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

Autor:	da Rocha JEB; Sydney Brenner Institute for Molecular Bioscience (SBIMB), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Othman H; Sydney Brenner Institute for Molecular Bioscience (SBIMB), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Botha G; Computational Biology Division and H3ABioNet, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa., Cottino L; Sydney Brenner Institute for Molecular Bioscience (SBIMB), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Twesigomwe D; Sydney Brenner Institute for Molecular Bioscience (SBIMB), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Ahmed S; Centre for Bioinformatics and Systems Biology, Faculty of Science, University of Khartoum, Khartoum, Sudan., Drögemöller BI; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada., Fadlelmola FM; Centre for Bioinformatics and Systems Biology, Faculty of Science, University of Khartoum, Khartoum, Sudan., Machanick P; Department of Computer Science, Rhodes University, Makhanda, South Africa., Mbiyavanga M; Computational Biology Division and H3ABioNet, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa., Panji S; Computational Biology Division and H3ABioNet, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa., Wright GEB; Neuroscience Research Program, Winnipeg Health Sciences Centre and Max Rady College of Medicine, Kleysen for Advanced Medicine, University of Manitoba, Winnipeg, MB, Canada.; Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada., Adebamowo C; Institute for Human Virology, Abuja, Nigeria.; Institute of Human Virology and Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States., Matshaba M; Botswana-Baylor Children's Clinical Center of Excellence, Gaborone, Botswana.; Baylor College of Medicine, Houston, TX, United States., Ramsay M; Sydney Brenner Institute for Molecular Bioscience (SBIMB), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Simo G; Molecular Parasitology and Entomology Unit, Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon., Simuunza MC; Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka, Zambia., Tiemessen CT; Centre for HIV and STIs, National Institute for Communicable Diseases, National Health Laboratory Services and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Baldwin S; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline R&D, Ware, United Kingdom., Chiano M; Human Genetics, GlaxoSmithKline R&D, Stevenage, United Kingdom., Cox C; Human Genetics, GlaxoSmithKline R&D, Stevenage, United Kingdom., Gross AS; Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline R&D, Sydney, NSW, Australia., Thomas P; Data and Computational Sciences, GlaxoSmithKline R&D, Stevenage, United Kingdom., Gamo FJ; Global Health, GlaxoSmithKline R&D, Tres Cantos, Madrid, Spain., Hazelhurst S; Sydney Brenner Institute for Molecular Bioscience (SBIMB), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; School of Electrical and Information Engineering, University of the Witwatersrand, Johannesburg, South Africa.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2021 Apr 28; Vol. 12, pp. 634016. Date of Electronic Publication: 2021 Apr 28 (Print Publication: 2021).
DOI:	10.3389/fphar.2021.634016
Abstrakt:	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. Competing Interests: GlaxoSmithKline provided funding for this project. The authors SB, MC, CC, ASG, PT and FJG are all employees of GlaxoSmithKline and participated in the analysis and writing of the paper. GlaxoSmithKline had no additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content is solely responsibility of the authors and does not necessarily represent the official views of GlaxoSmithKline. The remaining authors declare no conflicts of interest. (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.)
Databáze:	MEDLINE
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