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Pharmacogenetics of warfarin safety and effectiveness in children
Author(s) -
Shaw Kaitlyn,
Amstutz Ursula,
Hildebrand Claudette,
Rassekh S. Rod,
Dubé MariePierre,
Hayden Michael R,
Ross Colin J,
Carleton Bruce C
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.673.2
Subject(s) - vkorc1 , cyp2c9 , warfarin , pharmacogenetics , dosing , medicine , vitamin k epoxide reductase , genotyping , genotype , cohort , odds ratio , pharmacology , biology , atrial fibrillation , genetics , cytochrome p450 , metabolism , gene
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.