Risk Factor For Nicotine Dependence Research Articles

Age is associated with altered locomotor and hypothermic response to acute nicotine.

Cigarette smoking is at an all-time low. However, nicotine consumption has diversified with the introduction of commercial tobacco products that include Electronic Nicotine Delivery Systems. Nicotine is the main psychoactive component of tobacco and contributes to the addictive properties of tobacco products. Prolonged nicotine exposure induces neural adaptations that promote addiction-related behaviors in an age-dependent manner. Here, we investigated nicotine sensitivity among young adult and middle-aged male mice by comparing initial responses to nicotine tartrate from different suppliers. We observed that all nicotine compounds tested in the present study induced a robust reduction in locomotor activity and body temperature, and nicotine exposure resulted in increased serum cotinine concentration. We observed age-related differences in the magnitude and the time course of nicotine responses for locomotor and hypothermic effects. Reduction in locomotor activity was larger among young adult mice, but the time course of this response was similar for both age groups. Nicotine-induced reduction in body temperature was of a comparable magnitude for both age groups but young adults showed a faster decrease than middle-aged mice. These results suggest that age of exposure is a key factor contributing to nicotine sensitivity and its potential addictive effects. These responses were consistently produced for nicotine tartrate from different sources. Our findings reveal distinct responses between young adults and middle-aged mice, suggesting that age-specific neurobiological mechanisms in nicotine sensitivity continue developing into adulthood. These age-related variations in nicotine response are crucial for developing targeted interventions and understanding the risk factors for nicotine dependence across the lifespan.

Association of nicotine dependence and gut microbiota: a bidirectional two-sample Mendelian randomization study.

Nicotine dependence is a key factor influencing the diversity of gut microbiota, and targeting gut microbiota may become a new approach for the prevention and treatment of nicotine dependence. However, the causal relationship between the two is still unclear. This study aims to investigate the causal relationship between nicotine dependence and gut microbiota. A two-sample bidirectional Mendelian randomization (MR) study was conducted using the largest existing gut microbiota and nicotine dependence genome-wide association studies (GWAS). Causal relationships between genetically predicted nicotine dependence and gut microbiota abundance were examined using inverse variance weighted, MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO approaches. Cochrane's Q test, MR-Egger intercept test, and leave-one-out analysis were performed as sensitivity analyses to assess the robustness of the results. Multivariable Mendelian randomization analysis was also conducted to eliminate the interference of smoking-related phenotypes. Reverse Mendelian randomization analysis was then performed to determine the causal relationship between genetically predicted gut microbiota abundance and nicotine dependence. Genetically predicted nicotine dependence had a causal effect on Christensenellaceae (β: -0.52, 95% CI: -0.934-0.106, P = 0.014). The Eubacterium xylanophilum group (OR: 1.106, 95% CI: 1.004-1.218), Lachnoclostridium (OR: 1.118, 95% CI: 1.001-1.249) and Holdemania (OR: 1.08, 95% CI: 1.001-1.167) were risk factors for nicotine dependence. Peptostreptococcaceae (OR: 0.905, 95% CI: 0.837-0.977), Desulfovibrio (OR: 0.014, 95% CI: 0.819-0.977), Dorea (OR: 0.841, 95% CI. 0.731-0.968), Faecalibacterium (OR: 0.831, 95% CI: 0.735-0.939) and Sutterella (OR: 0.838, 95% CI: 0.739-0.951) were protective factor for nicotine dependence. The sensitivity analysis showed consistent results. The Mendelian randomization study confirmed the causal link between genetically predicted risk of nicotine dependence and genetically predicted abundance of gut microbiota. Gut microbiota may serve as a biomarker and offer insights for addressing nicotine dependence.

Postnatal Smoke Exposure Further Increases the Hepatic Nicotine Metabolism in Prenatally Smoke Exposed Male Offspring and Is Linked with Aberrant Cyp2a5 Methylation.

