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Pharmacogenet Genomics. 2017 May;27(5):169-178. doi: 10.1097/FPC.0000000000000271.

Variation in CYP2A6 and nicotine metabolism among two American Indian tribal groups differing in smoking patterns and risk for tobacco-related cancer.

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aCentre for Addiction and Mental Health (CAMH), Campbell Family Mental Health Research Institute Departments of bPharmacology and Toxicology cPsychiatry, University of Toronto, Toronto, Ontario, Canada dBlack Hills Center for American Indian Health, Rapid City, South Dakota eElson S. Floyd College of Medicine, Initiative for Research and Education to Advance Community Health (IREACH), Washington State University, Seattle, Washington fThe Georgetown-Howard Universities Center for Clinical and Translational Sciences, Washington, District of Columbia gMedStar Health Research Institute, Hyattsville, Maryland, USA.



The Northern Plains (NP) and Southwest (SW) American Indian populations differ in their smoking patterns and lung cancer incidence. We aimed to compare CYP2A6 genetic variation and CYP2A6 enzyme activity (representative of the rate of nicotine metabolism) between the two tribal populations as these have previously been associated with differences in smoking, quitting, and lung cancer risk.


American Indians (N=636) were recruited from two different tribal populations (NP in South Dakota, SW in Arizona) as part of a study carried out as part of the Collaborative to Improve Native Cancer Outcomes P50 Project. A questionnaire assessed smoking-related traits and demographics. Participants were genotyped for CYP2A6 genetic variants *1B, *2, *4, *7, *9, *12, *17, and *35. Plasma and/or saliva samples were used to measure nicotine's metabolites cotinine and 3'-hydroxycotinine and determine CYP2A6 activity (3'-hydroxycotinine/cotinine, i.e. the nicotine metabolite ratio, NMR).


The overall frequency of genetically reduced nicotine metabolizers, those with CYP2A6 decrease-of-function or loss-of-function alleles, was lower in the NP compared with the SW (P=0.0006). The CYP2A6 genotype was associated with NMR in both tribal groups (NP, P<0.0001; SW, P=0.04). Notably, the rate of nicotine metabolism was higher in NP compared with SW smokers (P=0.03), and in comparison with other ethnic groups in the USA. Of the variables studied, the CYP2A6 genotype was the only variable to significantly independently influence NMR among smokers in both tribal populations (NP, P<0.001; SW, P=0.05).


Unique CYP2A6 allelic patterns and rates of nicotine metabolism among these American Indian populations suggest different risks for smoking, and tobacco-related disease.

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