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Pharmacogene sequencing of a gabonese population with severe plasmodium falciparum malaria reveals multiple novel variants with putative relevance for antimalarial treatment

2021-07Artigo científico Acesso aberto
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dc.contributor.authorPernaute-Lau, Leyre
dc.contributor.authorAdegnika, Ayola Akim
dc.contributor.authorZhou, Yitian
dc.contributor.authorZinsou, Jeannot F.
dc.contributor.authorGil, Jose Pedro
dc.contributor.authorKrishna, Sanjeev
dc.contributor.authorKremsner, Peter G.
dc.contributor.authorLauschke, Volker M.
dc.contributor.authorVelavan, Thirumalaisamy P.
dc.contributor.institutionGlobal Health and Tropical Medicine (GHTM)
dc.contributor.institutionInstituto de Higiene e Medicina Tropical (IHMT)
dc.contributor.pblAmerican Society for Microbiology
dc.date.accessioned2022-01-20T03:33:40Z
dc.date.available2022-01-20T03:33:40Z
dc.date.issued2021-07
dc.descriptionFunding Information: T.P.V., P.G.K., and A.A.A. acknowledge financial support from the German Center for Infection Research (DZIF), Clinical Research Group, Lambarene, and a German Science Foundation grant (DFG Ku 775/17-1) for the German African Cooperation Project in Infectiology. Work was supported by UIDB/04046/2020 and UIDP/04046/2020 Centre grants from FCT, Portugal (to BioISI). L.P.-L. is the recipient of a fellowship from BioSys Ph.D. program PD65-2012 (reference number SFRH/BD/142860/2018) from FCT (Portugal). V.M.L. receives support from the Swedish Research Council (grant agreement numbers 2016-01153, 2016-01154, and 2019-01837), the EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant number 875510), the Swedish Strategic Research Programmes in Diabetes (SFO Diabetes), Stem Cells and Regenerative Medicine (SFO StratRegen), as well as the European Union’s Horizon 2020 research and innovation program U-PGx (grant agreement number 668353). Publisher Copyright: © 2021 American Society for Microbiology.
dc.description.abstractMalaria remains one of the deadliest diseases in Africa, particularly for children. While successful in reducing morbidity and mortality, antimalarial treatments are also a major cause of adverse drug reactions (ADRs). Host genetic variation in genes involved in drug disposition or toxicity constitutes an important determinant of ADR risk and can prime for parasite drug resistance. Importantly, however, the genetic diversity in Africa is substantial, and thus, genetic profiles in one population cannot be reliably extrapolated to other ethnogeographic groups. Gabon is considered a high-transmission country, with more than 460,000 malaria cases per year. Yet the pharmacogenetic landscape of the Gabonese population or its neighboring countries has not been analyzed. Using targeted sequencing, here, we profiled 21 pharmacogenes with importance for antimalarial treatment in 48 Gabonese pediatric patients with severe Plasmodium falciparum malaria. Overall, we identified 347 genetic variants, of which 18 were novel, and each individual was found to carry 87.369.2 (standard deviation [SD]) variants across all analyzed genes. Importantly, 16.7% of these variants were population specific, highlighting the need for high-resolution pharmacogenomic profiling. Between one in three and one in six individuals harbored reduced-activity alleles of CYP2A6, CYP2B6, CYP2D6, and CYP2C8 with important implications for artemisinin, chloroquine, and amodiaquine therapy. Furthermore, one in three patients harbored at least one G6PD-deficient allele, suggesting a considerably increased risk of hemolytic anemia upon exposure to aminoquinolines. Combined, our results reveal the unique genetic landscape of the Gabonese population and pinpoint the genetic basis for interindividual differences in antimalarial drug responses and toxicity.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent1393597
dc.identifier.doi10.1128/AAC.00275-21
dc.identifier.issn0066-4804
dc.identifier.otherPURE: 33047658
dc.identifier.otherPURE UUID: 13a85212-d979-4f12-b409-cc1a4a5d2fd6
dc.identifier.otherScopus: 85108154717
dc.identifier.otherPubMed: 33875422
dc.identifier.urihttp://hdl.handle.net/10362/131181
dc.identifier.urlhttps://www.scopus.com/pages/publications/85108154717
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGabon
dc.subjectMalaria
dc.subjectPopulation pharmacogenetics
dc.subjectPrecision medicine
dc.subjectPublic health
dc.subjectPharmacology
dc.subjectPharmacology (medical)
dc.subjectInfectious Diseases
dc.subjectSDG 1 - No Poverty
dc.subjectSDG 3 - Good Health and Well-being
dc.subjectSDG 5 - Gender Equality
dc.subjectSDG 9 - Industry, Innovation, and Infrastructure
dc.subjectSDG 10 - Reduced Inequalities
dc.subjectSDG 12 - Responsible Consumption and Production
dc.subjectSDG 17 - Partnerships for the Goals
dc.titlePharmacogene sequencing of a gabonese population with severe plasmodium falciparum malaria reveals multiple novel variants with putative relevance for antimalarial treatmenten
dc.typejournal article
degois.publication.issue7
degois.publication.titleAntimicrobial Agents and Chemotherapy
degois.publication.volume65
dspace.entity.typePublication
rcaap.rightsopenAccess

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