Prenatal smoke exposure (PreSE) is a risk factor for nicotine dependence, which is further enhanced by postnatal smoke exposure (PostSE). One susceptibility gene to nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine in the liver. Higher CYP2A6 activity is associated with nicotine dependence and could be regulated through DNA methylation. In this study we investigated whether PostSE further impaired PreSE-induced effects on nicotine metabolism, along with Cyp2a5, orthologue of CYP2A6, mRNA expression and DNA methylation. Using a mouse model where prenatally smoke-exposed adult offspring were exposed to cigarette smoke for 3 months, enzyme activity, mRNA levels, and promoter methylation of hepatic Cyp2a5 were evaluated. We found that in male offspring, PostSE increased PreSE-induced cotinine levels and Cyp2a5 mRNA expression. In addition, both PostSE and PreSE changed Cyp2a5 DNA methylation in male groups. PreSE however decreased cotinine levels whereas it had no effect on Cyp2a5 mRNA expression or methylation. These adverse outcomes of PreSE and PostSE were most prominent in males. When considered in the context of the human health aspects, the combined effect of prenatal and adolescent smoke exposure could lead to an accelerated risk for nicotine dependence later in life.

Prenatal smoke exposure induces persistent Cyp2a5 methylation and increases nicotine metabolism in the liver of neonatal and adult male offspring

ABSTRACT Prenatal smoke exposure (PSE) is a risk factor for nicotine dependence. One susceptibility gene for nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine and nicotine clearance in the liver. Higher activity of the CYP2A6 enzyme is associated with nicotine dependence, but no research has addressed the PSE effects on the CYP2A6 gene or its mouse homologue Cyp2a5. We hypothesized that PSE affects Cyp2a5 promoter methylation, Cyp2a5 mRNA levels, and nicotine metabolism in offspring. We used a smoke-exposed pregnant mouse model. RNA, DNA, and microsomal protein were isolated from liver tissue of foetal, neonatal, and adult offspring. Enzyme activity, Cyp2a5 mRNA levels, and Cyp2a5 methylation status of six CpG sites within the promoter region were analysed via HPLC, RT-PCR, and bisulphite pyrosequencing. Our data show that PSE induced higher cotinine levels in livers of male neonatal and adult offspring compared to controls. PSE-induced cotinine levels in neonates correlated with Cyp2a5 mRNA expression and promoter methylation at CpG-7 and CpG+45. PSE increased methylation in almost all CpG sites in foetal offspring, and this effect persisted at CpG-74 in male neonatal and adult offspring. Our results indicate that male offspring of mothers which were exposed to cigarette smoke during pregnancy have a higher hepatic nicotine metabolism, which could be regulated by DNA methylation. Given the detected persistence into adulthood, extrapolation to the human situation suggests that sons born from smoking mothers could be more susceptible to nicotine dependence later in life.

Prevalence of Some Genetic Risk Factors for Nicotine Dependence in Ukraine.

Tobacco smoking is known to be a strong risk factor for developing many diseases. The development and severity of smoking dependence results from interaction of environmental and lifestyle factors, psycho-emotional predispositions, and also from genetic susceptibility. In present study, we investigated polymorphic variants in genes contributed to nicotine dependence, as well as to increased impulsivity, known to be an important risk factor for substance use disorders, in Ukraine population. The genotype frequencies at CYP2A6, DNMT3B, DRD2, HTR2A, COMT, BDNF, GABRA2, CHRNA5, and DAT1 polymorphisms were determined in 171 Ukraine residents, and these data were compared with data for several other European populations and main ethnic groups. It has been found that genotype frequencies for all studied loci are in Hardy-Weinberg equilibrium in the Ukrainian population and correspond to the respective frequencies in European populations. These findings suggest a similar impact of these loci on nicotine dependence in Ukraine. Further studies with larger sample sizes are, however, needed to draw firm conclusions about the effect size of these polymorphisms.

Risk factors for nicotine dependence in Chinese patients with lung cancer.

ObjectiveSmoking is a poor prognostic factor for lung cancer. Nicotine dependence remains the major cause of failure of smoking cessation. We investigated the risk factors for nicotine dependence in patients with lung cancer.MethodsEligible patients were identified from November 2014 to February 2015. Age, marital status, educational level, annual household income, occupation, histology of lung cancer, tumor stage, smoking status, neuron-specific enolase (NSE) level, drive gene mutations, sleep quality, and patient personality were assessed. Physical nicotine dependence was assessed by the Fagerstrom Test for Nicotine Dependence (FTND).ResultsIn total, 202 smokers were included in this study. Univariate analysis showed that marital status and pain were significantly correlated with nicotine dependence. Pearson’s correlation analysis showed that age at the initiation of smoking, attempts to quit, NSE level, and sleep quality were significantly correlated with FTND scores.ConclusionsPain, more attempts to quit, and poorer sleep quality were significantly associated with nicotine dependence. These risk factors could help to prevent smoking in Chinese patients with lung cancer.

