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The pharmacogenomics of warfarin safety and effectiveness in children Shaw, Kaitlyn


Use of the anticoagulant warfarin for thromboembolic disease prophylaxis is limited by a large inter - patient dose variability and high risk of adverse drug reactions (ADRs). Polymorphisms in two genes , CYP2C9 and VK ORC1 , have consistently been shown to be associated with warfar in dose requirements in adults. However, evidence on the importance of genetics in warfarin therapy in children is limited. Further paediatric studies are required to understand the predictive factors contributing to dose variation and to help prevent warfarin - induced ADRs in children . In this study we aimed t o assess the contribution of genotypes and clinical factors to warfarin dose and relat ed outcomes in children. Clinical and genetic data was collected from 93 patients less than 19 years of age who received warfarin therapy. DNA was genotyped for 93 single nucleotide polymorphisms using a custom assay . Associations between CYP2C9/VKORC1/ CYP4F2 genotypes and therapeutic dose, time to therapeutic INR /time to over - anticoagulation , and incidence of adverse drug reactions were analyzed . Additional variants in genes involved in vitamin K and coagulation pathways were tested for an association with warfarin dose. 76.3% of dose variability was explained by weight, indication, VKORC1 ! 1639G/A and CYP2C9 *2/*3 , with genotypes accou nting for 21.1% of variability. There was a strong correlation (R² =0.68; p<0.001) between actual and predicted war farin dose using a pediatric genotype - based dosing model. VKORC1 genotype also had a significant impact on time to iii therapeutic INR(p=0.047) and time to INR>4 (p =0.024) during the initiation of therapy. Anadditional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose in a multivariate model. This study confirms the importance of VKORC1/CYP2C9 genotype s for warfarin dose and clinical outcomes in children and validates a pediatric - specific genotype - based dosing algorithm. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.

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