Why the study?
Warfarin dose variability is linked to metabolic pathway genes, but traditional focus has centered on CYP2C9 and VKORC1 with little focus on other genes.
Which genetic variants are associated with warfarin maintenance dose in black African and Mixed Ancestry populations?
Which genetic variants are associated with warfarin maintenance dose in black African and Mixed Ancestry populations?
African populations possess unique genetic variants beyond traditional CYP2C9 and VKORC1 alleles that significantly affect warfarin dosing requirements, highlighting the need for population-specific pharmacogenetic algorithms.
CYP2C variants were associated with warfarin dose variability in black Africans; leaves open their added value for dosing algorithms beyond CYP2C9/VKORC1.
BACKGROUND: Warfarin dose variability observed in patients is attributed to variation in genes involved in the warfarin metabolic pathway. Genetic variation in CYP2C9 and VKORC1 has been the traditional focus in evaluating warfarin dose variability, with little focus on other genes. OBJECTIVE: We set out to evaluate 27 single nucleotide polymorphisms (SNPs) in the CYP2C cluster loci and 8 genes (VKORC1, ABCB1, CYP2C9, CYP2C19, CYP2C8, CYP1A2, CYP3A4, and CYP3A5) involved in pharmacokinetics of warfarin. PATIENTS/METHODS: 503 participants were recruited among black Africans and Mixed Ancestry population groups, from South Africa and Zimbabwe, and a blood sample taken for DNA. Clinical parameters were obtained from patient medical records, and these were correlated with genetic variation. RESULTS: Among black Africans, the SNPs CYP2C rs12777823G>A, CYP2C9 c.449G>A (*8), CYP2C9 c.1003C>T (*11) and CYP2C8 c.805A>T (*2) were significantly associated with warfarin maintenance dose. Conversely, CYP2C9 c.430C>T (*2), CYP2C8 c.792C>G (*4) and VKORC1 g.-1639G>A were significantly associated with maintenance dose among the Mixed Ancestry. The presence of CYP2C8*2 and CYP3A5*6 alleles was associated with increased mean warfarin maintenance dose, whereas CYP2C9*8 allele was associated with reduced warfarin maintenance dose. CONCLUSION: African populations present with a diversity of variants that are important in predicting pharmacogenetics-based warfarin dosing in addition to those reported in CYP2C9 and VKORC1. It is therefore important, to include African populations in pharmacogenomics studies to be able to identify all possible biomarkers that are potential predictors for drug response.
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Ndadza et al. (2021) studied this question.
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