title: In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes.
abstract: Anticoagulation with vitamin K antagonists (VKAs) is problematic because of difficulties in safely managing dosing. Polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase genes (VKORC1) have been shown to affect VKA dosing in adults. The association of these polymorphisms on VKA dosing in children has not been investigated. The objective of the study was to assess associations of CYP2C9 and VKORC1 polymorphisms and clinical variables on VKA dosing in children. A nonselected cohort of pediatric patients receiving VKA were tested for CYP2C9 and VKORC1 polymorphisms, and clinical data were collected. Multiple linear regression modeling was used to assess relationships of VKA dose with genetic and clinical variables. Fifty-nine patients were recruited; 55.9% were receiving warfarin, and 44.1% were on phenprocoumon. There was a negative association of age with VKA dose (P < .001). Comparing VKORC1 genotypes, the AA group required significantly lower daily doses than GG group (P = .011). In the full model including age, VKORC1 and CYP2C9 genotypes accounted for 38% of dose variation. Age explained 28.3% of VKA dose variations; VKORC1 and CYP2C9 explained only 3.7% and 0.4%, respectively. In children, the most critical factor in determining VKA dose is age. VKORC1/CYP2C9 genotypes only marginally explain dose variations.
authors.affiliation: Pediatric Hematology/Oncology, University Children's Hospital, University of Münster, Münster, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nowak-Göttl
authors.forename: Kevin
authors.initials: K
authors.lastname: Dietrich
authors.forename: Daria
authors.initials: D
authors.lastname: Schaffranek
authors.forename: Noha Sharaf
authors.initials: NS
authors.lastname: Eldin
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yasui
authors.forename: Christof
authors.initials: C
authors.lastname: Geisen
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Mitchell
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000925:Anticoagulants / Q000008:administration & dosage; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010644:Phenprocoumon / Q000008:administration & dosage*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D013927:Thrombosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D010644:Phenprocoumon