Attention-Deficit/Hyperactivity Disorder and Nicotine Dependence in Adults

The aim of this study is to assess clinical characteristics and smoking profiles of individuals diagnosed with attention-deficit/hyperactivity disorder (ADHD) and compare their nicotine dependence status with healthy controls for better understanding the mutual and complex relationship between ADHD and smoking. We included the following participants in the study: 40 adults with the diagnosis of ADHD, 40 participants who visited the smoking cessation polyclinic without any psychiatric disorders, and 40 healthy controls. A sociodemographic data form, Wender Utah Rating Scale (WURS), Adult ADD/ADHD Diagnosis and Evaluation Inventory, and Fagerstrom Nicotine Dependence Test (FNDT) were administered to the participants. Mean age of the ADHD, nicotine dependence, and control groups was 28.68±7.22, 34.17±8.60, 33.70±7.45 years, respectively. Percentages of females and males were 27.5% and 72.5% in the ADHD group, 50% and 50% in the nicotine dependence group, 47.5% and 52.5% in the control group. The attention-deficit scores in the ADHD, nicotine dependence, and control groups were 21.18±5.05, 7.23±3.96, 4.75±2.65, respectively (p=0.001), whereas the hyperactivity scores were.73±5.84, 6.43±4.2, and 3.58±2.27, respectively (p=0.001). The related features scores were 56.53±12.96, 24.30±13.93, and 13.13±6.11, respectively (p=0.001), whereas the WURS scores were 61.88±12.69, 23.03±16.07, 11.90±8.15, respectively (p=0.001). FNDT scores in ADHD and nicotine dependence groups were 5.83±2.11 and 6.20±2.74, respectively (p=0.495). Considering the argument of ADHD being an independent risk factor for nicotine dependence, we think the co-occurrence of the smoking addiction and ADHD symptoms in the context of dopamine dysregulation is important in the clinical setting. Treatment modalities and of preventive strategies should be considered while keeping this in mind.

Nicotine Dependence and Alcohol Problems from Adolescence to Young Adulthood.

Despite the highly replicated relationship between symptoms associated with both alcohol and nicotine, little is known about this association across time and exposure to both drinking and smoking. In the present study, we evaluate if problems associated with alcohol use are related to emerging nicotine dependence symptoms and whether this relationship varies from adolescence to young adulthood, after accounting for both alcohol and nicotine exposure. The sample was drawn from the Social and Emotional Contexts of Adolescent Smoking Patterns Study which measured smoking, nicotine dependence, alcohol use and alcohol related problems over 6 assessment waves spanning 6 years. Analyses were based on repeated assessment of 864 participants reporting some smoking and drinking 30 days prior to individual assessment waves. Mixed-effects regression models were estimated to examine potential time, smoking and/or alcohol varying effects in the association between alcohol problems and nicotine dependence. Inter-individual differences in mean levels of alcohol problems and within subject changes in alcohol problems from adolescence to young adulthood were each significantly associated with nicotine dependence symptoms over and above levels of smoking and drinking behaviour. This association was consistent across both time and increasing levels of smoking and drinking. Alcohol related problems are a consistent risk factor for nicotine dependence over and above measures of drinking and smoking and this association can be demonstrated from the earliest experiences with smoking in adolescents, through the establishment of more regular smoking patterns across the transition to young adulthood. These findings add to accumulating evidence suggesting that smoking and drinking may be related through a mechanism that cannot be wholly accounted for by exposure to either substance.

New methods shed light on age of onset as a risk factor for nicotine dependence

IntroductionEarly onset of substance use is a risk factor for later drug use, abuse, and dependence. This study examines how the rate of nicotine dependence differs as a function of age of onset of regular smoking in continuous time, in order to identify critical age periods that are most predictive of later dependence for males and females. MethodsTime-varying effect modeling (TVEM) can reveal specific ages of onset that confer greatest risk for adult nicotine dependence. The rate of dependence in adulthood is modeled as a flexible function of age of onset using a subset of adults (N=15,748) from the National Epidemiologic Survey on Alcohol and Related Conditions who ever smoked regularly. ResultsThe peak risk of adult nicotine dependence coincides with onset of regular use at approximately 10years old, with an elevated risk persisting to 20years. The risk of dependence is significantly higher for females compared to males for onset of regular use between ages 9 and 18. ConclusionsResults suggest that the risk of adult nicotine dependence is highest when onset of regular smoking occurs at around 10years, though the associated risk is high for ages of onset into young adulthood. Early onset of regular use is a relatively stronger risk factor for adolescent females than males. Smoking prevention programs should focus on late childhood through early adolescence, particularly among females. TVEM provides a more nuanced understanding of the risk associated with different ages of onset of health risk behaviors.

