Pharmacogenetics of coumarin dosing: prevalence of CYP2C9 and VKORC1 polymorphisms in the Lebanese population

Abstract

Background: Polymorphisms in the genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and the vitamin K epoxide reductase (VKORC1) are known to contribute to variability in sensitivity to coumarins. Patients with certain common genetic variants of CYP2C9 (*2 & *3) or a VKORC1 polymorphism (−1639A Allele) require a lower dose of coumarin and are also at higher risk for over-anticoagulation and serious bleeding. In August 2007, the FDA label for warfarin was updated to highlight the benefit of genetic testing to predict warfarin response. Aim: Since the prevalence of these variants in the Lebanese population has not yet been reported, our aim was to determine the genotypes of CYP2C9 and VKORC1 in our population and to compare allele frequencies with previous findings from other ethnic groups. Materials and Methods: CYP2C9 (*1/*2/*3) and VKORC1 (*A/*G) allelic variants were assessed by polymerase chain reaction–restriction fragment length polymorphism assays in a diversified sample of 161 unrelated healthy Lebanese volunteers. Results: The allele frequencies of CYP2C9 *2 and *3 were 0.112 and 0.096 respectively, whereas VKORC1−1639A was 0.528. Carriers of the CYP2C9 *2 or *3 represented 34.2% of the subjects, whereas those of the VKORC1−1639A represented 73.9%. Conclusion: Our data show no significant difference in the frequency of CYP2C9 allelic variants when compared to the Caucasian population, whereas the allelic frequency of VKORC1−1639A was very high. Over 50% of the Lebanese population seem to be carrying more than two independent risk alleles, and is therefore potentially at high risk of over-anticoagulation.