacy, whereas the reverse was true for high sensation seekers. High MSV PSAs elicited higher negative beliefs in low sensation seekers. Adding physiological measures to a model predicting intention to quit did not improve the explained variance.
The present study represents the first comprehensive theory-based experimental investigation of the effects of different features of antitobacco PSAs and provides a framework for future research in identifying effective features of such PSAs. Results illustrate the importance of considering individual differences, characterizing both PSA content and format, and outcome and response measures when evaluating antitobacco PSAs.
Neuronal nicotinic acetylcholine receptors (nAChRs) are a key target in medication development efforts for a range of neuropsychiatric disorders, including nicotine dependence. Varenicline, a partial agonist at the α4β2 nAChRs, is a new efficacious medication for nicotine dependence. Its effects on the affective and cognitive dimensions of nicotine withdrawal have yet to be well characterized.
Sixty-seven treatment-seeking smokers were administered varenicline (× 21 days) and placebo (× 21 days) in a double-blind within-subject cross-over design. Following the medication run-up phase (days 1–10), there was a 3-day mandatory smoking abstinence phase (days 11–13) during which subjective symptoms and cognitive performance were assessed. Participants were re-exposed to a scheduled smoking lapse (day 14) and followed for days to lapse (days 15–21) in each medication period.
In the varenicline period, compared to placebo, withdrawal symptoms (p=.04), smoking urges (p<.001), and negative affect (p=.01) were significantly reduced, and levels of positive affect (p=.046), sustained attention (p=.018) and working memory (p=.001) were significantly greater during mandatory abstinence. Varenicline also significantly reduced the subjective rewarding effects of the scheduled smoking lapse (e.g., satisfaction, relief, liking) (p=.003). Medication effects on days to lapse following the scheduled smoking lapse were dependent on treatment order (p=.001); among participants who received placebo in the first period, varenicline increased days of abstinence in the follow-up period.
These data identify novel affective and cognitive effects of varenicline, and may have implications for medication development for other neuropsychiatric conditions.
nicotine; tobacco; dependence; varenicline; affect; cognition
Objectives and methods
The Val108/158Met polymorphism in the gene that encodes COMT, a dopamine metabolizing enzyme, results in a three- to four-fold reduction in COMT activity. To determine if the lower activity Met allele of COMT was associated with smoking cessation in women, we used two independent studies: a population-based case–control study and a nicotine replacement clinical trial.
In the case–control study, women with two Met alleles were significantly more likely to be ex-smokers than current smokers [OR = 1.82, 95% CI (1.05, 3.17), P = 0.03]. In the nicotine replacement clinical trial, among women, the Met/Met genotype was associated with a higher probability of smoking cessation based on both point prevalence and prolonged abstinence outcomes [OR= 2.96, 95% CI (1.07, 8.14), P = 0.04; OR= 3.23, 95% CI (1.13, 9.20), P = 0.03, respectively].
This first report of a significant association between COMT Val108/158Met and smoking cessation suggests that COMT variation has an effect on smoking behavior in women.
smoking cessation; COMT; women; tobacco dependence; pharmacogenetics
Based on a series of clinical trials showing no difference in the effectiveness or tolerability of most major classes of antihypertensive medications, the Joint National Commission on High Blood Pressure Treatment recommends that physicians prescribe β-blockers or diuretics as initial hypertensive therapy unless there are compelling indications for another type of medication. Nevertheless, many physicians continue to favor more expensive medications like angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers as first line agents. The persistent use of these agents raises questions as to whether physicians perceive ACE inhibitors and calcium channel blockers to be better than β-blockers and diuretics.
We surveyed 1,200 primary care physicians in 1997, and another 500 primary care physicians in 2000, and asked them to estimate the relative effectiveness and side effects of 4 classes of medication in treating a hypothetical patient with uncomplicated hypertension: ACE inhibitors, β-blockers, calcium channel blockers, and diuretics. In addition, we asked them to indicate whether they ever provided free samples of hypertension medications to their patients.
Perceptions of the relative effectiveness and side effects of the 4 classes of hypertension medications did not significantly change over the 3 years, nor did prescription recommendations. Physicians perceive that diuretics are less effective at lowering blood pressure than the other 3 classes (P < .001). They also perceive that β-blockers are less tolerated than the other 3 classes (P < .001). In a multivariate model, perceptions of effectiveness and tolerability displayed significant associations with prescription preference independent of background variables. The only other variable to contribute significantly to the model was provision of free medication samples to patients.
Despite numerous clinical trials showing no difference in the effectiveness or side-effect profiles of these 4 classes of drugs, most physicians believed that diuretics were less effective and β-blockers were less tolerated than other medications. Moreover, their prescription practices were associated with their provision of free samples provided by pharmaceutical representatives, even after adjusting for other demographic characteristics. Efforts to increase physicians' prescribing of β-blockers and diuretics may need to be directed at overcoming misunderstandings about the effectiveness and tolerability of these medicines.
hypertension treatment; physician survey; pharmaceutical promotion