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1. Pharmacogenet Genomics. 2012 Jun;22(6):429-40.

CYP2A6 and CYP2B6 genetic variation and its association with nicotine metabolism
in South Western Alaska Native people.

J Binnington M, Zhu AZ, Renner CC, Lanier AP, Hatsukami DK, Benowitz NL, Tyndale

aDepartments of Psychiatry, Pharmacology and Toxicology, Centre for Addiction &
Mental Health, University of Toronto, Toronto, Ontario, Canada bAlaska Native
Tribal Health Consortium (ANTHC), Clinical & Research Services, Anchorage, Alaska
cDepartment of Psychiatry, University of Minnesota, Minneapolis, Minnesota
dDepartments of Medicine, Bioengineering & Therapeutic Sciences, and Clinical
Pharmacology, University of California San Francisco, San Francisco, California,

OBJECTIVES: 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).
CONCLUSION: 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.

PMCID: PMC3349071 [Available on 2013/6/1]
PMID: 22569203 [PubMed - in process]