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

Shaw, Kaitlyn; Amstutz, Ursula; Hildebrand, Claudette; Rassekh, S Rod; Hosking, Martin; Neville, Kathleen; Leeder, J Steven; Hayden, Michael R; Ross, Colin J; Carleton, Bruce C (2014). VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. Pediatric blood & cancer, 61(6), pp. 1055-1062. Wiley-Liss 10.1002/pbc.24932

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Amstutz, Ursula

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1545-5009

Publisher:

Wiley-Liss

Language:

English

Submitter:

Barbara Keller

Date Deposited:

05 Mar 2015 16:10

Last Modified:

09 Nov 2015 11:40

Publisher DOI:

10.1002/pbc.24932

PubMed ID:

24474498

Uncontrolled Keywords:

anticoagulant, children, CYP2C9, pharmacogenetics, VKORC1, warfarin

BORIS DOI:

10.7892/boris.64127

URI:

https://boris.unibe.ch/id/eprint/64127

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