The contribution of rare and common variants in 30 genes to risk nicotine dependence.

Genetic and functional studies have revealed that both common and rare variants of several nicotinic acetylcholine receptor subunits are associated with nicotine dependence (ND). In this study, we identified variants in 30 candidate genes including nicotinic receptors in 200 sib pairs selected from the Mid-South Tobacco Family population with equal numbers of African Americans (AAs) and European Americans (EAs). We selected 135 of the rare and common variants and genotyped them in the Mid-South Tobacco Case-Control (MSTCC) population, which consists of 3088 AAs and 1430 EAs. None of the genotyped common variants showed significant association with smoking status (smokers vs non-smokers), Fagerström Test for ND scores or indexed cigarettes per day after Bonferroni correction. Rare variants in NRXN1, CHRNA9, CHRNA2, NTRK2, GABBR2, GRIN3A, DNM1, NRXN2, NRXN3 and ARRB2 were significantly associated with smoking status in the MSTCC AA sample, with weighted sum statistic (WSS) P-values ranging from 2.42 × 10(-3) to 1.31 × 10(-4) after 10(6) phenotype rearrangements. We also observed a significant excess of rare nonsynonymous variants exclusive to EA smokers in NRXN1, CHRNA9, TAS2R38, GRIN3A, DBH, ANKK1/DRD2, NRXN3 and CDH13 with WSS P-values between 3.5 × 10(-5) and 1 × 10(-6). Variants rs142807401 (A432T) and rs139982841 (A452V) in CHRNA9 and variants V132L, V389L, rs34755188 (R480H) and rs75981117 (N549S) in GRIN3A are of particular interest because they are found in both the AA and EA samples. A significant aggregate contribution of rare and common coding variants in CHRNA9 to the risk for ND (SKAT-C: P=0.0012) was detected by applying the combined sum test in MSTCC EAs. Together, our results indicate that rare variants alone or combined with common variants in a subset of 30 biological candidate genes contribute substantially to the risk of ND.

The impact of brief tobacco treatment training on practice behaviours, self-efficacy and attitudes among healthcare providers.

INTRODUCTION AND PURPOSE: The need for aggressive efforts to help tobacco users quit remains a healthcare priority. Brief interventions delivered in the healthcare environment continue to be a valuable component of a comprehensive tobacco control policy. Unfortunately, such treatments are offered less often than desired, and quality is variable. Previous research has demonstrated the value of training experiences in increasing treatment availability, quality, as well as improving clinical outcomes. Less is known about how specific clinical activities and other features are impacted as a function of training. These issues were explored within the context of a standardised 5A's (ASK, ADVISE, ASSESS, ASSIST, ARRANGE) brief intervention training program. METHODS: A variety of healthcare providers participated in this study. Survey methodology was employed to collect Practice Behaviour, Self-Efficacy and Attitude ratings at pretraining, post training and 6-month follow-up. Linear mixed effects models were used to evaluate primary outcomes, and linear regression to explore the relationships among clinical variables. RESULTS: Pretraining data suggested overall modest levels of tobacco treatment activity, with limited direct intervention (ASSIST) or follow-up (ARRANGE) efforts. The training experience was shown to have a substantial and sustained impact on 5A's Practice Behaviour ratings, and other clinical indicators (all Pre vs. Post and Pre vs. Follow-up comparisons p < 0.001). Self-Efficacy at post training predicted practice behaviours at follow-up (for ADVISE, ASSESS, ASSIST and ARRANGE: all p's < 0.05). CONCLUSIONS: The value of a structured training experience was confirmed, and findings served to clarify the specific nature of training program impact.

Genome-wide association analyses suggested a novel mechanism for smoking behavior regulated by IL15.

