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Genome-wide association for nicotine dependence and smoking cessation success in NIH research volunteers.

ABSTRACT: Phenotypes related to both nicotine dependence and ability to successfully quit smoking display substantial heritabilities in classical and molecular genetic studies. Twin studies suggest that some genetic components for dependence overlap with genetic components of ability to quit, but that many components do not overlap. Initial genome-wide association (GWA) studies have demonstrated haplotypes that distinguish nicotine-dependent from nondependent smokers. These haplotypes overlap partially with those that distinguish individuals who successfully quit smoking from those who were not able to quit smoking in clinical trials for smoking cessation. We now report novel genome-wide association results from National Institutes of Health research volunteers who reported smoking histories, symptoms of nicotine dependence, and ability to successfully quit smoking outside the context of a clinical trial. These results buttress data from several prior GWA studies. The data from these volunteers support the idea that previously reported studies of genes associated with smoking cessation success in clinical trial participants may also apply to smokers who are more or less able to initiate and sustain abstinence outside of clinical trial settings.

SUBMITTER: Drgon T

PROVIDER: S-EPMC2581605 | biostudies-literature | 2009 Jan-Feb

REPOSITORIES: biostudies-literature

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Genome-wide association for nicotine dependence and smoking cessation success in NIH research volunteers.

Drgon Tomas T Montoya Ivan I Johnson Catherine C Liu Qing-Rong QR Walther Donna D Hamer Dean D Uhl George R GR

Molecular medicine (Cambridge, Mass.) 20081002 1-2

Phenotypes related to both nicotine dependence and ability to successfully quit smoking display substantial heritabilities in classical and molecular genetic studies. Twin studies suggest that some genetic components for dependence overlap with genetic components of ability to quit, but that many components do not overlap. Initial genome-wide association (GWA) studies have demonstrated haplotypes that distinguish nicotine-dependent from nondependent smokers. These haplotypes overlap partially wi ...[more]

PMID: 19009022

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Project description:IntroductionGenetic variation in Cytochrome P450 2A6 (CYP2A6), the major nicotine metabolizing enzyme, is associated with nicotine dependence and smoking cessation. Nicotine dependence severity also predicts smoking cessation. Our goals were to determine how CYP2A6 variation and nicotine dependence alter smoking cessation, and whether dependence could refine CYP2A6-based treatment recommendations.Aims and methodsAdult smokers treated for 12 weeks with placebo, nicotine patch, or varenicline (NCT01314001) were grouped as CYP2A6 normal (n = 567) or slow (n = 432) nicotine metabolizers based on a CYP2A6 weighted genetic risk score. Fagerström test for nicotine dependence scores were measured at baseline and biochemically verified smoking cessation was assessed at end of treatment.ResultsDependence neither mediated nor moderated an association between CYP2A6 variation and smoking cessation overall, within any treatment arm, or after stratifying by ancestry (n = 591 European, n = 408 African ancestry) or sex (n = 444 women, n = 555 men). In within-treatment analyses, the mediation effect odds ratio (OR) ranged from 0.95 to 1.00 and the bias-corrected 95% confidence interval contained 1. Moderation (i.e. interaction) effect ORs ranged from 0.88 to 1.61 (p = .397-.828). For CYP2A6 normal metabolizers, quit rates on varenicline were similar for those with high (41.1%) and low (43.4%) dependence, while quit rates were lower for those with high versus low dependence on both patch (16.5 vs. 29.7%) and placebo (8.9 vs. 18.5%). CYP2A6 slow metabolizers with high versus low dependence had lower quit rates in all three treatment arms.ConclusionsAlthough nicotine dependence severity neither mediated nor moderated CYP2A6 associations with smoking cessation, incorporating information on dependence may optimize the choice of smoking cessation treatment aid in CYP2A6 normal and slow metabolizers.ImplicationsVariation in CYP2A6 and nicotine dependence severity alter smoking cessation success. Our findings suggest that while nicotine dependence severity is unlikely to mediate or moderate CYP2A6 associations with cessation, incorporating patient information on both CYP2A6 and nicotine dependence severity may lead to improved smoking cessation strategies.

Project description:Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.

Dataset Information

Genome-wide association for nicotine dependence and smoking cessation success in NIH research volunteers.

Publications

Genome-wide association for nicotine dependence and smoking cessation success in NIH research volunteers.

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