Pharmacogenetics of warfarin safety and effectiveness in children

Objectives To assess the contribution of CYP2C9 / VKORC1 genotypes and variation in other genes involved in warfarin biotransformation and coagulation pathways to warfarin‐related outcomes in children. Furthermore, to validate the performance of a previously published pediatric pharmacogenetics‐dosing model when predicting the required dose in an independent cohort of children. Methods Clinical and genetic data was collected from 93 patients ≤18 years of age who received warfarin therapy. Genotyping was performed using a custom 96 SNP genotyping assay. Results Together, VKORC1 –1639G/A and CYP2C9 *2/*3 accounted for 21.1% of dose variability. There was a strong correlation (R 2 =0.64; P <0.001) between actual and predicted warfarin dose using a pediatric pharmacogenetics‐dosing model. VKORC1 genotype also had a significant impact on time to therapeutic INR ( P =0.047), time to INR>;4 ( P =0.028), and risk of over‐anticoagulation (INR>;4) during the initiation of therapy (odds ratio, 3.3; P =0.014). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose in a multivariate model. Conclusions This study confirms the importance of VKORC1/CYP2C9 genotype for warfarin outcomes in children and validates a pediatric‐specific genotype‐based dosing algorithm. Research funding provided by CIHR‐DSEN and CFI.