Abstract
BackgroundWarfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing.ObjectiveTo explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose.MethodsIn this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews.ResultsWe identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients.ConclusionVariants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is needed for the prospective estimation of warfarin dose.
Highlights
Warfarin is the most widely used oral anticoagulant for the treatment and prevention of thromboembolic manifestations associated with atrial fibrillation, prosthetic heart valves, orthopedic surgery, and history of vascular thrombosis [1, 2]
Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively
The most important genes consistently affecting warfarin dose among different populations are the CYP2C9- a gene coding for cytochrome P450 2C9 enzyme which metabolizes the more potent S enantiomer of warfarin, and VKORC1- a gene coding for the vitamin K epoxide reductase which is an enzyme inhibited by warfarin [9, 10]
Summary
Warfarin is the most widely used oral anticoagulant for the treatment and prevention of thromboembolic manifestations associated with atrial fibrillation, prosthetic heart valves, orthopedic surgery, and history of vascular thrombosis [1, 2]. Despite the negative results from the COAG trial indicating no benefit of genetic-guided dosing, compared to clinical dosing, it showed that the percent time in therapeutic range (PTTR) was significantly lower in blacks in the genetic-guided arm compared to the clinical dosing arm [14]. This is probably due to the fact that blacks may have other less-common genetic variants affecting their warfarin dose that were not well-represented in the genetic-algorithm used in the COAG trial [16]. Different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing
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