Cigarette smoking is the leading preventable cause of death in the United States. Although smoking behavior has a significant genetic determination, the specific genes and associated mechanisms underlying the smoking behavior are largely unknown. Here, we carried out a genome-wide association study on smoking behavior in 840 Caucasians, including 417 males and 423 females, in which we examined approximately 380,000 single nucleotide polymorphisms (SNPs). We found that a cluster of nine SNPs upstream from the IL15 gene were associated with smoking status in males, with the most significant SNP, rs4956302, achieving a P-value (8.80 x 10(-8)) of genome-wide significance. Another SNP, rs17354547 that is highly conserved across multiple species achieved a P-value of 5.65 x 10(-5). These two SNPs, together with two additional SNPs (rs1402812 and rs4956396) were selected from the above nine SNPs for replication in an African-American sample containing 1251 subjects, including 412 males and 839 females. The SNP rs17354547 was replicated successfully in the male subgroup of the replication sample; it was associated with smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerstrom Test for Nicotine Dependence (FTND), with P-values of 0.031, 0.0046 and 0.019, respectively. In addition, a haplotype formed by rs17354547, rs1402812 and rs4956396 was also associated with SQ, HSI and FTND, achieving P-values of 0.039, 0.0093 and 0.0093, respectively. To further confirm our findings, we carried out an in silico replication study of the nine SNPs in a Framingham Heart Study sample containing 7623 Caucasians from 1731 families, among which, 3491 subjects were males and 4132 were females. Again, the male-specific association with smoking status was observed, for which seven of the nine SNPs achieved significant P-values (P<0.05) and two achieved marginally significant P-values (P<0.10) in males. Several of the nine SNPs, including the highly conserved one across species, rs17354547, are located at potential transcription factor binding sites, suggesting transcription regulation as a possible function for these SNPs. Through this function, the SNPs may modulate the gene expression of IL15, a key cytokine regulating immune function. As the immune system has long been recognized to influence drug addiction behavior, our association findings suggest a novel mechanism for smoking addiction involving immune modulation through the IL15 pathway.

Bitter taste receptor gene polymorphisms are an important factor in the development of nicotine dependence in African Americans.

CONTEXT: Bitter sensitivity varies among individuals and ethnic groups partly due to polymorphisms in taste receptor genes (TAS2Rs). Although previous psychophysical studies suggest that taste status plays a role in nicotine dependence (ND), genetic evidence is lacking. OBJECTIVES: To determine whether single nucleotide polymorphisms (SNPs) in TAS2R16 and TAS2R38 are associated with ND and if the effects differ by sex and ethnicity. DESIGN, SETTING, AND PARTICIPANTS: 2037 individuals from 602 nuclear families of African American (AA) or European American (EA) origin were recruited from the US mid-south states during 1999-2004. MAIN OUTCOME MEASURES: ND was assessed by three measures: indexed Smoking Quantity (SQ), Heaviness of Smoking Index (HSI), and the Fagerström Test for Nicotine Dependence (FTND). Peripheral blood samples were obtained for DNA extraction and genotyping. RESULTS: The TAS2R38 taster haplotype PAV was inversely associated (p = 0.0165), and the non-taster haplotype AVI was positively associated (p = 0.0120), with SQ in AA smokers. The non-taster haplotype was positively associated with all ND measures in AA female smokers (p = 0.01 approximately 0.003). No significant associations were observed in the EA sample. CONCLUSIONS: TAS2R38 polymorphisms are an important factor in determining ND in AAs. Heightened oral sensitivity confers protection against ND. Conversely, decreased sensitivity represents a risk factor for ND, especially in AA females. Together, our findings suggest that taster status plays a role in governing the development of ND and may represent a way to identify individuals at risk for developing ND, particularly in AA smokers.

Genome-wide linkage scan for nicotine dependence in European Americans and its converging results with African Americans in the Mid-South Tobacco Family sample.

