Significant associations of CHRNA2 and CHRNA6 with nicotine dependence in European American and African American populations.

The direct physiological effects that promote nicotine dependence (ND) are mediated by nicotinic acetylcholine receptors (nAChRs). In line with the genetic and pharmacological basis of addiction, many previous studies have revealed significant associations between variants in the nAChR subunit genes and various measures of ND in different ethnic samples. In this study, we first examined the association of variants in nAChR subunits α2 (CHRNA2) and α6 (CHRNA6) genes on chromosome 8 with ND using a family sample consisting of 1,730 European Americans (EAs) from 495 families and 1,892 African Americans (AAs) from 424 families (defined as the discovery family sample). ND was assessed by two standard quantitative measures: smoking quantity (SQ) and the Fagerström Test for ND (FTND). We found nominal associations for all seven tested SNPs of the genes with at least one ND measure in the EA sample and for two SNPs in CHRNA2 in the AA sample. Of these, associations of SNPs rs3735757 with FTND (P = 0.0068) and rs2472553 with both ND measures (with a P value of 0.0043 and 0.00086 for SQ and FTND, respectively) continued to be significant in the EA sample even after correction for multiple tests. Further, we found several haplotypes that were significantly associated with ND in the EA sample in CHRNA6 and in the both EA and AA samples in CHRNA2. To confirm the associations of the two genes with ND, we conducted a replication study with an independent case-control sample from the SAGE study, which showed a significant association of the two genes with ND, although the significantly associated SNPs were not always the same in the two samples. Together, these findings indicate that both CHRNA2 and CHRNA6 play a significant role in the etiology of ND in AA and EA smokers. Further replication in additional independent samples is warranted.

Using MIMIC models to examine the relationship between current smoking and early smoking experiences.

INTRODUCTION: The present study expands previous research on early experiences with tobacco by using a Multiple Indicator Multiple Causes (MIMIC) model, which permits combining indicators tapping into pleasant experiences into one latent construct and those indicators of unpleasant experiences into another latent construct. METHODS: A sample of 458 participants was recruited via newspaper advertisements. Response to early experimentation with cigarettes was assessed using the Early Smoking Experiences questionnaire, in which participants were asked the following question: "The first time you tried cigarettes, did you experience any of the following? (pleasurable and displeasurable sensations [overall], pleasurable rush or buzz, dizziness, relaxation, nausea, cough, difficulty inhaling)." These experiences were rated on a scale ranging from 1 = none to 4 = intense. RESULTS: The MIMIC model revealed that current smoking status and age of initial experimentation with cigarettes were significantly associated with both early pleasant and unpleasant experiences (p < .05). African Americans were less likely than Whites to have early unpleasant experiences (p < .05). No association was found between race and early pleasant experiences. DISCUSSION: Our findings are consistent with the inferences that pleasant experiences in response to early experimentation with smoking lead to regular smoking and that positive experiences play a stronger role than negative experiences in the transition to regular smoking. Our study also demonstrates that the MIMIC model is pertinent and practicable in nicotine and smoking research. We recommend it as a useful tool for identifying endophenotypes related to nicotine dependence and tobacco use latent constructs.

Substance use, trait measures, and subjective response to nicotine in never-smokers stratified on parental smoking history and sex.

INTRODUCTION: Male and female never-smokers stratified on parental history of smoking were tested for possible differences in susceptibility to the hedonic effects of nicotine. METHODS: We recruited nicotine-exposed never-smokers with two never-smoking biological parents (PH-) or two ever-smoking biological parents (PH+). After completing a baseline assessment battery focusing on conditions or behaviors associated with smoking, participants were tested for subjective and hedonic effects in response to administration of three different nicotine doses (0.0, 0.5, and 1.0 mg) via nasal spray. Physiological and biochemical reactivity also was monitored. RESULTS: PH+ were significantly more likely to report having experienced a "buzz" upon early smoking experimentation and to have histories of alcohol abuse and alcoholism; they also scored higher on disordered eating. In response to nicotine dosing, PH+ reported an increase in depressed mood, compared with a minimal response in PH-, in keeping with our expectation that nicotine would have more pronounced effects in PH+. Regardless of parental history, women reported experiencing greater anxiety in response to the highest nicotine dose, compared with men. DISCUSSION: Further exploration in larger samples, using more stringent selection criteria, a wider range of measures, and a less aversive dosing method, may provide a full test of the possible utility of the parental history model for illuminating biobehavioral mechanisms underlying response to nicotine. Also important would be broadening the scope of inquiry to include comparisons with ever-smokers to determine what protected PH+ from becoming smokers, despite the presence of factors that might be expected to decrease resilience and increase susceptibility.

