Pharmacogenomic Landscape of Antimalarial Drug Metabolism Genes in Six Geopolitical Zones of Nigeria: Towards Precision Malaria Treatment

Inter-individual and inter-ethnic variation in antimalarial drug pharmacokinetics is substantially determined by genetic polymorphisms in drug metabolism genes including CYP2C8, CYP3A4, CYP3A5, CYP2D6, and UGT1A9. Clinically actionable pharmacogenomic diversity in these genes across Nigeria's six geopolitical zones has not been comprehensively characterised, limiting the evidence base for precision malaria treatment guidelines. This dissertation characterised the pharmacogenomic landscape of antimalarial drug metabolism genes across all six Nigerian geopolitical zones. Three thousand adults (500 per zone) were recruited from community sites in Lagos (South West), Enugu (South East), Port Harcourt (South South), Abuja/Plateau (North Central), Kano (North West), and Maiduguri (North East). Targeted next-generation sequencing of 12 pharmacogenomically relevant loci was performed, and diplotype-to-phenotype translation was conducted using PharmVar and CPIC guidelines. Population genetic statistics and geographic differentiation of pharmacogenomically relevant diplotypes were assessed. Clinically relevant poor metaboliser phenotypes for CYP2C8 and CYP2D6 were distributed unevenly across geopolitical zones, with significantly higher CYP2C8*2 homozygosity in South West populations. Ultra-rapid metaboliser phenotypes for CYP2D6 were concentrated in North West populations. These zone-level pharmacogenomic maps provide the evidentiary foundation for regionally differentiated precision antimalarial prescribing guidelines. Keywords: pharmacogenomics, antimalarial, CYP2C8, precision medicine, Nigeria geopolitical zones