The Nicotine Metabolite Ratio (NMR, ratio of trans-3’-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.
Although HIV is contracted by individuals, it is typically transmitted in dyads. Most efforts to promote safer sex practices, however, focus exclusively on individuals. The goal of this paper is to provide a theoretical framework that specifies how models of dyadic processes and relationships can inform models of HIV-prevention. At the center of the framework is the proposition that safer sex between two people requires a dyadic capacity for successful coordination. According to this framework, relational, individual, and structural variables that affect the enactment of safer sex do so through their direct and indirect effects on that dyadic capacity. This dyadic perspective does not require an ongoing relationship between two individuals; rather, it offers a way of distinguishing between dyads along a continuum from anonymous strangers (with minimal coordination of behavior) to long-term partners (with much greater coordination). Acknowledging the dyadic context of HIV-prevention offers new targets for interventions and suggests new approaches to tailoring interventions to specific populations.
HIV-prevention; Dyads; Interpersonal relationships; Safer sex; Models
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
CHRNA5; CHRNA3; CHRNB4; meta-analysis; nicotine; smoke
Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.
To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.
Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.
Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.
Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36–1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21–1.33, n = 19 505) (P = .01).
These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
We utilized a cohort of 828 treatment seeking self-identified white cigarette smokers (50% female) to rank candidate gene single nucleotide polymorphisms (SNPs) associated with the Fagerström Test for Nicotine Dependence (FTND), a measure of nicotine dependence which assesses quantity of cigarettes smoked and time- and place-dependent characteristics of the respondent’s smoking behavior. 1123 SNPs at 55 autosomal candidate genes, nicotinic acetylcholine receptors and genes involved in dopaminergic function, were tested for association to baseline FTND scores adjusted for age, depression, education, sex and study site. SNP P values were adjusted for the number of transmission models, the number of SNPs tested per candidate gene, and their intragenic correlation. DRD2, SLC6A3 and NR4A2 SNPs with adjusted P values < 0.10 were considered sufficiently noteworthy to justify further genetic, bioinformatic and literature analyses. Each independent signal among the top-ranked SNPs accounted for ~1% of the FTND variance in this sample. The DRD2 SNP appears to represent a novel association with nicotine dependence. The SLC6A3 SNPs have previously been shown to be associated with SLC6A3 transcription or dopamine transporter density in vitro, in vivo and ex vivo. Analysis of SLC6A3 and NR4A2 SNPs identified a statistically significant gene-gene interaction (P=0.001), consistent with in vitro evidence that the NR4A2 protein product (NURR1) regulates SLC6A3 transcription. A community cohort of N=175 multiplex ever smoking pedigrees (N=423 ever smokers) provided nominal evidence for association with the FTND at these top ranked SNPs, uncorrected for multiple comparisons.
dopamine transporter; Fagerström Test for Nicotine Dependence; single nucleotide polymorphism; candidate gene association scan; gene-gene interaction
Nicotine withdrawal symptoms are related to smoking cessation. A Rasch model has been used to develop a unidimensional sensitivity score representing multiple correlated measures of nicotine withdrawal. A previous autosome-wide screen identified a nonparametric linkage (NPL) log-likelihood ratio (LOD) score of 2.7 on chromosome 6q26 for the sum of nine withdrawal symptoms.
The objectives of these analyses are: a) to assess the influence of nicotine withdrawal sensitivity on relapse, b) conduct autosome-wide NPL analysis of nicotine withdrawal sensitivity among 158 pedigrees with 432 individuals with microsatellite genotypes and nicotine withdrawal scores, and c) explore family-based association of single nucleotide polymorphism (SNPs) at the mu opioid receptor (MOR) candidate gene (OPRM1) to nicotine withdrawal sensitivity in 172 nuclear pedigrees with 419 individuals with both SNP genotypes and nicotine withdrawal scores.
An increased risk for relapse was associated with nicotine withdrawal sensitivity score (odds ratio, OR=1.25, 95% confidence interval, 95%CI=1.10,1.42). A maximal NPL LOD score of 3.15, suggestive of significant linkage, was identified at chr6q26 for nicotine withdrawal sensitivity. Evaluation of 18 OPRM1 SNPs via the family based association test (FBAT) with the nicotine withdrawal sensitivity score identified eight tagging SNPs with global P-values<0.05 and false discovery rate Q-values<0.06.
An increased risk of relapse, suggestive linkage at chr6q26, and nominally significant association with multiple OPRM1 SNPs was found with Rasch modeled nicotine withdrawal sensitivity score in a multiplex smoking pedigree sample. Future studies should attempt to replicate these findings and investigate the relationship between nicotine withdrawal symptoms and variation at OPRM1.