Web-based smoking-cessation programs: results of a randomized trial.

BACKGROUND: Initial trials of web-based smoking-cessation programs have generally been promising. The active components of these programs, however, are not well understood. This study aimed to (1) identify active psychosocial and communication components of a web-based smoking-cessation intervention and (2) examine the impact of increasing the tailoring depth on smoking cessation. DESIGN: Randomized fractional factorial design. SETTING: Two HMOs: Group Health in Washington State and Henry Ford Health System in Michigan. PARTICIPANTS: 1866 smokers. INTERVENTION: A web-based smoking-cessation program plus nicotine patch. Five components of the intervention were randomized using a fractional factorial design: high- versus low-depth tailored success story, outcome expectation, and efficacy expectation messages; high- versus low-personalized source; and multiple versus single exposure to the intervention components. MEASUREMENTS: Primary outcome was 7 day point-prevalence abstinence at the 6-month follow-up. FINDINGS: Abstinence was most influenced by high-depth tailored success stories and a high-personalized message source. The cumulative assignment of the three tailoring depth factors also resulted in increasing the rates of 6-month cessation, demonstrating an effect of tailoring depth. CONCLUSIONS: The study identified relevant components of smoking-cessation interventions that should be generalizable to other cessation interventions. The study also demonstrated the importance of higher-depth tailoring in smoking-cessation programs. Finally, the use of a novel fractional factorial design allowed efficient examination of the study aims. The rapidly changing interfaces, software, and capabilities of eHealth are likely to require such dynamic experimental approaches to intervention discovery.

Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with 'pleasurable buzz' during early experimentation with smoking.

AIMS: To extend the previously identified association between a single nucleotide polymorphism (SNP) in neuronal acetylcholine receptor subunit alpha-5 (CHRNA5) and nicotine dependence to current smoking and initial smoking-experience phenotypes. DESIGN, SETTING, PARTICIPANTS: Case-control association study with a community-based sample, comprising 363 Caucasians and 72 African Americans (203 cases, 232 controls). MEASUREMENTS: Cases had smoked > or = five cigarettes/day for > or = 5 years and had smoked at their current rate for the past 6 months. Controls had smoked between one and 100 cigarettes in their life-time, but never regularly. Participants also rated, retrospectively, pleasurable and displeasurable sensations experienced when they first smoked. We tested for associations between smoking phenotypes and the top 25 SNPs tested for association with nicotine dependence in a previous study. FINDINGS: A non-synonymous coding SNP in CHRNA5, rs16969968, was associated with case status [odds ratio (OR) = 1.5, P = 0.01] and, in Caucasians, with experiencing a pleasurable rush or buzz during the first cigarette (OR = 1.6, P = 0.01); these sensations were associated highly with current smoking (OR = 8.2, P = 0.0001). CONCLUSIONS: We replicated the observation that the minor allele of rs16969968 affects smoking behavior, and extended these findings to sensitivity to smoking effects upon experimentation. While the ability to test genetic associations was limited by sample size, the polymorphism in the CHRNA5 subunit was shown to be associated significantly with enhanced pleasurable responses to initial cigarettes in regular smokers in an a priori test. The findings suggest that phenotypes related to subjective experiences upon smoking experimentation may mediate the development of nicotine dependence.

Favorite cigarette of the day in a random sample of women smokers.

