title: The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans.
abstract: OBJECTIVE
  To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism.
  
  
  METHODS
  The conversion of deuterated (D2)-nicotine to D2-cotinine was quantified in 189 European-Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes.
  
  
  RESULTS
  The final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5'-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02).
  
  
  CONCLUSIONS
  Among European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.
authors: Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA. bloomj@psychiatry.wustl.edu
authors: Joseph
authors: J
authors: Bloom
authors: Anthony L
authors: AL
authors: Hinrichs
authors: Jen C
authors: JC
authors: Wang
authors: Linda B
authors: LB
authors: von Weymarn
authors: Evan D
authors: ED
authors: Kharasch
authors: Laura J
authors: LJ
authors: Bierut
authors: Alison
authors: A
authors: Goate
authors: Sharon E
authors: SE
authors: Murphy
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