Adolescents who abuse substances are more likely to engage in health-risking sexual behavior (HRSB) and are at particularly high risk for HIV/AIDS. Thus, substance abuse treatment presents a prime opportunity to target HIV-risk behaviors. The present study evaluated a one-session HIV-risk intervention embedded in a controlled clinical trial for drug-abusing adolescents. The trial was conducted in New Mexico and Oregon with Hispanic and Anglo adolescents. Youths were randomly assigned to individual cognitive behavior therapy (CBT) or to an integrated behavioral and family therapy (IBFT) condition, involving individual and family sessions. The HIV-specific intervention was not associated with change. IBFT and CBT were both efficacious in reducing HIV-risk behaviors from intake to the 18-month follow-up for high-risk adolescents. For low-risk adolescents, CBT (versus IBFT) was more efficacious in suppressing HRSB. These data suggest that drug abuse treatments can have both preventative and intervention effects for adolescents, depending on their relative HIV-risk.
Adolescent; Substance-abuse; Treatment; HIV-risk
Collaborating with community stakeholders is an often suggested step when integrating cultural variables into psychological treatments for members of ethnic minority groups. However, there is a dearth of literature describing how to accomplish this process within the context of substance abuse treatment studies. This paper describes a qualitative study conducted through a series of focus groups with stakeholders in the Latino community. Data from focus groups were used by researchers to guide the integration of cultural variables into an empirically-supported substance abuse treatment for Latino adolescents currently being evaluated for efficacy. A model for culturally accommodating empirically-supported treatments for ethnic minority participants is also described.
This study examined whether parents of adolescents experiencing depressive symptoms or disorder make more negative and fewer positive attributions for their adolescents’ behavior than do parents of non-depressed adolescents, and whether parental attributions for adolescents’ behavior contribute to parenting behavior, above and beyond the adolescents’ behavior. Parents and adolescents (76 girls and 48 boys) participated in videotaped problem-solving interactions (PSIs). Each parent subsequently watched the videotape and offered attributions for their adolescent’s behavior. In addition, parent and adolescent behavior during the PSIs was coded. Mothers and fathers in families of non-depressed adolescents made significantly fewer negative attributions for their children’s behavior than did parents in families of adolescents with diagnostic or subdiagnostic levels of depressive symptoms. Moreover, mothers’ and fathers’ negative attributions were related to greater levels of observed aggressive behavior and lower levels of observed facilitative behavior during the PSIs controlling for both demographic characteristics and the relative level of adolescent aggressive and facilitative behavior during the PSI.
adolescent depression; parental attributions
This project studied the convergent validity of current recall of tobacco-related health behaviors, compared with prospective self-report collected earlier at two sites. Cohorts were from the Oregon Research Institute at Eugene (N = 346, collected 19.5 years earlier) and the University of Pittsburgh, Pennsylvania (N = 294, collected 3.9 years earlier). Current recall was examined through computer-assisted interviews with the Lifetime Tobacco Use Questionnaire from 2005 through 2008. Convergent validity estimates demonstrated variability. Validity estimates of some tobacco use measures were significant for Oregon subjects (age at first cigarette, number of cigarettes/day, quit attempts yes/no and number of attempts, and abstinence symptoms at quitting; all P < 0.03). Validity estimates of Pittsburgh subjects’ self-reports of tobacco use and abstinence symptoms were significant (P < 0.001) for all tobacco use and abstinence symptoms and for responses to initial use of tobacco. These findings support the utility of collecting recalled self-report information for reconstructing salient lifetime health behaviors and underscore the need for careful interpretation.
data collection; mental recall; prospective studies; reproducibility of results; retrospective studies; tobacco use disorder
Characterizing cotinine pharmacokinetics is a useful way to study nicotine metabolism because the same liver enzyme is primarily responsible for the metabolism of both, and the clearances of nicotine and cotinine are highly correlated. We conducted a whole-genome linkage analysis to search for candidate regions influencing quantitative variation in cotinine pharmacokinetics in a large-scale pharmacokinetic study with 61 families containing 224 healthy adult participants. The strongest linkage signal was identified at 135 cM of chromosome 9 with LOD=2.81 and P=0.0002; two other suggestive linkage peaks appear at 31.4 and 73.5 cM of chromosome 11 with LOD=1.96 (P=0.0013) and 1.94 (P=0.0014). The confidence level of the linkage between the three genome regions and cotinine pharmacokinetics is statistically significant with a genome-wide empirical probability of P=0.029.
pharmacokinetics; nicotine; dependence; linkage analysis
This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene × environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements.