From a random digit dialing survey of American women, we assessed current smokers (n=371). Respondents were 33.6+/-7.6 years old, 49.6% married, and 87.6% White, with an FTND score of 3.9+/-2.6. When asked "which cigarette of the day would be the most difficult for you to give up?" 30 women gave uncodable responses and 341 women provided answers subsequently coded into 5 categories: FIRST; 43.7%, MEAL; 29.3%, LAST; 13.8%, ROUTINE; 7.3%, and ENHANCE; 5.9%. Response groups differed significantly on age (p<.01), smoking rate (p<.001), time to first cigarette (p<.001), and self-rated health (p<.05). In post hoc analyses, FIRST were older, smoked more cigarettes/day, and smoked sooner after waking than at least one other group. LAST smoked the fewest cigarettes/day, and ENHANCE rated their health significantly better than did all other groups. The FTND is coded as 1 for "first" and 0 for any other response. Examining more closely the richness contained in that "other" category is a novel approach that may prove useful as a phenotyping tool.

Association of withdrawal features with nicotine dependence as measured by the Fagerström Test for Nicotine Dependence (FTND).

The aim of this study was to advance our understanding of how nicotine dependence level, defined by the Fagerström Test of Nicotine Dependence (FTND), relates to nicotine withdrawal features. We classified nicotine dependence in two categories, 1) low dependence (LD; FTND<4) and 2) high dependence (HD; FTND> or =4). A sample of 241 smokers was recruited via newspaper ads and public notices. Using a multivariate response model with adjustments for age, sex, age at first cigarette, race, and current or lifetime depression, we observed a small to modest statistically robust association between nicotine dependence level and withdrawal features such as, irritation/anger (adjusted relative risk, aRR=1.2; 95% CI 1.0, 1.3); nervousness (aRR=1.3; 95% CI 1.1, 1.6); restlessness (aRR=1.2; 95% CI 1.1, 1.4); difficulty concentrating (aRR=1.3; 95% CI 1.1, 1.7); and trouble sleeping (aRR=1.8; 95% CI 1.2, 2.6). Our findings are consistent with the inference that the FTND measures "physiological dependence" and that multidimensional approaches are needed to capture the full range of smoking phenotypology.

Validity and reliability of the Weight Control Smoking Scale.

The Weight Control Smoking Scale (WCSS), originally developed as part of a Reasons for Smoking Scale, includes 3 items (smoke to avoid weight gain; smoke to control appetite; less hungry when smoking). Although widely used, it has not previously been subjected to psychometric analysis. To fill this gap, we analyzed data from 1512 smokers. WCSS score correlated significantly and positively with the Dieting and Bingeing Severity Scale, self-efficacy about relapse if postcessation weight gain occurred, increased appetite/weight gain as a withdrawal symptom, and the Three Factor Eating Questionnaire subscales, and negatively with Body Satisfaction. Cronbach's alpha was .834. Female participants scored significantly higher than males. When only Black and White smokers were included, a significant interaction emerged such that White women scored higher than any other category. In a subsample of 50 smokers who completed the questionnaire twice, test-retest correlations were significant for all items and for the scale as a whole. Overall, our results suggest that the WCSS is a reliable and valid instrument that lends itself to use as a screening tool.

Body image, body satisfaction, and eating patterns in normal-weight and overweight/obese women current smokers and never-smokers.

To explore differences between women smokers and never-smokers in body image and eating patterns, we analyzed data obtained from 587 women (18-55 years old) recruited to participate in laboratory investigations not focused on weight concerns. The sample consisted of 420 current smokers and 167 never-smokers; 44% of each group were overweight or obese (BMI>or=25). Questionnaires included measures of body image, body dissatisfaction, and restrained and disinhibited eating. Smokers did not differ from never-smokers on perceived body shape but endorsed a thinner preferred body shape and scored lower on body satisfaction than never-smokers. Smokers also scored higher on measures of disinhibited eating. Among smokers, those who were overweight/obese scored higher than normal-weight smokers on concerns about post-cessation weight gain and lower on self-efficacy to avoid relapse if weight increased. Our findings suggest that women smokers may require help in attaining a more realistic body image and attention to dysfunctional eating patterns if they are to achieve and maintain a healthful weight and/or to quit smoking successfully. They also indicate that overweight smokers may be at elevated risk of relapse in the face of post-cessation weight gain.

