The Genetics of Warfarin Dose-Response Variability in Africans: An Expert Perspective on Past, Present, and Future

Coumarins such as warfarin are prescribed for prevention and treatment of thromboembolic disorders. Warfarin remains the most widely prescribed and an anticoagulant of choice in Africa. Warfarin use is, however, limited by interindividual variability in pharmacokinetics and a narrow therapeutic index. The difference in patients' pharmacodynamic responses to warfarin has been attributed to genetic variation in warfarin metabolism and molecular targets (e.g., CYP2C9 and VKORC1) and host-environment interactions. This expert review offers a synthesis of human genetics studies in Africans with respect to pharmacogenetics-informed warfarin dosing. We identify areas that need future research attention or could benefit from harnessing existing pharmacogenetics knowledge toward rational and optimal therapeutics with warfarin in African patients. A literature search was conducted until January 2019. A total of 343 articles were retrieved from nine African countries: Botswana, Ethiopia, Egypt, Ghana, Kenya, South Africa, Sudan, Tanzania, and Mozambique. We found 19 studies on genetics of warfarin treatment specifically among Africans. Genes examined included CYP2C9, VKORC1, CYP4F2, APOE, CALU, GGCX, and EPHX1. CYP2C9*2 and *3 alleles were highly frequent among Egyptians, while rare in other African populations. CYP2C9*5, *8, *9, and *11, and VKORC1 Asp36Tyr genetic variants explained warfarin variability in Africans better, compared to CYP2C9*2 and *3. In Africa, there is limited pharmacogenetics data on warfarin. Therefore, future research and funding commitments should be prioritized to ensure safe and effective use of warfarin in Africa. Lessons learned in Africa from the science of pharmacogenetics would inform rational therapeutics in hematology, cardiology, and surgical specialties worldwide.