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.

The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP2B6 gene. Genetic variation within the CYP2B6 gene locus impacts the metabolism or bioactivation of clinically important drugs. Of particular importance are efficacy and safety concerns regarding: efavirenz, which is used for the treatment of HIV type‐1 infection; methadone, a mainstay in the treatment of opioid use disorder and as an analgesic; ketamine, used as an antidepressant and analgesic; and bupropion, which is prescribed to treat depression and for smoking cessation. This GeneFocus provides a comprehensive overview and summary of CYP2B6 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

The Nicotine Metabolite Ratio (NMR; 3‐hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in nonsmokers, former smokers, or intermittent smokers, for example, in evaluating tobacco‐related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation. We previously created a CYP2A6 weighted genetic risk score (wGRS) for European (EUR)‐ancestry populations by incorporating independent signals from genome‐wide association studies to capture a larger proportion of NMR variation. However, CYP2A6 genetic architecture is unique to ancestral populations. In this study, we developed and replicated an African‐ancestry (AFR) wGRS, which captured 30–35% of the variation in NMR. We demonstrated model robustness against known environmental sources of NMR variation. Furthermore, despite the vast diversity within AFR populations, we showed that the AFR wGRS was consistent between different US geographical regions and unaltered by fine AFR population substructure. The AFR and EUR wGRSs can distinguish slow from normal metabolizers in their respective populations, and were able to reflect unique smoking cessation pharmacotherapy outcomes previously observed for the NMR. Additionally, we evaluated the utility of a cross‐ancestry wGRS, and the capacity of EUR, AFR, and cross‐ancestry wGRSs to predict the NMR within stratified or admixed AFR‐EUR populations. Overall, our findings establish the clinical benefit of applying ancestry‐specific wGRSs, demonstrating superiority of the AFR wGRS in AFRs.