Actual versus perceived risk of cervical cancer among college women smokers.

UNLABELLED: Cervical cancer is a well-established smoking-related illness, but many at-risk women are unaware of this link. OBJECTIVE: The authors designed this study to (1) investigate the relationship of smoking behavior with the history of abnormal Pap test results, sexual history, and perceived risk of cervical cancer and (2) determine whether self-classified smoking status (and hence perceived risk) corresponds with actual smoking behavior in a college student population. PARTICIPANTS AND METHOD SUMMARY: College women students (N = 135) completed a survey assessing smoking history, health history, sexual risk behavior, and risk awareness. RESULTS: Relative to those who had not smoked in the past month, current smokers (n = 36, or 27% of the total sample) perceived themselves to be at higher risk for developing cervical cancer, but did not demonstrate increased awareness of specific cervical cancer risk factors, including smoking. Twenty-eight percent (10 of 36) of past-month smokers did not define themselves as current smokers. CONCLUSION: The authors conclude that anti-smoking and health-related messages targeting smokers may misfire for individuals who do not define themselves as smokers but are nonetheless at risk for smoking-related consequences and escalating use.

Differences in smoking patterns among women smokers with childhood versus later onset of weight problems.

We hypothesized that among overweight women smokers, those with Childhood Onset weight problems may be more likely to engage in unhealthy eating and dieting behaviors, including smoking to control weight. Data were collapsed from 89 currently overweight (BMI> or =25) women smokers who were recruited to participate in smoking research projects that focused on weight, body image, and food intake. We compared those who reported first becoming overweight before Junior High School (n=22) with those who recalled first experiencing weight problems during Junior High School or later (n=67). Women with Childhood Onset weight problems reported first trying cigarettes at a significantly younger age than those with Later Onset (13 vs. 15 years of age, respectively), and they reported more nicotine withdrawal symptoms during smoking abstinence, with a significantly greater likelihood of endorsing anger/irritability and trouble concentrating. No group differences were evident for cigarettes per day or other indicators of nicotine dependence (e.g., FTND). Although it is unclear whether having weight problems during childhood contributes directly to smoking initiation, our results provide evidence that Childhood Onset weight problems may serve as a marker for earlier smoking experimentation and may also complicate cessation efforts due to their association with elevated withdrawal symptomatology. Future longitudinal studies with prospective measures of weight, dieting, and smoking initiation may be helpful in establishing causal pathways in different subgroups of smokers.

Differences in smoking-related variables based on phenylthiocarbamide "taster" status.

Test strips impregnated with phenylthiocarbamide (PTC) have been used to identify genetic differences based on whether a bitter taste is perceived. To determine whether smokers who perceive PTC as bitter tasting ("tasters") would differ from those who describe it as tasteless ("non-tasters") on smoking-related variables, we studied 464 current smokers (70% female, 79% White; mean age 30.5+/-9 years) recruited to participate in laboratory experiments and clinical trials. Of these, 217 (47%) reported the PTC strips as tasteless and 154 (33%) as tasting bitter. The remaining 93 (20%) described the taste as salty, sweet, or other and were excluded from further analyses. Comparing tasters with non-tasters, we found significant differences in mean (S.D.) total years smoked (14.5 [9.2] for non-tasters, vs. 12.6 [8.4] for tasters, p<.05), Fagerstrom Tolerance Questionnaire scores (6.4 [2.1] vs. 5.8 [2.1], p<.01), and scores on the Positive Reinforcement scale of the Michigan-Nicotine Reinforcement Questionnaire (8.1 [2.9] vs. 6.8 [3.1], p<.05). Results suggest that among smokers, ability to taste PTC may confer some protection from development of nicotine dependence and positive reinforcement from smoking.

Differences in accuracy of offspring assessment based on parental smoking status.

