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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Nicotine metabolism: The impact of CYP2A6 on estimates of additive genetic influence
Pharmacogenetics and Genomics, Volume 15, No. 2, Year 2005
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Description
To conduct a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty nine twin pairs [110 monozygotic (MZ) and 29 dizygotic (DZ)] underwent a 30-min infusion of stable isotope-labelled nicotine and its major metabolite, cotinine, followed by an 8-h in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine and metabolites by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry and subsequent characterization of pharmacokinetic and metabolism phenotypes. DNA was genotyped to confirm zygosity and for variation in the gene for the primary enzyme involved in nicotine metabolism, CYP2A6 (alleles tested: *1, *1 x 2, *2, *4, *7, *9 and *12), Univariate biometric analyses quantified genetic and environmental influences on each pharmacokinetic measure in the presence and absence of covariates, including measured CYP2A6 genotype. The best-fitting model identified a substantial amount of variation in the weight-adjusted rate of total clearance of nicotine attributable to additive genetic influences [59.4%, 95% confidence interval (CI) =44.7-70.7]. The majority of variation in the clearance of nicotine via the cotinine pathway was similarly genetically influenced (60.8%, 95% CI=46.9-71.5). Heritability estimates were reduced to 54.2% and 51.8%, respectively, but remained substantial after taking into account the effect of variation in CYP2A6 genotype. These results suggest the involvement of additional genetic factors (e.g. uncharacterized or novel CYP2A6 alleles as well as other genes in the metabolic pathway) that remain to be identified. © 2005 Lippincott Williams & Wilkins.
Authors & Co-Authors
Swan, Gerald E.
United States, Menlo Park
Sri International
Benowitz, Neal L.
United States, San Francisco
University of California, San Francisco
Jacob, Peyton J.
United States, San Francisco
University of California, San Francisco
Tyndale, Rachel F.
Canada, Toronto
Centre for Addiction and Mental Health
Wilhelmsen, Kirk C.
United States, San Francisco
University of California, San Francisco
United States, Raleigh
The University of North Carolina System
Statistics
Citations: 71
Authors: 5
Affiliations: 4
Identifiers
Doi:
10.1097/01213011-200502000-00007
ISSN:
17446872
Research Areas
Genetics And Genomics
Health System And Policy
Noncommunicable Diseases