Key result
VKORC1 and CYP2C9 genotypes accounted for 21.1% of warfarin dose variability in children, and CYP2C9*3 carriers had an increased risk of major bleeding (adjusted OR 11.28).
Why the study?
Do VKORC1 and CYP2C9 genotypes predict warfarin dose requirements and clinical outcomes in children?
Cohort (n=93)
Do VKORC1 and CYP2C9 genotypes predict warfarin dose requirements and clinical outcomes in children?
Odds Ratio: 11.28
VKORC1 and CYP2C9 genotypes significantly predict warfarin dose requirements and risk of major bleeding in a young pediatric cohort.
Genotype associations with pediatric warfarin outcomes warrant prospective validation; leaves open whether testing improves dosing or safety.
BACKGROUND: Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children. PROCEDURE: Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay. RESULTS: With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model. CONCLUSIONS: This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.
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Shaw et al. (2014) conducted a cohort in Children receiving warfarin therapy (n=93). VKORC1 and CYP2C9 genotypes vs. Non-carriers was evaluated on Major bleeding (for CYP2C9*3 carriers) (adjusted OR 11.28). VKORC1 and CYP2C9 genotypes accounted for 21.1% of warfarin dose variability in children, and CYP2C9*3 carriers had an increased risk of major bleeding (adjusted OR 11.28).
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