Depression and nicotine dependence from adolescence to young adulthood

IntroductionDespite the highly replicated relationship between depression and nicotine dependence, little is known about this association across both time and levels of lifetime smoking exposure. In the present study, we evaluate if symptoms of depression are associated with emerging nicotine dependence after accounting for smoking exposure and whether this relationship varies from adolescence to young adulthood and across increasing levels of smoking. Patients and methodsThe sample was drawn from the Social and Emotional Contexts of Adolescent Smoking Patterns Study which measured smoking, nicotine dependence and depression over 6 assessment waves spanning 6years. Analyses were based on repeated assessment of 941 participants reporting any smoking 30days prior to individual assessment waves. Mixed-effects regression models were estimated to examine potential time and smoking exposure varying effects in the association between depression and nicotine dependence. ResultsInter-individual differences in mean levels of depression and within subject changes in depression from adolescence to young adulthood were each significantly associated with nicotine dependence symptoms over and above lifetime smoking exposure. This association was consistent across both time and increasing levels of lifetime smoking. DiscussionDepression is a consistent risk factor for nicotine dependence over and above exposure to cigarettes and this association can be demonstrated from the earliest experiences with smoking in adolescents through the establishment of more regular smoking patterns across the transition to young adulthood. ConclusionDepression remains a prominent risk factor for nicotine dependence, and youth with depression symptoms represent an important subgroup in need of targeted smoking intervention.

Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans.

Studies have shown association between common variants in the α6-β3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence. We examined consistency of association across studies and race between the α6β3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies. United States of America. European Americans and African Americans from three case-control studies of substance dependence. Subjects were evaluated using the Semi-Structured Assessment for the Genetics of Alcoholism. Nicotine dependence was determined using the Fagerström Test for Nicotine Dependence. The single nucleotide polymorphism rs13273442 was associated significantly with nicotine dependence across all three studies in both ancestry groups [odds ratio (OR) = 0.75, P = 5.8 × 10(-4) European Americans; OR = 0.80, P = 0.05 African Americans]. No other substance dependence was associated consistently with this variant in either group. Another SNP in the region, rs4952, remains modestly associated with nicotine dependence in the combined data after conditioning on rs13273442. The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence. Although these data are modestly powered for other substances, our results provide no evidence that correlates of rs13273442 represent a general substance dependence liability. Additional variants probably account for some of the association of this region to nicotine dependence.

Predictors of nicotine dependence symptoms among never-smoking adolescents: A longitudinal analysis from the Nicotine Dependence in Teens Study

BackgroundRecent cross-sectional studies suggest some adolescents who have never smoked cigarettes experience nicotine dependence (ND) symptoms and that exposure to second-hand smoke, social exposure to smoking, and alcohol use are plausible correlates. The aim of this study was to replicate and extend these findings by investigating possible predictors of ND symptoms longitudinally. MethodParticipants included 847 secondary school students who had never smoked cigarettes enrolled in the Nicotine Dependence in Teens Study. Adolescents completed self-report questionnaires measuring smoking status, ND symptoms, and risk factors for ND in smokers (i.e., socio-demographic indicators, social exposure to smoking, psychosocial indicators, and substance use) in 20 survey cycles from 7 to 11th grade. Generalized estimating equations, which account for repeated measures within individuals, were used to test the predictors of ND symptoms. ResultsConsistent with previous research, 7.8% of never-smokers across all cycles endorsed at least one ND symptom. Younger age (p≤.001), country of birth (p≤.05), peer smoking (p≤.001), teacher smoking (p≤.05), depression (p≤.05), stress (p≤.001), lower self-esteem (p≤.05), impulsivity (p≤.05), and alcohol use (p≤.001) predicted greater ND symptoms in multivariable modeling. ConclusionsReplicating previous cross-sectional findings, peer smoking and alcohol use predicted ND symptoms among never-smoking adolescents. Extending these findings, previous predictors only observed among ever-smokers, including socio-demographic and psychosocial indicators, also predicted ND symptoms. This longitudinal investigation demonstrated the temporal relation of the predictors preceding ND symptoms. Future research should consider longer prospective studies with younger children to capture early onset of ND symptoms and with longer follow-up to detect eventual smoking uptake.

