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

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Abstrakt

Tytuł:: Profiling of warfarin pharmacokinetics-associated genetic variants: Black Africans portray unique genetic markers important for an African specific warfarin pharmacogenetics-dosing algorithm.
Autorzy:: Ndadza A; Pharmacogenomics and Drug Metabolism Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Muyambo S; Department of Clinical Pharmacology, College of Health Science, University of Zimbabwe, Harare, Zimbabwe.; Department of Biological Sciences, Faculty of Science and Engineering, Bindura University of Science and Education, Bindura, Zimbabwe.
Mntla P; Department of Cardiology, Sefako Makgatho Health Sciences University and Dr. George Mukhari Hospital, Pretoria, South Africa.
Wonkam A; Pharmacogenomics and Drug Metabolism Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Chimusa E; Pharmacogenomics and Drug Metabolism Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Kengne AP; Non-Communicable Diseases Research Unit, South African Medical Research Council and University of Cape Town, Cape Town, South Africa.
Ntsekhe M; Division of Cardiology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Dandara C; Pharmacogenomics and Drug Metabolism Research Group, Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Źródło:: Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2021 Dec; Vol. 19 (12), pp. 2957-2973. Date of Electronic Publication: 2021 Sep 29.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: 2023- : [New York] : Elsevier
Original Publication: Oxford : Blackwell Pub.
MeSH Terms:: Pharmacogenetics*
Warfarin*
Algorithms ; Anticoagulants ; Black People ; Cytochrome P-450 CYP2C9/genetics ; Genetic Markers ; Genotype ; Humans ; Vitamin K Epoxide Reductases/genetics
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Grant Information:: Medical Research Council (MRC) of South Africa (SAMRC); 113540 National Research Foundation, NRF
Contributed Indexing:: Keywords: South Africa; Southern Africans; Zimbabwe; pharmacogenetics; pharmacokinetics; warfarin
Substance Nomenclature:: 0 (Anticoagulants)
0 (Genetic Markers)
5Q7ZVV76EI (Warfarin)
EC 1.14.13.- (Cytochrome P-450 CYP2C9)
EC 1.17.4.4 (VKORC1 protein, human)
EC 1.17.4.4 (Vitamin K Epoxide Reductases)
Entry Date(s):: Date Created: 20210812 Date Completed: 20211208 Latest Revision: 20230829
Update Code:: 20240105
PubMed Central ID:: PMC9543705
DOI:: 10.1111/jth.15494
PMID:: 34382722
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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.
(© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

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