Previously, we reported a genome-wide scan for nicotine dependence (ND) in the African American (AA) sample of the Mid-South Tobacco Family (MSTF) cohort. In this study, we conducted a genome-wide scan in 629 individuals representing 200 nuclear families of European American (EA) origin of the MSTF cohort with the goals of identifying vulnerability loci for ND in the EAs and determining converging regions across the ethnic groups. We examined 385 autosomal microsatellite markers for ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerström test for ND (FTND). After performing linkage analyses using various methods implemented in the GENEHUNTER and SAGE programs, we found eight regions on chromosomes 2, 4, 9-12, 17 and 18 that met the criteria for suggestive linkage to at least one ND measure in the EA sample. Of these, the region on chromosome 4 at 43 cM showed suggestive linkage to indexed SQ, the HSI and the FTND, and the region on chromosome 9 at 24 cM showed suggestive linkage to the HSI and the FTND. To increase detection power, we analyzed a combined AA and EA sample using age, gender and ethnicity as covariates and found that the region on chromosome 12 near marker D12S372 showed significant linkage to SQ. Additionally, we found six regions on chromosomes 9-11, 13 and 18 that showed suggestive linkage to at least one ND measure in the combined sample. When we compared the linkage peaks detected for ND among the two samples and a combined sample, we found that four regions on chromosomes 9 (two regions), 11 and 18 overlapped. On the other hand, we identified five regions on chromosomes 2, 4, 10, 12 and 17 that showed linkage to ND only in the EA sample, and two regions on chromosomes 10 and 13 that showed linkage to ND only in the AA sample. For those linkages identified in only one sample, we found that the combined analysis of AA plus EA samples actually decreased the linkage signal. This indicates that some chromosomal regions may be more homogenous than others across the ethnic samples. All regions except for the one on chromosome 12 have been detected at nominally significant levels in other studies, providing independent replication of ND loci in different populations.

Beta-arrestins 1 and 2 are associated with nicotine dependence in European American smokers.

On the basis of our previous identified linkage regions for nicotine dependence (ND), we selected seven and four single nucleotide polymorphisms (SNPs) in the beta-arrestins 1 (ARRB1) and 2 (ARRB2), respectively, to determine the associations of the two genes with ND in a total of 2037 subjects from 602 nuclear families of European American (EA) and African American (AA) origin. ND was assessed by Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerström Test for ND (FTND) score. Individual SNP analysis indicated that SNPs rs472112 within ARRB1 and rs4790694 within ARRB2 in the EA sample was significantly associated with HSI and FTND score, and the association of rs4790694 for ARRB2 remained significant after correction for multiple testing. Haplotype analysis revealed that haplotype C-G-C-G-G-T within ARRB1 at a frequency of 20%, formed by SNPs rs528833, rs1320709, rs480174, rs5786130, rs611908 and rs472112, was positively associated with HSI and FTND in EAs. We also found a haplotype within ARRB2, C-C-A-T at a frequency of 10.7%, formed by SNPs rs3786047, rs4522461, rs1045280 and rs4790694, that showed a significant positive association with HSI and FTND in the EA sample. No significant associations for either individual SNPs or major haplotype of both ARRB1 and ARRB2 were found in the AA sample. Further, the strength of these associations increased after removing the SQ component from HSI and FTND scores in both the EA and AA samples, suggesting that ARRB1 and ARRB2 play an important role in biological processes involved in the regulation of smoking urgency (that is time to smoke first cigarette). In summary, our results provide the first evidence of a significant association for ARRB1 and ARRB2 variants with ND in an EA sample.

Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence.

Our previous linkage study demonstrated that the 9q22-q23 chromosome region showed a 'suggestive' linkage to nicotine dependence (ND) in the Framingham Heart Study population. In this study, we provide further evidence for the linkage of this region to ND in an independent sample. Within this region, the gene encoding Src homology 2 domain-containing transforming protein C3 (SHC3) represents a plausible candidate for association with ND, assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerström Test for ND (FTND). We utilized 11 single-nucleotide polymorphisms within SHC3 to examine the association with ND in 602 nuclear families of either African-American (AA) or European-American (EA) origin. Individual SNP-based analysis indicated three SNPs for AAs and one for EAs were significantly associated with at least one ND measure. Haplotype analysis revealed that the haplotypes A-C-T-A-T-A of rs12519-rs3750399-rs4877042-rs2297313-rs1547696-rs1331188, with a frequency of 27.8 and 17.6%, and C-T-A-G-T of rs3750399-rs4877042-rs2297313-rs3818668-rs1547696, at a frequency of 44.7 and 30.6% in the AA and Combined samples, respectively, were significantly inversely associated with the ND measures. In the EA sample, another haplotype with a frequency of 10.6%, A-G-T-G of rs1331188-rs1556384-rs4534195-rs1411836, showed a significant inverse association with ND measures. These associations remained significant after Bonferroni correction. We further demonstrated the SHC3 contributed 40.1-59.2% (depending on the ND measures) of the linkage signals detected on chromosome 9. As further support, we found that nicotine administered through infusion increased the Shc3 mRNA level by 60% in the rat striatum, and decreased it by 22% in the nucleus accumbens (NA). At the protein level, Shc3 was decreased by 38.0% in the NA and showed no change in the striatum. Together, these findings strongly implicate SHC3 in the etiology of ND, which represents an important biological candidate for further investigation.