To investigate the accuracy of offspring assessments of parental smoking status, we studied 116 parents and 151 adult children (276 parent-child dyads) who provided data on both their own and their parents' smoking status. All currently smoking and all ex-smoking parents were correctly classified as ever-smokers by their offspring (n = 79 and 100, respectively). Of the 97 offspring who reported on never-smoking parents, 88 correctly classified their parents as never-smokers. Thus, sensitivity for detecting ever-smoking in parents was 100%, and specificity, 91%. Because all incorrect classifications involved never-smoking parents, further analyses focused on this group. Too few parents were misclassified to permit testing of parental characteristics. Offspring who misclassified their parents were significantly older than those who did not; neither sex nor smoking status of the offspring was associated with the increased likelihood of misclassification. No significant differences were discovered for dyadic factors (concordance/discordance for sex; parent-offspring age difference). Overall, these results support the utility of proxy reports of parental smoking phenotype by adult informants when self-report is unavailable.

Validity of retrospective assessments of nicotine dependence: a preliminary report.

Information about levels of nicotine dependence in ex-smokers when they smoked, or in current smokers at an earlier date, is useful for clinical and research purposes. To estimate the accuracy of retrospective reports of dependence, 28 individuals who completed either the Fagerström Tolerance Questionnaire (FTQ) or Fagerström Test for Nicotine Dependence (FTND) in smoking cessation trials conducted 5 to 12 years earlier were asked to respond again to the same questions, thinking back to their smoking behavior just prior to their on-study quit attempt. Concordance and Kappa values for the items ranged from 50.0% to 95.0% and 0.00 to 0.92, respectively. The mean difference between the baseline and follow-up total scale scores was 0.05 for the FTQ and 0.38 for the FTND, and the correlation between these assessments was 0.62 for the FTQ (p<0.005) and 0.72 for the FTND (p<0.05). These preliminary results suggest that retrospectively assessed FTQ/FTND scale scores have acceptable reliability.

Validation of retrospective reports of early experiences with smoking.

Initial sensitivity to the pharmacological effects of a drug may affect patterns of future use and dependence for a wide variety of drugs. Retrospective reports of sensations experienced upon early experimentation, however, may be limited by recall bias based on time elapsed and subsequent experiences. To validate reports of early experiences with nicotine, we studied 34 smokers who had contributed retrospective data on early experiences with smoking. Half had reported experiencing a buzz from smoking their first cigarette (the "yes" group), the other half had not (the "no" group). To simulate initial sensitivity to nicotine, we asked participants to remain abstinent from smoking for 5 days to allow for the dissipation of tolerance. They then participated in a laboratory session in which they were reexposed to nicotine in an unfamiliar form (nicotine nasal spray) and asked to indicate pleasurable responses by depressing a foot pedal if and when they experienced a "pleasurable buzz." Smokers in the "yes" group were marginally more likely to be male. The two groups did not differ significantly on age or race. The "yes" group smoked significantly more cigarettes/day than the "no" group. When the two groups were compared for response to nasal spray following 5 days' abstinence, smokers in the "yes" group were marginally more likely to have signaled experiencing at least one pleasurable buzz and rated "pleasurable sensation from spray" on a 100-mm visual analogue scale administered 10 min after nicotine dosing significantly higher than were those in the "no" group. To the extent that several days' abstinence can serve as a model for initial sensitivity to nicotine, our findings validate retrospective reports of pleasurable sensations upon early smoking experimentation.

Unaided smoking cessation among smokers in treatment for alcohol dependence.

To investigate the possible impact of treatment of alcohol dependence on smoking, we studied 144 smokers in an alcohol treatment center for whom 6-month data were available. Of those, 18 reported not smoking at 6 months. No significant differences in age, gender, or race were observed between quitters and continuing smokers. Quitters at 6 months were significantly more likely to be low dependent smokers than were continuing smokers and were significantly more likely to report no drinking during the past 28 days at the end of 1 month's treatment (93%) than continuing smokers (62%). These findings suggest that quitting smoking may be associated with low levels of nicotine dependence and favorable alcohol treatment response in alcoholic smokers.

Prolonged nicotine patch use in quitters with past abstinence-induced depressed mood.

