title: Lack of Associations of CHRNA5-A3-B4 Genetic Variants with Smoking Cessation Treatment Outcomes in Caucasian Smokers despite Associations with Baseline Smoking.
abstract: CHRNA5-A3-B4 variants, rs16969968, rs588765 and rs578776, are consistently associated with tobacco consumption among smokers, but the association with smoking cessation is less consistent. Among the studies that reported significant associations with cessation, the effects were observed in smokers treated with placebo treatment in some studies and conversely in those receiving active pharmacological therapy (bupropion and nicotine replacement therapies) in others. Thus, it remains unclear whether CHRNA5-A3-B4 is a useful marker for optimizing smoking cessation. Using data from 654 Caucasian smokers treated with placebo, nicotine patch or varenicline, we investigated whether CHRNA5-A3-B4 variants were associated with smoking cessation outcomes, and whether there were significant genotype-by-treatment or haplotype-by-treatment interactions. We observed no significant associations between CHRNA5-A3-B4 variants and smoking cessation, despite replicating previous associations with baseline tobacco consumption. At end of treatment the effect size on smoking cessation in the placebo, patch and varenicline groups for rs16969968 [GG vs. GA+AA] was OR = 0.66 (P = 0.23), OR = 1.01 (P = 0.99), and OR = 1.30 (P = 0.36) respectively, of rs588765 [CC vs. CT+TT] was OR = 0.96 (P = 0.90), OR = 0.84 (P = 0.58), and OR = 0.74 (P = 0.29) respectively, and for rs578776 [GG vs. GA+AA] on smoking cessation was OR = 1.02 (P = 0.95), OR = 0.75 (P = 0.35), and OR = 1.20 (P = 0.51) respectively. Furthermore, we observed no associations with cessation using the CHRNA5-A3-B4 haplotype (constructed using rs16969968 and rs588765), nor did we observe any significant genotype-by-treatment interactions, with or without adjusting for the rate of nicotine metabolism (all P>0.05). We also observed no significant genetic associations with 6 month or 12 month smoking abstinence. In conclusion, we found no association between CHRNA5-A3-B4 variants and smoking cessation rates in this clinical trial; however, as expected, significant associations with baseline tobacco consumption were replicated. Our data suggest that CHRNA5-A3-B4 gene variants do not exhibit a robust association with smoking cessation and are unlikely to be useful for clinically optimizing smoking cessation pharmacotherapy for Caucasian smokers.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Division of Brain & Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andy Z X
authors.initials: AZ
authors.lastname: Zhu
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada; Division of Brain & Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tony P
authors.initials: TP
authors.lastname: George
authors.affiliation: Department of Behavioral Science, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Cinciripini
authors.affiliation: Department of Psychology, University at Buffalo, State University of New York (SUNY), Buffalo, New York, United States of America; Center for Children and Families, University at Buffalo, State University of New York (SUNY), Buffalo, New York, United States of America.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Hawk
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Schnoll
authors.affiliation: Department of Medicine, Stanford University, Palo Alto, California, United States of America.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Department of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.affiliation: Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
mesh_terms: D000328:Adult; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000235:genetics / Q000628:therapy*; D016540:Smoking Cessation / Q000379:methods; D061485:Tobacco Use Cessation Devices; D016896:Treatment Outcome; D000068580:Varenicline / Q000627:therapeutic use; D044465:White People / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; D000068580:Varenicline; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human