Psychometric properties of the Weekly Stress Inventory (WSI): extension to a patient sample with coronary heart disease.

The psychometric characteristics of the Weekly Stress Inventory (WSI) were examined in a sample of medical patients (N = 84) diagnosed with coronary heart disease. In addition to the WSI, patients completed measures assessing recent depressive symptoms, physical symptoms, Type A behavior, and trait anxiety. Patients also monitored stress for 3 weeks (n = 46), completing the Daily Stress Inventory (a measure of minor stress) daily and the WSI at concurrent 1-week intervals. Results indicated that the WSI is an internally consistent and moderately stable measure. Validity of the WSI was supported by (a) strong correlations with a concurrently administered measure of minor stress (concurrent validity); (b) significant positive correlations with measures assessing recent depressive symptoms, physical symptoms, and Type A behavior; and (c) a lack of relationship with a measure of trait anxiety (discriminant validity).

Reactivity to smoking cues: mediating roles of nicotine dependence and duration of deprivation.

This study examined the roles of nicotine dependence and duration of smoking deprivation as mediators of smoking cue reactivity in 117 individuals enrolled in treatment. Participants were randomly assigned to 15, 90, or 180 min of deprivation; all were exposed to smoking cues (observing a research assistant smoke a cigarette) while a variety of self-report, behavioral, and psychophysiological measurements were obtained. Results indicated that in general, psychophysiological reactivity to smoking-relevant cues was greater with increasing deprivation; heart rate analysis revealed an interaction between nicotine dependence and duration of deprivation. Smoking desire, negative affect, physical withdrawal symptoms, and other ratings were interrelated during cue exposure, and generally demonstrated predicted relationships with the independent variables. Multiple regression analysis revealed that desire to smoke during cue exposure was predicted by a combination of psychophysiological, self-report, and demographic variables. These findings have implications for methodological considerations and theoretical underpinnings of smoking cue reactivity research.

Chest pain self-management training for patients with coronary artery disease.

This study was designed to evaluate the efficacy of a brief, structured pain management program to improve control over chest pain episodes in patients diagnosed with coronary artery disease. Twenty-six male veterans who attended the three-session program were compared with twenty-six matched controls. Results indicated significant short-term reductions in self-report of number of chest pain episodes in treated subjects. Self-report of pretreatment daily physical activity level moderated treatment outcome, as individuals reporting lower levels of physical activity derived greater benefit than their high-activity counterparts. These results suggest the potential utility of incorporating chest pain control strategies into comprehensive cardiac rehabilitation programs.

Assessing nicotine dependence: a comparison of the Fagerström Tolerance Questionnaire (FTQ) with the Fagerström Test for Nicotine Dependence (FTND) in a clinical sample.

A recent effort to improve the psychometric properties of the Fagerström Tolerance Questionnaire (FTQ) resulted in the revised Fagerström Test for Nicotine Dependence (FTND). We endeavored to replicate and extend findings suggesting the superiority of the FTND by examining the psychometric properties of both instruments, as well as their relationship to self-report and biochemical variables associated with nicotine dependence in 110 smoking clinic participants. Results verified that the FTND represents a modest improvement over the FTQ, however, the need for continued development of self-report measures of nicotine dependence is noted.

Cognitive and affective responses to successful coping during smoking cessation.