To test the efficacy of sustained nicotine patch use among at-risk smokers, 55 smokers with a history of abstinence-induced depressed mood were randomly assigned to either Nicotine Maintenance or Standard Treatment following preliminary high-dose patch treatment. The Nicotine Maintenance group received 21 mg transdermal nicotine for 8 additional weeks; the Standard Treatment group followed a tapered dosing regimen. Significant differences favoring the Nicotine Maintenance group were found in self-reported craving but not withdrawal. No difference was observed in continuous abstinence or in relapse rates. When dropouts who did not relapse during patch use were classified as successful, however, the Nicotine Maintenance group had significantly lower relapse rates. Rate of lapse in the Nicotine Maintenance group during post-trial tapering did not differ significantly from that in the Standard Treatment group during tapering in the trial, suggesting that the benefits of sustained dosing may persist only as long as dosing continues.

Patterns of depressive symptomatology in women smokers, ex-smokers, and never-smokers.

To investigate the possibility that specific symptom patterns contribute differentially to excess depression among smokers, we analyzed Center for Epidemiological Studies-Depression (CES-D) and subscale scores in 931 women current smokers (CS), ex-smokers (ES), and never-smokers (NS). After adjusting for differences in age, education, and marital status, significant group differences were found for the CES-D overall and for Depressed Affect, Anhedonia, and Somatic Features, but not Interpersonal Distress. Both CS and ES scored significantly higher than NS on most measures, whereas differences between CS and ES failed to reach significance. CS were significantly more likely than NS to be taking antidepressants. Alcohol intake also showed significant group differences, with CS>ES>NS, suggesting that the link between current smoking and alcohol intake is mediated by factors other than depression, since CS and ES were comparably depressed. We conclude that studying specific symptom patterns may elucidate the smoking-depression link. Our observation that ES and CS exhibit similar levels of depressive symptomatology further suggests that interventions for depressed smokers need to take into account the likely persistence of depression following cessation.

Heterogeneity in phenotypes based on smoking status in the Great Lakes Smoker Sibling Registry.

We investigated whether 52 same-sex sibling pairs discordant for ever-smoking differed on psychiatric cofactors, alcohol and caffeine use, and responses to initial exposure to smoking. Ever-smokers scored significantly higher on measures of novelty seeking, depression, and childhood ADHD, and on alcohol dependence, alcohol intake, and caffeine intake. They reported significantly more pleasurable experiences, dizziness, "buzz," and relaxation upon initial exposure to smoking and significantly fewer displeasurable sensations, nausea, and cough than did nicotine-exposed, never-smoking siblings. Ever-smokers had significantly fewer years of education than their never-smoking siblings, suggesting that the concentration of smokers in lower socioeconomic strata may be partly due to downward mobility among smokers, possibly because of the observed elevation in psychiatric cofactors, which may interfere with academic performance. These findings are consistent with differences previously identified in unrelated ever- and never-smokers. Because same-sex siblings typically share a large set of common environments during childhood, our findings could be due either to genetic differences among siblings and/or (excepting educational level and responses to early exposure) to differences in adult environments.

Association of parental smoking history with nicotine dependence, smoking rate, and psychological cofactors in adult smokers.

Family history is a powerful predictor of variation in risk of common diseases and conditions because it can represent the influence of both shared genes and shared environments. To investigate the relationship of parental smoking history with nicotine dependence and smoking rate, as well as with known psychological cofactors for smoking (depression, anxiety, alcoholism, disordered eating), we studied smoking adults who provided smoking history for both parents. We found that having two ever-smoking parents, in comparison to zero or one, was associated with higher nicotine dependence scores, cigarettes per day, and levels of anxiety in participant, with a trend for depression. Participants whose mothers smoked during pregnancy had significantly higher scores on nicotine dependence, smoking rate, and disordered eating than participants with either ever-smoking mothers who did not smoke during pregnancy or never-smoking mothers. These findings suggest that family history of smoking may be a key determinant of interindividual variation in smoking behavior, nicotine dependence, and psychological cofactors among smokers.