Influence of genetic, biological and pharmacological factors on warfarin dose in a Southern Brazilian population of European ancestry

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Warfarin is an oral anticoagulant widely used for thromboembolic disease prophylaxis. The pharmacokinetics and pharmacodynamics of this drug vary with environmental and genetic factors. Several algorithms including genetic and non‐genetic factors have been developed for different populations. These investigations have shown that polymorphisms in CYP2C9 and VKORC1 genes are related to warfarin dose variation. WHAT THIS STUDY ADDS • This study confirms that CYP2C9 and VKORC1 genes are the main predictors of warfarin dose, but there are other genes with smaller effects that can improve the algorithm for better dose prediction. • This study observed for the first time an effect of the F2 gene on warfarin dose prediction. • The inclusion for the first time of co‐medication with amlodipine, carbamazepine, β‐adrenoceptor blockers and diuretics refined the construction of an algorithm for dose prediction. AIMS To investigate the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2 and F2 genes on warfarin dose–response and develop a model including genetic and non‐genetic factors for warfarin dose prediction needed for each patient. METHODS A total of 279 patients of European ancestry on warfarin medication were investigated. Genotypes for −1639G>A, 1173C>T, and 3730G>A SNPs in the VKORC1 gene, CYP2C9*2 and CYP2C9*3, 1347C>T in the CYP4F2 gene and 494C>T in the F2 gene were determined by allelic discrimination with Taqman 5'‐nuclease assays. RESULTS The CYP2C9*2 and CYP2C9*3 polymorphisms in the CYP2C9 gene, −1639G>A and 1173C>T in the VKORC1 gene and 494C>T in the F2 gene are responsible for lower anticoagulant doses. In contrast, 1347C>T in the CYP4F2 gene and 3730G>A in the VKORC1 gene are responsible for higher doses of warfarin. An algorithm including genetic, biological and pharmacological factors that explains 63.3% of warfarin dose variation was developed. CONCLUSION The model suggested has one of the highest coefficients of determination among those described in the literature.