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.
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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Transferability Of Ancestry-Specific And Cross-Ancestry CYP2A6 Activity Genetic Risk Scores In African And European Populations
AU - El-Boraie, Ahmed
AU - Chenoweth, Meghan J
AU - Pouget, Jennie G
AU - Benowitz, Neal L
AU - Fukunaga, Koya
AU - Mushiroda, Taisei
AU - Kubo, Michiaki
AU - Nollen, Nicole L
AU - Cox, Lisa Sanderson
AU - Lerman, Caryn
AU - Knight, Jo
AU - Tyndale, Rachel F
N1 - 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.
PY - 2021/10/31
Y1 - 2021/10/31
N2 - 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.
AB - 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.
U2 - 10.1002/cpt.2135
DO - 10.1002/cpt.2135
M3 - Journal article
C2 - 33300144
VL - 110
SP - 975
EP - 985
JO - Clinical pharmacology and therapeutics
JF - Clinical pharmacology and therapeutics
SN - 0009-9236
IS - 4
ER -