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VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children

Authors

  • Kaitlyn Shaw MSc,

    1. Department of Pediatrics, Faculty of Medicine, University of British Columbia (UBC), Vancouver, BC, Canada
    2. Pharmaceutical Outcomes Programme, B.C. Children's Hospital, Vancouver, BC, Canada
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  • Ursula Amstutz PhD,

    1. Department of Pediatrics, Faculty of Medicine, University of British Columbia (UBC), Vancouver, BC, Canada
    2. Pharmaceutical Outcomes Programme, B.C. Children's Hospital, Vancouver, BC, Canada
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  • Claudette Hildebrand RN,

    1. Pharmaceutical Outcomes Programme, B.C. Children's Hospital, Vancouver, BC, Canada
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  • S. Rod Rassekh MD, MHSc,

    1. Division of Pediatric Hematology/Oncology/BMT, B.C. Children's Hospital, Vancouver, BC, Canada
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  • Martin Hosking MD,

    1. Division of Pediatric Cardiology, B.C. Children's Hospital, Vancouver, BC, Canada
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  • Kathleen Neville MD, MSc,

    1. Division of Pediatric Hematology/Oncology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri
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  • J. Steven Leeder PharmD, PhD,

    1. Division of Clinical Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri
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  • Michael R. Hayden MD, PhD, FRCPC,

    1. Centre for Molecular Medicine and Therapeutics, UBC, Vancouver, BC, Canada
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  • Colin J. Ross MSc, PhD,

    1. Department of Pediatrics, Faculty of Medicine, University of British Columbia (UBC), Vancouver, BC, Canada
    2. Centre for Molecular Medicine and Therapeutics, UBC, Vancouver, BC, Canada
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  • Bruce C. Carleton PharmD

    Corresponding author
    1. Department of Pediatrics, Faculty of Medicine, University of British Columbia (UBC), Vancouver, BC, Canada
    2. Pharmaceutical Outcomes Programme, B.C. Children's Hospital, Vancouver, BC, Canada
    • Correspondence to: Bruce C. Carleton, Pharmaceutical Outcomes Programme, Child and Family Research Institute, 950 West 28th Avenue, Rm A3-207, Vancouver, BC, Canada V5Z 4H4.

      E-mail: bcarleton@popi.ubc.ca

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  • Conflict of interest: Nothing to declare.

Abstract

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 (R2 = 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. Pediatr Blood Cancer 2014;61:1055–1062. © 2014 Wiley Periodicals, Inc.

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