title: Nicotine dependence as a moderator of genetic influences on smoking cessation treatment outcome.
abstract: BACKGROUND
  Genetic influences on smoking cessation treatment outcome may be affected by pretreatment patient characteristics. Nicotine dependence is arguably the most salient clinical factor in smoking cessation.
  
  
  METHODS
  In this secondary analysis of clinical trial data (N=793), we examined nicotine dependence severity as a moderator of the effects of 1198 single nucleotide polymorphisms (SNPs) in 53 biologically-relevant gene regions on smoking cessation outcomes. P-values were adjusted to account for multiple correlated SNPs within a gene region; corrected system-wide significance was 5 × 10(-4).
  
  
  RESULTS
  SNP × nicotine dependence interactions reached region-wide significance for several SNPs in the Dopamine Beta Hydroxylase (DBH) locus (0.0005<Adjusted-P<0.05), including rs1541333, which reached system-wide significance for predicting end of treatment (EOT) abstinence (Adjusted-P=0.0004). A haplotype including 6 DBH SNPs predicted abstinence at EOT (OR=1.7, P=0.001) and 6-month follow-up (OR=1.6, P=0.008) in those with high nicotine dependence (n=526) but not in those with low dependence (n=227). The DBH signal observed here may be distinct from a previously reported genome-wide significant signal for former smoking status and from the principal haplotype associated with plasma dopamine beta-hydroxylase activity. A haplotype within the Chromosome 15 Nicotinic Acetylcholine Receptor gene region predicted abstinence at EOT in those with high (OR=2.0, P=0.0004) but not low (P=0.6) dependence in post hoc analyses.
  
  
  CONCLUSIONS
  Considering pre-treatment nicotine dependence level may optimize the prediction of genetic influences on cessation outcomes. If replicated, results like these may inform prognosticative genomic screening panels designed to identify smokers at high risk of relapse when coupled with severe nicotine dependence.
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Psychology, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: adam.leventhal@usc.edu.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Leventhal
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Wonho
authors.initials: W
authors.lastname: Lee
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bergen
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.affiliation: Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, ON, ON M5S 1A1 Canada.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
mesh_terms: D000328:Adult; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D011978:Receptors, Nicotinic / Q000235:genetics*; D012720:Severity of Illness Index; D016540:Smoking Cessation; D014029:Tobacco Use Disorder / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D011978:Receptors, Nicotinic; D004299:Dopamine beta-Hydroxylase
keywords: Dopamine; Genetics; Nicotine dependence; Smoking cessation