Genome-wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter-marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19).
nicotine; dependence; linkage; genetics; smoking
This study compared family relationships across three groups of adolescents: a) those with unipolar depressive disorders (n = 82); b) those with subdiagnostic depressive symptoms (n = 78); and c) those without emotional or behavioral difficulties (n = 83). Results based on multi-source, multi-method constructs indicated that depressed adolescents, as well as those with subdiagnostic symptomatology, experience less supportive and more conflictual relationships with each of their parents than do healthy adolescents. These findings are notable in demonstrating that adverse father-adolescent relationships are associated with depressive symptomatology in much the same way as mother-adolescent relationships. As well, they add to the emerging evidence that adolescents with subdiagnostic symptoms experience difficulties in social relationships similar to those experienced by adolescents with depressive disorder.
This study describes the lifetime prevalence and future intentions
related to trying cigarettes, chewing tobacco, alcohol, marijuana, and inhalants
of students in the 1st through 7th grade. This article also describes the
identification of these substances by children in the 1st through 3rd grade.
Participants were 1,075 1st through 5th graders within a school district in
western Oregon who were followed for 3 years. Across most substances, prevalence
and intentions increased with grade, with a moderate increase between 3rd and
4th grade and a larger increase between 5th and 6th grade. Boys were more likely
than girls to identify alcohol and cigarettes and were more likely than girls to
report trying chewing tobacco. In addition, 3rd-grade boys were more likely to
identify marijuana and, in the early grades, alcohol. Boys were also more likely
than girls to intend to use tobacco and drink alcohol when older. For alcohol
and cigarettes, intention was related to subsequent trying of the substance,
suggesting that intention may be an early warning sign of subsequent substance
A comprehensive validation study was conducted of the Program for Academic Survival Skills (PASS), a consultant-based, teacher-mediated program for student classroom behavior. The study addressed questions related to: (a) brief consultant training, (b) subsequent teacher training by consultants using PASS manuals, (c) contrasts between PASS experimental teachers and students and equivalent controls on measures of teacher management skills, student classroom behavior, teacher ratings of student problem behaviors, and academic achievement, (d) reported satisfaction of participants, and (e) replication of effects across two separate school sites. Results indicated that in both sites significant effects were noted in favor of the PASS experimental group for (a) teacher approval, (b) student appropriate classroom behavior, and (c) four categories of student inappropriate behavior. Program satisfaction ratings of students, teachers, and consultants were uniformly positive, and continued use of the program was reported a year later. Discussion focused upon issues of cost-effectiveness, differential site effects, and the relationship between appropriate classroom behavior and academic achievement.
Classroom control and discipline; group contingencies; group reinforcement; behavior management programs; program evaluation; social validation; children
overcorrection; generalization; maintenance; verbal reprimands; multiple baseline; group home; retardates; behavioral contrast
This study illustrated the use of normative behavioral observation data as a standard for evaluating the practicality of treatment effects produced in other settings. Three groups of eight subjects each, displaying relatively low proportions of appropriate classroom behavior when compared with regular classroom peers, were selected for treatment within an experimental classroom setting. The three groups were exposed to intervention procedures designed to reinforce either direct academic performance and/or facilitative nonacademic classroom responses. The treatment was effective in changing levels of appropriate behavior (1) above baseline levels in the experimental classroom, and (2) to within normal peer-defined limits when reintegrated into the regular classroom. Further, the data reflect successful maintenance of these effects for a seven- to 12-week follow-up period. Several applications of a normative model for evaluating treatment, generalization, and maintenance effects were presented and discussed.
classroom behavior; maintenance; generalization; evaluation of treatment; methodology; mainstreaming of handicapped; reintegration; tokens; normative data; peers
The relative effects of rules, rules + feedback, and rules + feedback + group and individual consequences for appropriate behavior were investigated in three elementary classrooms during reading and mathematics periods. The consequences were individual and group praise, and group activities. The total intervention package (rules + feedback + group and individual consequences) was most effective in increasing appropriate behavior. Rules + feedback produced increased appropriate behavior in two of the three classrooms. Rules alone produced no change in classroom behavior. Maintenance of appropriate classroom behavior was noted approximately three weeks after the program ended. Teacher's correct use of praise was also maintained for two of the three teachers at levels generated during the total package condition.