Correlation Engine 2.0
Clear Search sequence regions


  • adult (1)
  • alleles (1)
  • auc (1)
  • behaviors (1)
  • cohort (2)
  • CYP2A6 (12)
  • cyp2a6 protein, human (1)
  • female (1)
  • gene (3)
  • genotypes (2)
  • humans (1)
  • NMR (9)
  • outcomes treatment (2)
  • P 450 (2)
  • phenotypes (1)
  • protein human (1)
  • signals (1)
  • smoking (3)
  • Sizes of these terms reflect their relevance to your search.

    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. © 2019 Society for the Study of Addiction.

    Citation

    Ahmed El-Boraie, Taraneh Taghavi, Meghan J Chenoweth, Koya Fukunaga, Taisei Mushiroda, Michiaki Kubo, Caryn Lerman, Nicole L Nollen, Neal L Benowitz, Rachel F Tyndale. Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity. Addiction biology. 2020 Jan;25(1):e12741

    Expand section icon Mesh Tags

    Expand section icon Substances


    PMID: 30815984

    View Full Text