|Title||Novel CYP2A6 diplotypes identified through next-generation sequencing are associated with in-vitro and in-vivo nicotine metabolism.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Tanner, 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|
|Date Published||2018 Jan|
|Keywords||Cytochrome 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 Journal||Pharmacogenet Genomics|
|PubMed Central ID||PMC5729933|
|Grant List||F32 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