Based on Marlatt's relapse model, this study examined the previously unexplored role of cognitive and affective responses that follow successful coping experiences during smoking cessation. Twenty-six smokers completed self-report measures of attribution, efficacy, and affect in response to smoking cessation behaviors during treatment and at 2-, 4-, and 8-week follow-ups. Subjects abstinent at 3-month follow-up were more likely to attribute their successful quitting behaviors to more internal, stable, and controllable factors, and they reported enhanced self-efficacy, compared with smokers. Differences in affective responses to successful coping by quitters and smokers were not significant. Implications of the findings with respect to relapse theory and relapse prevention treatment are discussed.

Reactivity to alcohol-relevant beverage and imaginal cues in alcoholics.

This study was designed to explore three primary facets of reactivity to alcohol-relevant stimuli among alcoholics: (a) comparison of exposure to an alcohol-containing beverage vs. an appropriate, standardized control beverage; (b) efficacy of imaginally presented cues to elicit reactivity, alone and in combination with beverage cues; and (c) examination of the recovery process. Forty-eight male veterans attending an inpatient alcohol treatment program served as participants and were randomly assigned to one of four groups in a 2 (Alcohol vs. Lemonade Beverage) X 2 (High-Risk vs. Low-Risk Imagery) design. Heart rate reactivity to Beverage cues was consistent with previous research. An interaction of Beverage and Imagery manipulations during recovery revealed both experimental manipulations influenced heart rate, although the Alcohol/High-Risk Imagery exposure group did not demonstrate enhanced effects. Both manipulations also had an impact on ratings of desire to consume alcohol. These findings provide further support for the reliability of cue reactivity effects, and suggest the utility of imaginal exposure procedures as a component of a comprehensive cue reactivity assessment.

Treatment of a 15-year-old girl with chronic muscle-contraction headache using implosive therapy.

A 15-year-old girl with chronic muscle-contraction headache was treated initially using a behaviourally based headache programme. Little change in headache activity resulted. Implosive therapy was incorporated into treatment after the girl revealed a past episode of sexual abuse. A substantial reduction in headache activity was noted at post-treatment and follow-up.

The impact of cigarette smoking on headache activity in headache patients.

The present study was designed to explore the relationship between cigarette smoking and headache activity in a sample of patients presenting for treatment. Subjects completed various self-report measures and monitored headache activity four times per day over a 4-week period. Analyses revealed that smokers experienced greater weekly peak headache intensity, and reported higher levels of depression and general physical symptoms. Among smokers, nicotine content of the preferred brand was associated with mean headache index and weekly headache-free days, as well as depression and anxiety scores. Daily smoking rate and pack-year history were related to level of general physical symptoms only. Thus, both smoking status and the nicotine content of the preferred cigarette appear to adversely impact headache activity. Further, smokers who are more anxious or depressed may increase their headache activity via their preference for higher nicotine-content cigarettes. These results are discussed in the context of possible mechanisms underlying these effects, and implications for the clinical management of headache suffers who smoke.

Exposure to smoking-relevant cues: effects on desire to smoke and topographical components of smoking behavior.

The effects of exposure to two classes of smoking-relevant cues (environmental; negative affect) on desire to smoke and smoking topography were evaluated. Sixty chronic smokers were randomly assigned to one of six groups in a two-way ANOVA design in which the salience of environmental cues and presence of negative affective cues were manipulated. This was followed by a 20-minute interval during which ad libitum smoking was videotaped in an unobtrusive manner. Results indicated that the experimental manipulations differentially influenced ratings of desire and topographical components of smoking behavior. Implications are raised regarding the role of cue reactivity in the maintenance of smoking behavior.

Conditioning arbitrary stimuli to cigarette smoke intake: a preliminary study.

This study represents an attempt to classically condition arbitrary stimuli to cigarette smoke intake. A smoker either smoked or mock-smoked a cigarette in two discriminative contexts for 20 sessions. The contingencies were reversed during an additional last two sessions. Measures of heart rate, skin temperature, and puff duration were monitored during all sessions. Results suggested that both manipulations of smoke delivery and context cues were related to puff duration. The pattern of psychophysiological reactivity was mixed and not easily interpreted. This experimental paradigm may be useful in the investigation of conditioning factors underlying addictive behaviors.