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. (Blood. 2010;116(26):6101-6105) IntroductionAlthough vitamin K antagonists (VKAs) have been in use for more than 5 decades, safe management of these drugs remains a major challenge. Bleeding complications are associated with the variation in drug response and account for a significant number of emergency admissions on a yearly basis. 1 Clinical factors such as age, sex, drug interactions, diet, and underlying disorders affect response to VKA. 2 In addition, polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase gene (VKORC1) have a well-described effect on VKA dosing in adults. The CYP2C9 enzyme is responsible for clearance of the Senantiomer of warfarin and patients with the CYP2C9*2 or *3 require lower dosages. [3][4][5][6][7][8][9] The VKORC1 gene encodes vitamin K epoxide reductase complex, which recycles reduced vitamin K, an essential component for post translational gamma carboxylation of the vitamin K dependent factors. Therefore, the pharmacodynamics of VKA are affected by VKORC1, and it is well described that patients with polymorphisms require lower dosages of VKA. [5][6][7][10][11][12] The impact of these 2 genetic markers has resulted in the Food and Drug Administration implementing a label change on warfarin suggesting lower dosages in patients with these polymorphisms. 13 In adults, the variation in dose of VKA is accounted for between 30% and 40% on the genetic factors and between 15%-22% on clinical characteristics. 10,12,14,15 In children, as in the adult, there are multiple characteristics affecting dose such as age, underlying medical condition, medication and diet. 16,17 However, age is overwhelming the single most important varia...
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