Profiling of warfarin pharmacokinetics‐associated genetic variants: Black Africans portray unique genetic markers important for an African specific warfarin pharmacogenetics‐dosing algorithm

Ndadza, Arinao, Muyambo, Sarudzai, Mntla, Pindile, Wonkam, Ambroise, Chimusa, Emile Rugamika, Kengne, Andre P., Ntsekhe, Mpiko and Dandara, Collet (2021) Profiling of warfarin pharmacokinetics‐associated genetic variants: Black Africans portray unique genetic markers important for an African specific warfarin pharmacogenetics‐dosing algorithm. Journal of Thrombosis and Haemostasis, 19 (12). pp. 2957-2973. ISSN 1538-7933

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Abstract

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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