title: Organic cation transporter variation and response to smoking cessation therapies.
abstract: BACKGROUND
  We evaluated chr6q25.3 organic cation transporter gene (SLC22A1, SLC22A2, SLC22A3) variation and response to smoking cessation therapies. The corresponding proteins are low-affinity transporters of choline, acetylcholine and monoamines, and smoking cessation pharmacotherapies expressed in multiple tissues.
  
  
  METHODS
  We selected 7 common polymorphisms for mega-regression analysis. We assessed additive model association of polymorphisms with 7-day point prevalence abstinence overall and by assigned pharmacotherapy at end of treatment and at 6 months among European-ancestry participants of 7 randomized controlled trials adjusted for demographic, population genetic, and trial covariates.
  
  
  RESULTS
  Initial results were obtained in 6 trials with 1,839 participants. Nominally statistically significant associations of 2 SLC22A2 polymorphisms were observed: (1) with rs316019 at 6 months, overall ([c.808T>G; p.Ser270Ala], OR = 1.306, 95% CI = 1.034-1.649, p = .025), and among those randomized to nicotine replacement therapy (NRT) (OR = 1.784, 95% CI = 1.072-2.970, p = .026); and (2) with rs316006 (c.1502-529A>T) among those randomized to varenicline (OR = 1.420, 95% CI = 1.038-1.944, p = .028, OR = 1.362, 95% CI = 1.001-1.853, p = .04) at end of treatment and 6 months. Individuals randomized to NRT from a seventh trial were genotyped for rs316019; rs316019 was associated with a nominally statistically significant effect on abstinence overall at 6 months among 2,233 participants (OR = 1.249, 95% CI = 1.007-1.550, p = .043).
  
  
  CONCLUSIONS
  The functional OCT2 Ser270Ala polymorphism is nominally statistically significantly associated with abstinence among European-ancestry treatment-seeking smokers after adjustments for pharmacotherapy, demographics, population genetics, and without adjustment for multiple testing of 7 SNPs. Replication of these preliminary findings in additional randomized controlled trials of smoking cessation therapies and from multiple continental populations would describe another pharmacogenetic role for SLC22A2/OCT2.
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, CA; andrew.bergen@sri.com.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bergen
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, CA;
authors.forename: Harold S
authors.initials: HS
authors.lastname: Javitz
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, CA;
authors.forename: Ruth
authors.initials: R
authors.lastname: Krasnow
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, CA;
authors.forename: Martha
authors.initials: M
authors.lastname: Michel
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, CA;
authors.forename: Denise
authors.initials: D
authors.lastname: Nishita
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA;
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA; BioRealm, LLC, Monument, CO;
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Edlund
authors.affiliation: Department of Dermatology, University of California, San Francisco, CA;
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Group Health Research Institute, Seattle, WA;
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: McClure
authors.affiliation: Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada;
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.affiliation: Department of Psychiatry, University of California, San Francisco, CA;
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Hall
authors.affiliation: Centre for Addiction and Mental Health, and Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada;
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.affiliation: Center for Tobacco Research and Intervention, University of Wisconsin, Madison, WI;
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Baker
authors.affiliation: Departments of Medicine and Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA;
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.affiliation: Stanford Prevention Research Center, Stanford University School of Medicine, Palo Alto, CA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
mesh_terms: D000328:Adult; D001552:Benzazepines / Q000627:therapeutic use; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D011810:Quinoxalines / Q000627:therapeutic use; D012907:Smoking / Q000188:drug therapy* / Q000235:genetics*; D016540:Smoking Cessation / Q000379:methods*; D014029:Tobacco Use Disorder / Q000188:drug therapy / Q000235:genetics; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011810:Quinoxalines; C491013:SLC22A2 protein, human; D000068580:Varenicline