title: CYP2A6 and CYP2B6 genetic variation and its association with nicotine metabolism in South Western Alaska Native people.
abstract: OBJECTIVE
  Alaska Native (AN) people have a high prevalence of tobacco use and associated morbidity and mortality when compared with the general USA population. Variations in the CYP2A6 and CYP2B6 genes, encoding enzymes responsible for nicotine metabolic inactivation and procarcinogen activation, have not been characterized in AN and may contribute toward the increased risk.
  
  
  METHODS
  AN people (n=400) residing in the Bristol Bay region of South Western Alaska were recruited for a cross-sectional study on tobacco use. They were genotyped for CYP2A6*1X2A, *1X2B, *1B, *2, *4, *7, *8, *9, *10, *12, *17, *35 and CYP2B6*4, *6, *9 and provided plasma and urine samples for the measurement of nicotine and metabolites.
  
  
  RESULTS
  CYP2A6 and CYP2B6 variant frequencies among the AN Yupik people (n=361) were significantly different from those in other ethnicities. Nicotine metabolism [as measured by the plasma and urinary ratio of metabolites trans-3'-hydroxycotinine to cotinine (3HC/COT)] was significantly associated with CYP2A6 (P<0.001), but not CYP2B6 genotype (P=0.95) when controlling for known covariates. It was noteworthy that the plasma 3HC/COT ratios were high in the entire Yupik people, and among the Yupik CYP2A6 wild-type participants, they were substantially higher than those in previously characterized racial/ethnic groups (P<0.001 vs. Caucasians and African Americans).
  
  
  CONCLUSIONS
  Yupik AN people have a unique CYP2A6 genetic profile that associated strongly with in-vivo nicotine metabolism. More rapid CYP2A6-mediated nicotine and nitrosamine metabolism in the Yupik people may modulate the risk of tobacco-related diseases.
authors.affiliation: Departments of Psychiatry, Pharmacology and Toxicology, Centre for Addiction & Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Binnington
authors.forename: Andy Z X
authors.initials: AZ
authors.lastname: Zhu
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Renner
authors.forename: Anne P
authors.initials: AP
authors.lastname: Lanier
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Hatsukami
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000328:Adult; D000368:Aged; D000413:Alaska; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003367:Cotinine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009538:Nicotine / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D044382:Population Groups / Q000235:genetics*; D012907:Smoking / Q000097:blood / Q000652:urine
chemical_list: C001381:hydroxycotinine; D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D003367:Cotinine