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Addict Biol. 2019 Feb 27. doi: 10.1111/adb.12741. [Epub ahead of print]

Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity.

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Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.
Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, 230-0045, Japan.
Department of Psychiatry and Abramson Cancer Center, University of Pennsylvania, Philadelphia, 19104, Pennsylvania.
Department of Preventive Medicine and Public Health, University of Kansas, Kansas City, 66160, Kansas.
Departments of Medicine and Biopharmaceutical Sciences, Division of Clinical Pharmacology and Experimental Therapeutics, Medical Services and Center for Tobacco Control Research and Education, University of California, San Francisco, 94110, California.
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, M6J 1H4, Canada.


The nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine's metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome-wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European-ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine-d2/(nicotine-d2 + cotinine-d2)). CYP2A6 genotypes and the NMR were assessed in European-ancestry participants. The wGRS training set included N = 933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N = 196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory-based pharmacokinetic study (N = 92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P < 0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ = 0.70 and ρ = 0.79, respectively; P < 0.001), and to one another (ρ = 0.82; P < 0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC = 0.79; P < 0.001), and to replicate previous NMR-stratified cessation outcomes showing unique treatment outcomes between metabolizer groups.


CYP2A6; European-ancestry; genetic risk score; nicotine metabolism; pharmacogenetics


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