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Pharmacogenet Genomics. 2018 Jan;28(1):7-16. doi: 10.1097/FPC.0000000000000317.

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

Author information

1
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH).
2
Department of Pharmacology and Toxicology.
3
Department of Pharmaceutics, University of Washington, Seattle, Washington.
4
Department of Molecular and Human Genetics, The Baylor College of Medicine Human Genome Sequencing Center, Houston, Texas, USA.
5
Pharmaceutical Sciences Department, St Jude Children's Research Hospital, Memphis, Tennessee.
6
Department of Psychiatry, Annenberg School for Communication, and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
7
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

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.

PMID:
29232328
PMCID:
PMC5729933
DOI:
10.1097/FPC.0000000000000317
[Indexed for MEDLINE]
Free PMC Article

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