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

Addiction Biology
Ahmed El-BoraieRachel F Tyndale

Abstract

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 predict...Continue Reading

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Citations

May 2, 2021·The Journal of Biological Chemistry·Sharon E Murphy
Apr 7, 2021·Nicotine & Tobacco Research : Official Journal of the Society for Research on Nicotine and Tobacco·Kevin ButlerBernard Le Foll
Jun 25, 2021·Clinical Pharmacology and Therapeutics·Ahmed El-Boraie, Rachel F Tyndale
Jul 28, 2021·Nicotine & Tobacco Research : Official Journal of the Society for Research on Nicotine and Tobacco·Andrew W BergenJames W Baurley
Sep 4, 2021·Clinical and Translational Science·Ahmed El-BoraieRachel F Tyndale
Dec 26, 2021·Clinical Pharmacology and Therapeutics·Danielle JohnsonBritt I Drögemöller

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