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


METHODS
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.
Department of Pediatrics, Faculty of Medicine, University of British Columbia (UBC), Vancouver, BC, Canada; Pharmaceutical Outcomes Programme, B.C. Children's Hospital, Vancouver, BC, Canada.
Kaitlyn
K
Shaw
Ursula
U
Amstutz
Claudette
C
Hildebrand
S Rod
SR
Rassekh
Martin
M
Hosking
Kathleen
K
Neville
J Steven
JS
Leeder
Michael R
MR
Hayden
Colin J
CJ
Ross
Bruce C
BC
Carleton
D000293:Adolescent; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000502:physiology; D001711:Biotransformation / Q000235:genetics; D006348:Cardiac Surgical Procedures; D002648:Child; D002675:Child, Preschool; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D007223:Infant; D019934:International Normalized Ratio; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications / Q000517:prevention & control; D057285:Precision Medicine; D012306:Risk; D013997:Time Factors; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000502:physiology; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
CYP2C9; VKORC1; anticoagulant; children; pharmacogenetics; warfarin