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

• Published in: Nicotine & tobacco research 2020-05, Vol.22 (6), p.910-918
• Main Authors: Claw, Katrina G, Beans, Julie A, Lee, Seung-Been, Avey, Jaedon P, Stapleton, Patricia A, Scherer, Steven E, El-Boraie, Ahmed, Tyndale, Rachel F, Nickerson, Deborah A, Dillard, Denise A, Thummel, Kenneth E, Robinson, Renee F
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Alaska; Alaska Natives - genetics; Alaska Natives - statistics & numerical data; Cytochrome P-450 CYP2A6 - genetics; Cytochrome P-450 CYP2B6 - genetics; Genetic Variation; Genotype; Humans; Indians, North American - genetics; Indians, North American - statistics & numerical data; Middle Aged; Nicotine - metabolism; Original Investigations; Pharmacogenetics; Smoking - drug therapy; Smoking - epidemiology; Smoking - genetics; Smoking Cessation - methods; Smoking Cessation Agents - pharmacology; Young Adult
• ISSN: 1469-994X; 1462-2203; 1469-994X
• DOI: 10.1093/ntr/ntz105

Abstract 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.