Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients

Background Warfarin is the most frequently prescribed oral anticoagulant worldwide. Due to its narrow therapeutic index and inter-patient variability in dose requirement, this drug has been considered an ideal target for personalised medicine. Several warfarin dosing algorithms have been proposed to tailor the warfarin dosage in the European, Asian and African-American populations. However, minimal interest was directed towards Middle East countries. The factors affecting warfarin dose requirement could be different in patients from different geographical and ethnic groups, limiting the value of published dosing algorithms. Objective The first objective of this study was to examine the contribution of genetic and nongenetic factors on the variability of warfarin dose requirements in the Egyptian population using an easy, cost-effective and rapid analysis of vitamin K epoxide reductase complex subunit 1 ( VKORC1 ) and cytochrome P450 ( CYP ) 2C9 single nucleotide polymorphism (SNP) genotyping of patients. A second objective was to develop and validate an algorithm for warfarin dose prediction that is tailored to Egyptian patients. Methods Eighty-four patients, 41 males and 43 females, with a median (25th–75th percentiles) age of 39 (31–48) years were recruited in this study. Fifty patients whose international normalised ratio (INR) was in the range of 2–3 were allocated to a study cohort. SYBR Green-based multiplex allele-specific real-time PCR was used for genotyping of CYP2C9 (1075A>C) and VKORC1 (1173C>T) polymorphisms. Linear regression analysis, including the variables age, gender, CYP2C9 and VKORC1 SNP genotypes, was run to derive the best model for estimating the warfarin dose that achieves an INR of 2–3. The new warfarin dosing algorithm was examined in a second cohort of patients ( n = 34) to check its validity. The predicted dose requirements for a subgroup of our patients were calculated according to Gage and International Warfarin Pharmacogenetics Consortium (IWPC) algorithms available at http://www.warfarindosing.org. Results In the study cohort, warfarin dose/week in VKORC1 TT subjects was statistically significantly lower than in VKORC1 CC/CT subjects ( p = 0.032), while there was no statistically significant difference in warfarin dose/week between CYP2C9 *1*1 and *1*3 ( p = 0.925). A multivariate stepwise linear regression analysis revealed that age and VKORC1 had independent and significant contributions to the overall variability in wa