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    The Extent and Impact of Variation in ADME Genes in Sub-Saharan African Populations

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    Author
    da Rocha, Jorge E B
    Othman, Houcemeddine
    Botha, Gerrit
    Cottino, Laura
    Twesigomwe, David
    Ahmed, Samah
    Drögemöller, Britt I
    Fadlelmola, Faisal M
    Machanick, Philip
    Mbiyavanga, Mamana
    Panji, Sumir
    Wright, Galen E B
    Adebamowo, Clement
    Matshaba, Mogomotsi
    Ramsay, Michéle
    Simo, Gustave
    Simuunza, Martin C
    Tiemessen, Caroline T
    Baldwin, Sandra
    Chiano, Mathias
    Cox, Charles
    Gross, Annette S
    Thomas, Pamela
    Gamo, Francisco-Javier
    Hazelhurst, Scott
    Show allShow less

    Date
    2021-04-28
    Journal
    Frontiers in Pharmacology
    Publisher
    Frontiers Media S.A.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3389/fphar.2021.634016
    Abstract
    Introduction: Investigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterizing pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterized in European and Asian populations, but data from African populations are under-studied-which has implications for drug safety and effective use in Africa. Results: We identified significant ADME gene variation in African populations using data from 458 high-coverage whole genome sequences, 412 of which are novel, and from previously available African sequences from the 1,000 Genomes Project. ADME variation was not uniform across African populations, particularly within high impact coding variation. Copy number variation was detected in 116 ADME genes, with equal ratios of duplications/deletions. We identified 930 potential high impact coding variants, of which most are discrete to a single African population cluster. Large frequency differences (i.e., >10%) were seen in common high impact variants between clusters. Several novel variants are predicted to have a significant impact on protein structure, but additional functional work is needed to confirm the outcome of these for PGx use. Most variants of known clinical outcome are rare in Africa compared to European populations, potentially reflecting a clinical PGx research bias to European populations. Discussion: The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations. Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterization of variants in African populations including in vitro and in silico studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations.
    Rights/Terms
    Copyright © 2021 da Rocha, Othman, Botha, Cottino, Twesigomwe, Ahmed, Drögemöller, Fadlelmola, Machanick, Mbiyavanga, Panji, Wright, Adebamowo, Matshaba, Ramsay, Simo, Simuunza, Tiemessen, Baldwin, Chiano, Cox, Gross, Thomas, Gamo and Hazelhurst.
    Keyword
    ADME
    Africa
    CNV
    genetic diversity
    pharmacogenomics
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17052
    ae974a485f413a2113503eed53cd6c53
    10.3389/fphar.2021.634016
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