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National Institute of Environmental Health Sciences

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Publication Detail

Title: Novel CYP2A6 diplotypes identified through next-generation sequencing are associated with in-vitro and in-vivo nicotine metabolism.

Authors: Tanner, Julie-Anne; Zhu, Andy Z; Claw, Katrina G; Prasad, Bhagwat; Korchina, Viktoriya; Hu, Jianhong; Doddapaneni, HarshaVardhan; Muzny, Donna M; Schuetz, Erin G; Lerman, Caryn; Thummel, Kenneth E; Scherer, Steven E; Tyndale, Rachel F

Published In Pharmacogenet Genomics, (2018 Jan)

Abstract: OBJECTIVES: Smoking patterns and cessation rates vary widely across smokers and can be influenced by variation in rates of nicotine metabolism [i.e. cytochrome P450 2A6 (CYP2A6), enzyme activity]. There is high heritability of CYP2A6-mediated nicotine metabolism (60-80%) owing to known and unidentified genetic variation in the CYP2A6 gene. We aimed to identify and characterize additional genetic variants at the CYP2A6 gene locus. METHODS: A new CYP2A6-specific sequencing method was used to investigate genetic variation in CYP2A6. Novel variants were characterized in a White human liver bank that has been extensively phenotyped for CYP2A6. Linkage and haplotype structure for the novel single nucleotide polymorphisms (SNPs) were assessed. The association between novel five-SNP diplotypes and nicotine metabolism rate was investigated. RESULTS: Seven high-frequency (minor allele frequencies ≥6%) noncoding SNPs were identified as important contributors to CYP2A6 phenotypes in a White human liver bank (rs57837628, rs7260629, rs7259706, rs150298687 (also denoted rs4803381), rs56113850, rs28399453, and rs8192733), accounting for two times more variation in in-vitro CYP2A6 activity relative to the four established functional CYP2A6 variants that are frequently tested in Whites (CYP2A6*2, *4, *9, and *12). Two pairs of novel SNPs were in high linkage disequilibrium, allowing us to establish five-SNP diplotypes that were associated with CYP2A6 enzyme activity (rate of nicotine metabolism) in-vitro in the liver bank and in-vivo among smokers. CONCLUSION: The novel five-SNP diplotype may be useful to incorporate into CYP2A6 genotype models for personalized prediction of nicotine metabolism rate, cessation success, and response to pharmacotherapies.

PubMed ID: 29232328 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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