Genetic Factors Influencing Warfarin Dose in Black‐African Patients: A Systematic Review and Meta‐Analysis

Abstract

Warfarin is the most commonly used oral anticoagulant in sub‐Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black‐Africans, we performed a meta‐analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (‐1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black‐Africans to evaluate genetic factors determining warfarin response.

Improving anticoagulation in sub-Saharan Africa -- what are the challenges, and how can we overcome them?

“…The importance of pharmacogenetic variability on warfarin dose requirements in SSA was demonstrated in a recent systematic review. [104] For example, three variants that are more prevalent in Black Africans than in other populations, CYP2C9*5 ,CYP2C9*6 , and CYP2C9*11 , affected warfarin dose requirements by -13, -8, and -5 mg/week respectively. [104] Potential drug-drug interactions between warfarin and co-prescribed medications hinder good anticoagulation control.…”

“…[104] For example, three variants that are more prevalent in Black Africans than in other populations, CYP2C9*5 ,CYP2C9*6 , and CYP2C9*11 , affected warfarin dose requirements by -13, -8, and -5 mg/week respectively. [104] Potential drug-drug interactions between warfarin and co-prescribed medications hinder good anticoagulation control. In SSA, antiretroviral therapy is a significant source of potential drug-drug interactions.…”

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

“…The data on ADR incidence and the efficacy of most medications in populations of African descent are relatively scarce due to inefficient or absent pharmacovigilance programs [ 13 ]. There is however increasing evidence that the integration of PGx knowledge with other clinical data that influence drug response such as gender, age, weight, co-morbidities and lifestyle, will greatly assist clinicians in prescribing safe and efficient drug regimens to patients in SSA [ 14 ].…”

“…Varying frequencies of genetic variants across different sub-populations in SSA might suggest inter-ethnic and inter-individual variability in drug response in this region [ 21 ]. A meta-analysis of GWAS on African cohorts have revealed novel CYP2C9 and VKORCI gene variants with high genome-wide association, particularly in warfarin drug response, leading to subsequent dose adjustments for these cohorts [ 14 ]. This highlights the benefit and need to identify more African PGx markers through large-scale PGx research for PGx testing in SSA.…”

Pharmacogenomics for Primary Care: An Overview

“…CYP2C9*5 , *6 , *8 and *11 are ROF alleles with a collective frequency of ~20% in African ancestry individuals [ 135 ], but are rare in other ethnicities. All of these variants, except CYP2C9*8 , have been confirmed by meta-analysis to reduce warfarin dose requirements in black African patients [ 136 ]. The non-coding variant, rs12777823, within the CYP2C cluster upstream of CYP2C18 , has also been associated with reduced WSD requirements, independent of CYP2C9 [ 137 ].…”