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    Rights statement: This is the peer reviewed version of the following article: El-Boraie, A., Chenoweth, M.J., Pouget, J.G., Benowitz, N.L., Fukunaga, K., Mushiroda, T., Kubo, M., Nollen, N.L., Sanderson Cox, L., Lerman, C., Knight, J. and Tyndale, R.F. (2021), Transferability of Ancestry-Specific and Cross-Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations. Clin. Pharmacol. Ther., 110: 975-985. https://doi.org/10.1002/cpt.2135 which has been published in final form at https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.2135 This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.

    Accepted author manuscript, 656 KB, PDF document

    Embargo ends: 1/01/22

    Available under license: CC BY-NC: Creative Commons Attribution-NonCommercial 4.0 International License

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Transferability Of Ancestry-Specific And Cross-Ancestry CYP2A6 Activity Genetic Risk Scores In African And European Populations

Research output: Contribution to journalJournal articlepeer-review

Published
  • Ahmed El-Boraie
  • Meghan J Chenoweth
  • Jennie G Pouget
  • Neal L Benowitz
  • Koya Fukunaga
  • Taisei Mushiroda
  • Michiaki Kubo
  • Nicole L Nollen
  • Lisa Sanderson Cox
  • Caryn Lerman
  • Jo Knight
  • Rachel F Tyndale
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<mark>Journal publication date</mark>31/10/2021
<mark>Journal</mark>Clinical pharmacology and therapeutics
Issue number4
Volume110
Number of pages11
Pages (from-to)975-985
Publication StatusPublished
Early online date1/01/21
<mark>Original language</mark>English

Abstract

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 non-, former- 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-ancestry populations (EUR) 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.

Bibliographic note

This is the peer reviewed version of the following article: El-Boraie, A., Chenoweth, M.J., Pouget, J.G., Benowitz, N.L., Fukunaga, K., Mushiroda, T., Kubo, M., Nollen, N.L., Sanderson Cox, L., Lerman, C., Knight, J. and Tyndale, R.F. (2021), Transferability of Ancestry-Specific and Cross-Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations. Clin. Pharmacol. Ther., 110: 975-985. https://doi.org/10.1002/cpt.2135 which has been published in final form at https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.2135 This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.