Pharmacogenomics of Nicotine Metabolism: Novel CYP2A6 and CYP2B6 Genetic Variation Patterns in Alaska Native and American Indian Populations.

TitlePharmacogenomics of Nicotine Metabolism: Novel CYP2A6 and CYP2B6 Genetic Variation Patterns in Alaska Native and American Indian Populations.
Publication TypeJournal Article
Year of Publication2020
AuthorsClaw, KG, Beans, JA, Lee, S-B, Avey, JP, Stapleton, PA, Scherer, SE, El-Boraie, A, Tyndale, RF, Nickerson, DA, Dillard, DA, Thummel, KE, Robinson, RF
JournalNicotine Tob Res
Date Published2020 May 26
KeywordsAdolescent, Adult, Aged, Alaska, Alaskan Natives, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Genetic Variation, Genotype, Humans, Indians, North American, Middle Aged, Nicotine, Pharmacogenetics, Smoking, Smoking Cessation, Smoking Cessation Agents, Young Adult

INTRODUCTION: Alaska Native and American Indian (AN/AI) populations have higher tobacco use prevalence than other ethnic/racial groups. Pharmacogenetic testing to tailor tobacco cessation treatment may improve cessation rates. This study characterized polymorphic variations among AN/AI people in genes associated with metabolism of nicotine and drugs used for tobacco cessation.

METHODS: Recruitment of AN/AI individuals represented six subgroups, five geographic subgroups throughout Alaska and a subgroup comprised of AIs from the lower 48 states living in Alaska. We sequenced the CYP2A6 and CYP2B6 genes to identify known and novel gain, reduced, and loss-of-function alleles, including structural variation (eg, gene deletions, duplications, and hybridizations).

RESULTS: Variant allele frequencies differed substantially between AN/AI subgroups. The gene deletion CYP2A6*4 and reduced function CYP2A6*9 alleles were found at high frequency in Northern/Western subgroups and in Lower 48/Interior subgroups, respectively. The reduced function CYP2B6*6 allele was observed in all subgroups and a novel, predicted reduced function CYP2B6 variant was found at relatively high frequency in the Southeastern subgroup.

CONCLUSIONS: Diverse CYP2A6 and CYP2B6 variation among the subgroups highlight the need for comprehensive pharmacogenetic testing to guide tobacco cessation therapy for AN/AI populations.

IMPLICATIONS: Nicotine metabolism is largely determined by CYP2A6 genotype, and variation in CYP2A6 activity has altered the treatment success in other populations. These findings suggest pharmacogenetic-guided smoking cessation drug treatment could provide benefit to this unique population seeking tobacco cessation therapy.

Alternate JournalNicotine Tob Res
PubMed ID31241144
PubMed Central IDPMC7249913
Grant ListU54 GM115371 / GM / NIGMS NIH HHS / United States
P30 ES007033 / ES / NIEHS NIH HHS / United States
P01 GM116691 / GM / NIGMS NIH HHS / United States
S06 GM123545 / GM / NIGMS NIH HHS / United States
U01 GM092676 / GM / NIGMS NIH HHS / United States
F32 GM119237 / GM / NIGMS NIH HHS / United States
FDN-154294 / / CIHR / Canada

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