Publication: Genetic variation present in the CYP3A4 gene in Ni-Vanuatu and Kenyan populations in malaria endemicity
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2024-08
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Drug Metabolism and Pharmacokinetics
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Abstract
Cytochrome P450 3A4 (CYP3A4) enzyme is involved in the metabolism of about 30 % of clinically used drugs,
including the antimalarials artemether and lumefantrine. CYP3A4 polymorphisms yield enzymatic variants that
contribute to inter-individual variation in drug metabolism. Here, we examined CYP3A4 polymorphisms in
populations from malaria-endemic islands in Lake Victoria, Kenya, and Vanuatu, to expand on the limited data
sets. We used archived dried blood spots collected from 142 Kenyan and 263 ni-Vanuatu adults during cross-
sectional malaria surveys in 2013 and 2005–13, respectively, to detect CYP3A4 variation by polymerase chain
reaction (PCR) and sequencing. In Kenya, we identified 14 CYP3A4 single nucleotide polymorphisms (SNPs),
including the 4713G (CYP3A4*1B; allele frequency 83.9 %) and 19382A (CYP3A4*15; 0.7 %) variants that were
previously linked to altered metabolism of antimalarials. In Vanuatu, we detected 15 SNPs, including the 4713A
(CYP3A4*1A; 88.6 %) and 25183C (CYP3A4*18; 0.6 %) variants. Additionally, we detected a rare and novel SNP
C4614T (0.8 %) in the 5′ untranslated region. A higher proportion of CYP3A4 genetic variance was found among
ni-Vanuatu populations (16 %) than among Lake Victoria Kenyan populations (8 %). Our work augments the
scarce data sets and contributes to improved precision medicine approaches, particularly to anti-malarial
chemotherapy, in East African and Pacific Islander populations.