Desire thinking across the continuum of nicotine dependence

Introduction: Desire thinking is a voluntary cognitive process involving verbal and imaginal elaboration of a desired target. Recent research has highlighted the role of desire thinking in the maintenance of addictive disorders over and above that of other psychological antecedents including negative affect and urges. The goal of this research project was to explore the role of desire thinking across the continuum of nicotine dependence.Method: A sample of 156 smokers recruited from the general population completed measures of negative affect, smoking urges, desire thinking and nicotine dependence.Results: Individuals high on nicotine dependence reported significantly higher scores on desire thinking dimensions controlling for age, gender, negative affect and smoking urges. In addition, the verbal perseveration component of desire thinking was the strongest predictor of nicotine dependence independently of negative affect and smoking urges across the nicotine dependence spectrum.Conclusions: Findings suggest that desire thinking may be a risk factor for nicotine dependence and that cognitive-behavioural interventions for treating nicotine dependence may benefit from targeting specifically desire thinking.

A Twin Association Study of Nicotine Dependence with Markers in the CHRNA3 and CHRNA5 Genes

Twin and family studies have provided overwhelming evidence for the genetic basis of individual differences in tobacco initiation (TI), regular smoking (RS) and nicotine dependence (ND). However, only a few genes have been reliably associated with ND. We used a finite mixture distribution model to examine the significance and effect size of the association of previously identified and replicated specific variants in the CHRNA5 and CHRNA3 receptor genes with ND, against the background of genetic and environmental risk factors for ND. We hypothesize that additional phenotypic information in relatives who have not been genotyped can be used to increase the power of detecting the genetic variant. The nicotine measures were assessed by personal interview in female, male and opposite sex twin pairs (N=4,153) from the population-based Virginia Twin Registry. Three SNPs in the CHRNA5 and CHRNA3 receptor genes, previously shown to be significantly associated with ND in this sample, were replicated in the augmented analyses; they accounted for less than one percent of the genetic variance in liability to ND, which is estimated to be over 50% of the phenotypic variance. The significance of these effects was increased by adding twins with phenotype but without genotype data, but gains are limited and variable. The SNPs associated with ND did not show a significant association with either TI or RS and appear to be specific to the addictive stage of ND, characterized by current smoking and smoking a large amount of cigarettes per day. Furthermore, these SNPs did not appear to be associated with the remaining items comprising the FTND scale. This study confirmed a significant contribution of the CHRNA receptor on different forms of tobacco dependence. However, the genetic variant only accounted for little of the total genetic variance for liability to ND. Including phenotypic data on ungenotyped relatives can improve the statistical power to detect the effects of genetic variants when they contribute to individual differences in the phenotype.

A Role for the DRD4 Exon III VNTR in Modifying the Association Between Nicotine Dependence and Neuroticism

Neurotic psychopathology has been extensively examined as a risk factor for nicotine dependence (ND). Genetic stratification may partially explain variability in risk estimates. Genetic variants that compromise dopaminergic neurotransmission may motivate exposure to dopamine-stimulating agents, including nicotine. The 7-repeat allele of a Variable Number Tandem Repeat (VNTR) polymorphism in DRD4 (and evolutionary derivatives 5, 6, and 8 repeats; 7R+) is associated with reduced dopamine receptor function. The purpose of this study was to examine association between both smoking initiation (SI) and progression to ND by young adulthood and (a) history of neuroticism during adolescence, (b) DRD4 7R+, and (c) interaction between neuroticism and DRD4 7R+. Participants were drawn from the Victorian Adolescent Health Cohort Study, a longitudinal study of the health and well-being of young Australians across 8 waves (14-24 years). Neuroticism was measured at Waves 3 and 6 (mean 15.9 and 17.4 years). SI was defined as any smoking at any wave. ND was measured at Wave 8 (mean 24.1 years). Genotype data for the DRD4 VNTR were available for 839 participants. While adolescent neuroticism was associated with SI, evidence for association with progression to ND was weak. However, there was evidence of interaction between neuroticism and DRD4 7R+: The odds of progression to ND among those with a history of neuroticism were more than 3.5-fold higher among 7R+ carriers. Without considering stratification by 7R+, the association between progression to ND and neuroticism would have been assumed barely significant. However, among those carrying DRD4 7R+, risk of progression was considerably intensified.

