| David Twesigomwe, Britt I. Drögemöller, Galen E. B. Wright, Clement Adebamowo, Godfred Agongo, Palwendé R. Boua, Mogomotsi Matshaba, Maria Paximadis, Michèle Ramsay, Gustave Simo, Martin C. Simuunza, Caroline T. Tiemessen, Zané Lombard, Scott Hazelhurst Characterization of CYP2B6 and CYP2A6 Pharmacogenetic Variation in Sub-Saharan African Populations Journal Article In: Clinical pharmacology and therapeutics, vol. 115, iss. 3, pp. 576-594, 2024, ISSN: 1532-6535. @article{Twesigomwe2024,
title = {Characterization of CYP2B6 and CYP2A6 Pharmacogenetic Variation in Sub-Saharan African Populations},
author = {David Twesigomwe and Britt I. Dr\"{o}gem\"{o}ller and Galen E. B. Wright and Clement Adebamowo and Godfred Agongo and Palwend\'{e} R. Boua and Mogomotsi Matshaba and Maria Paximadis and Mich\`{e}le Ramsay and Gustave Simo and Martin C. Simuunza and Caroline T. Tiemessen and Zan\'{e} Lombard and Scott Hazelhurst},
url = {https://pubmed.ncbi.nlm.nih.gov/38049200/},
doi = {10.1002/CPT.3124},
issn = {1532-6535},
year = {2024},
date = {2024-01-01},
journal = {Clinical pharmacology and therapeutics},
volume = {115},
issue = {3},
pages = {576-594},
publisher = {Clin Pharmacol Ther},
abstract = {Genetic variation in CYP2B6 and CYP2A6 is known to impact interindividual response to antiretrovirals, nicotine, and bupropion, among other drugs. However, the full catalogue of clinically relevant pharmacogenetic variants in these genes is yet to be established, especially across African populations. This study therefore aimed to characterize the star allele (haplotype) distribution in CYP2B6 and CYP2A6 across diverse and understudied sub-Saharan African (SSA) populations. We called star alleles from 961 high-depth full genomes using StellarPGx, Aldy, and PyPGx. In addition, we performed CYP2B6 and CYP2A6 star allele frequency comparisons between SSA and other global biogeographical groups represented in the new 1000 Genomes Project high-coverage dataset (n = 2,000). This study presents frequency information for star alleles in CYP2B6 (e.g., *6 and *18; frequency of 21\textendash47% and 2\textendash19%, respectively) and CYP2A6 (e.g., *4, *9, and *17; frequency of 0\textendash6%, 3\textendash10%, and 6\textendash20%, respectively), and predicted phenotypes (for CYP2B6), across various African populations. In addition, 50 potentially novel African-ancestry star alleles were computationally predicted by StellarPGx in CYP2B6 and CYP2A6 combined. For each of these genes, over 4% of the study participants had predicted novel star alleles. Three novel star alleles in CYP2A6 (*54, *55, and *56) and CYP2B6 apiece, and several suballeles were further validated via targeted Single-Molecule Real-Time resequencing. Our findings are important for informing the design of comprehensive pharmacogenetic testing platforms, and are highly relevant for personalized medicine strategies, especially relating to antiretroviral medication and smoking cessation treatment in Africa and the African diaspora. More broadly, this study highlights the importance of sampling diverse African ethnolinguistic groups for accurate characterization of the pharmacogene variation landscape across the continent.},
keywords = {Africa South of the Sahara, Alleles, Britt I Dr\"{o}gem\"{o}ller, Cytochrome P-450 CYP2A6 / genetics, Cytochrome P-450 CYP2B6 / genetics, David Twesigomwe, doi:10.1002/cpt.3124, Gene Frequency, Genotype, Humans, MEDLINE, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, Nicotine*, NIH, NLM, Non-U.S. Gov't, Pharmacogenetics*, pmid:38049200, PubMed Abstract, Research Support, Scott Hazelhurst},
pubstate = {published},
tppubtype = {article}
}
Genetic variation in CYP2B6 and CYP2A6 is known to impact interindividual response to antiretrovirals, nicotine, and bupropion, among other drugs. However, the full catalogue of clinically relevant pharmacogenetic variants in these genes is yet to be established, especially across African populations. This study therefore aimed to characterize the star allele (haplotype) distribution in CYP2B6 and CYP2A6 across diverse and understudied sub-Saharan African (SSA) populations. We called star alleles from 961 high-depth full genomes using StellarPGx, Aldy, and PyPGx. In addition, we performed CYP2B6 and CYP2A6 star allele frequency comparisons between SSA and other global biogeographical groups represented in the new 1000 Genomes Project high-coverage dataset (n = 2,000). This study presents frequency information for star alleles in CYP2B6 (e.g., *6 and *18; frequency of 21–47% and 2–19%, respectively) and CYP2A6 (e.g., *4, *9, and *17; frequency of 0–6%, 3–10%, and 6–20%, respectively), and predicted phenotypes (for CYP2B6), across various African populations. In addition, 50 potentially novel African-ancestry star alleles were computationally predicted by StellarPGx in CYP2B6 and CYP2A6 combined. For each of these genes, over 4% of the study participants had predicted novel star alleles. Three novel star alleles in CYP2A6 (*54, *55, and *56) and CYP2B6 apiece, and several suballeles were further validated via targeted Single-Molecule Real-Time resequencing. Our findings are important for informing the design of comprehensive pharmacogenetic testing platforms, and are highly relevant for personalized medicine strategies, especially relating to antiretroviral medication and smoking cessation treatment in Africa and the African diaspora. More broadly, this study highlights the importance of sampling diverse African ethnolinguistic groups for accurate characterization of the pharmacogene variation landscape across the continent. |
