Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6).

BACKGROUND AND AIMS Evidence suggests that both the nicotinic receptor α5 subunit (CHRNA5) and Cytochrome P450 2A6 (CYP2A6) genotypes influence smoking cessation success and response to pharmacotherapy. We examine the effect of CYP2A6 genotype on smoking cessation success and response to cessation pharmacotherapy, and combine these effects with those of CHRNA5 genotypes. DESIGN Placebo-controlled randomized smoking cessation trial. SETTING Ambulatory care facility in Wisconsin, USA. PARTICIPANTS Smokers (n = 709) of European ancestry were randomized to placebo, bupropion, nicotine replacement therapy or combined bupropion and nicotine replacement therapy. MEASUREMENTS Survival analysis was used to model time to relapse using nicotine metabolism derived from CYP2A6 genotype-based estimates. Slow metabolism is defined as the lowest quartile of estimated metabolic function. FINDINGS CYP2A6-defined nicotine metabolic function moderated the effect of smoking cessation pharmacotherapy on smoking relapse over 90 days [hazard ratio (HR) = 2.81, 95% confidence interval (CI) = 1.32-5.99, P = 0.0075], with pharmacotherapy significantly slowing relapse in fast (HR = 0.39, 95% CI = 0.28-0.55, P = 1.97 × 10(-8)), but not slow metabolizers (HR = 1.09, 95% CI = 0.55-2.17, P = 0.80). Further, only the effect of nicotine replacement, and not bupropion, varies with CYP2A6-defined metabolic function. The effect of nicotine replacement on continuous abstinence is moderated by the combined genetic risks from CYP2A6 and CHRNA5 (Wald = 7.44, d.f. = 1, P = 0.0064). CONCLUSIONS Nicotine replacement therapy is effective among individuals with fast, but not slow, CYP2A6-defined nicotine metabolism. The effect of bupropion on relapse likelihood is unlikely to be affected by nicotine metabolism as estimated from CYP2A6 genotype. The variation in treatment responses among smokers with genes may guide future personalized smoking cessation interventions.

[1]  Lucas M Bachmann,et al.  Individual patient data meta-analysis of diagnostic studies: opportunities and challenges , 2013, Evidence-Based Medicine.

[2]  N. Benowitz,et al.  Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state , 2013, Pharmacogenetics and genomics.

[3]  P. Kwok,et al.  Nicotinic acetylcholine receptor variation and response to smoking cessation therapies , 2013, Pharmacogenetics and genomics.

[4]  R. Altman,et al.  PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 8 , 2012, Pharmacogenetics and genomics.

[5]  F. Lotrich.  The emerging potential of pharmacogenetics in psychiatry. , 2012, The American journal of psychiatry.

[6]  Megan E. Piper,et al.  Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success. , 2012, The American journal of psychiatry.

[7]  A. Goate,et al.  Use of a predictive model derived from in vivo endophenotype measurements to demonstrate associations with a complex locus, CYP2A6. , 2012, Human molecular genetics.

[8]  D. Heitjan,et al.  Reproducibility of the Nicotine Metabolite Ratio in Cigarette Smokers , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[9]  S. Shiffman,et al.  DSM criteria for tobacco use disorder and tobacco withdrawal: a critique and proposed revisions for DSM-5. , 2012, Addiction.

[10]  M. Spitz,et al.  Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk. , 2011, Journal of the National Cancer Institute.

[11]  L. Bierut,et al.  The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European–Americans , 2011, Pharmacogenetics and genomics.

[12]  William Wheeler,et al.  Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD , 2010, PLoS genetics.

[13]  C. Gieger,et al.  Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior , 2010, Nature Genetics.

[14]  Inês Barroso,et al.  Meta-analysis and imputation refines the association of 15q25 with smoking quantity , 2010, Nature Genetics.

[15]  C. Jepson,et al.  Genetic Variation in Nicotine Metabolism Predicts the Efficacy of Extended‐Duration Transdermal Nicotine Therapy , 2010, Clinical pharmacology and therapeutics.

[16]  Ming D. Li,et al.  Genome-wide meta-analyses identify multiple loci associated with smoking behavior , 2010, Nature Genetics.

[17]  Megan E. Piper,et al.  A randomized placebo-controlled clinical trial of 5 smoking cessation pharmacotherapies. , 2009, Archives of general psychiatry.

[18]  C. Lerman,et al.  Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: A validation study , 2009, Pharmacology Biochemistry and Behavior.

[19]  C. Lerman,et al.  Nicotine Dependence Pharmacogenetics: Role of Genetic Variation in Nicotine-Metabolizing Enzymes , 2009, Journal of neurogenetics.

[20]  L. Epstein,et al.  Toward Personalized Therapy for Smoking Cessation: A Randomized Placebo‐controlled Trial of Bupropion , 2008, Clinical pharmacology and therapeutics.

[21]  A. Moscicki,et al.  Rate of Nicotine Metabolism and Withdrawal Symptoms in Adolescent Light Smokers , 2008, Pediatrics.

[22]  Caryn Lerman,et al.  Molecular genetics of successful smoking cessation: convergent genome-wide association study results. , 2008, Archives of general psychiatry.

[23]  Megan E. Piper,et al.  Efficacy of bupropion alone and in combination with nicotine gum. , 2007, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[24]  C. Lerman,et al.  Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation , 2006, Clinical pharmacology and therapeutics.

[25]  Makiko Maeda,et al.  CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation , 2006, The Pharmacogenomics Journal.

[26]  M. Haberl,et al.  Three haplotypes associated with CYP2A6 phenotypes in Caucasians , 2005, Pharmacogenetics and genomics.

[27]  J. Yokota,et al.  Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. , 2004, Carcinogenesis.

[28]  R. Tyndale,et al.  Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. , 2004, Pharmacogenetics.

[29]  C. Pomerleau,et al.  Nicotine metabolite ratio as a predictor of cigarette consumption. , 2003, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[30]  T. Perneger,et al.  Measurement of self reported active exposure to cigarette smoke , 2001, Journal of epidemiology and community health.

[31]  C. Lindley,et al.  Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[32]  S. Yusuf,et al.  Overcoming the limitations of current meta-analysis of randomised controlled trials , 1998, The Lancet.

[33]  E. Perez-stable,et al.  Is serum cotinine a better measure of cigarette smoking than self-report? , 1995, Preventive medicine.

[34]  L. Kozlowski,et al.  The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. , 1991, British journal of addiction.

[35]  Linda C. Sobell,et al.  Timeline Follow-Back A Technique for Assessing Self-Reported Alcohol Consumption , 1992 .