Distinguishing risk factors for the onset of cravings, withdrawal symptoms and tolerance in novice adolescent smokers

Aim:While many studies report determinants of adolescent cigarette smoking, few identify risk factors for nicotine dependence (ND). This study distinguished between risk factors for three hallmarks of ND including cravings,...

Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes

Previous research revealed significant associations between haplotypes in the CHRNA5-A3-B4 subunit cluster and scores on the Fagerström Test for Nicotine Dependence among individuals reporting daily smoking by age 17. The present study used subsamples of participants from that study to investigate associations between the CHRNA5-A3-B4 haplotypes and an array of phenotypes not analyzed previously (i.e., withdrawal severity, ability to stop smoking, and specific scales on the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) that reflect loss of control, strong craving, and heavy smoking. Two cohorts of current or former smokers (N = 886) provided both self-report data and DNA samples. One sample (Wisconsin) comprised smokers making a quit smoking attempt, which permitted the assessment of withdrawal and relapse during the attempt. The other sample (Utah) comprised participants studied for risk factors for nicotine dependence and chronic obstructive pulmonary disease and included individuals originally recruited in the Lung Health Study. The CHRNA5-A3-B4 haplotypes were significantly associated with the targeted WISDM-68 scales (Tolerance, Craving, Loss of Control) in both samples of participants but only among individuals who began smoking early in life. The haplotypes were significantly associated with relapse likelihood and withdrawal severity, but these associations showed no evidence of an interaction with age at daily smoking. The CHRNA5-A3-B4 haplotypes are associated with a broad range of nicotine dependence phenotypes, but these associations are not consistently moderated by age at initial smoking.

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...

A Risk Allele for Nicotine Dependence in CHRNA5 Is a Protective Allele for Cocaine Dependence

A nonsynonymous coding polymorphism, rs16969968, of the CHRNA5 gene that encodes the alpha-5 subunit of the nicotinic acetylcholine receptor (nAChR) has been found to be associated with nicotine dependence. The goal of this study was to examine the association of this variant with cocaine dependence. Genetic association analysis was performed in two independent samples of unrelated case and control subjects: 1) 504 European Americans participating in the Family Study on Cocaine Dependence (FSCD) and 2) 814 European Americans participating in the Collaborative Study on the Genetics of Alcoholism (COGA). In the FSCD, there was a significant association between the CHRNA5 variant and cocaine dependence (odds ratio = .67 per allele, p = .0045, assuming an additive genetic model), but in the reverse direction compared with that previously observed for nicotine dependence. In multivariate analyses that controlled for the effects of nicotine dependence, both the protective effect for cocaine dependence and the previously documented risk effect for nicotine dependence were statistically significant. The protective effect for cocaine dependence was replicated in the COGA sample. In COGA, effect sizes for habitual smoking, a proxy phenotype for nicotine dependence, were consistent with those observed in FSCD. The minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence. The biological plausibility of such a bidirectional association stems from the involvement of nAChRs with both excitatory and inhibitory modulation of dopamine-mediated reward pathways.

The Role of the TPH1 and TPH2 Genes for Nicotine Dependence: A Genetic Association Study in Two Different Age Cohorts

Based on pharmacological and genetic studies suggesting a role of the serotonergic system for nicotine dependence, two genetic variants, one on the tryptophan hydroxylase 1 (TPH1) and one on the TPH2 gene, were investigated. The TPH2 –703G/T promoter polymorphism was associated with smoking status and age of smoking onset in two independent Caucasian samples of different age cohorts. Sample 1 consisted of 3,602 subjects of a population-based cohort study of whom 95% were 40–65 years old, and sample 2 consisted of 723 subjects in the twenties. The TPH1 779A/C was only investigated in sample 2 where additional data with respect to the degree of nicotine dependence were assessed. Results yield support for previous findings of an association between the AA genotype of TPH1 779A/C and nicotine status and a tendency for a heterosis effect with respect to the degree of nicotine dependence. The TPH2 –703G/T was significantly associated with age of smoking onset in both samples. The interaction between the T allele and gender was significant in both samples. Carriers of the GG genotype started significantly earlier to smoke than carriers with a T allele. In the older cohort, age of onset was earlier in carriers of the GG genotype only in men, and in the younger cohort the GG genotype predisposes only women to start smoking earlier in life. This interaction could constitute a gene-by-environment interaction that is discussed on the background of previous studies relating the –703G/T polymorphism to anxiety, a personality dimension that has been shown to be a risk factor for nicotine dependence.