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

TitleNovel CYP2A6 diplotypes identified through next-generation sequencing are associated with in-vitro and in-vivo nicotine metabolism.
Publication TypeJournal Article
Year of Publication2018
AuthorsTanner, J-A, Zhu, AZ, Claw, KG, Prasad, B, Korchina, V, Hu, J, Doddapaneni, H, Muzny, DM, Schuetz, EG, Lerman, C, Thummel, KE, Scherer, SE, Tyndale, RF
JournalPharmacogenet Genomics
Date Published2018 Jan
KeywordsCytochrome P-450 CYP2A6, European Continental Ancestry Group, Gene Frequency, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, In Vitro Techniques, Linkage Disequilibrium, Liver, Nicotine, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Tissue Banks

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.

Alternate JournalPharmacogenet Genomics
PubMed ID29232328
PubMed Central IDPMC5729933
Grant ListF32 GM119237 / GM / NIGMS NIH HHS / United States
P30 ES007033 / ES / NIEHS NIH HHS / United States
U01 DA020830 / DA / NIDA NIH HHS / United States
U01 GM092676 / GM / NIGMS NIH HHS / United States

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