title: Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects.
abstract: Warfarin is used in paediatric populations, but dosing algorithms incorporating pharmacogenetic data have not been developed for children. Previous studies have produced estimates of the effect of polymorphisms in Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on stable warfarin dosing, but data on time in therapeutic range, initial dosing and adverse effects are limited. Participants (n=97) were recruited, and routine clinical data and salivary DNA samples were collected from all participants and analysed for CYP2C9*2, *3 and VKORC1-1639 polymorphisms.VKORC1 -1639 was associated with a greater proportion of the first 6 months' treatment time spent within the target International Normalised Ratio (INR) range, accounting for an additional 9.5% of the variance in the proportion of time. CYP2C9*2 was associated with a greater likelihood of INR values exceeding the target range during the initiation of treatment (odds ratio (OR; per additional copy) 4.18, 95% confidence interval (CI) 1.42, 12.34). CYP2C9*2 and VKORC1-1639 were associated with a lower dose requirement, and accounted for almost 12% of the variance in stable dose. VKORC1-1639 was associated with an increased likelihood of mild bleeding complications (OR (heterozygotes vs homozygotes) 4.53, 95% CI 1.59, 12.93). These data show novel associations between VKORC1-1639 and CYP2C9*2 and INR values in children taking warfarin, as well as replicating previous findings with regard to stable dose requirements. The development of pharmacogenomic dosing algorithms for children using warfarin has the potential to improve clinical care in this population.
authors.affiliation: 1] Institute of Translational Medicine, University of Liverpool, Liverpool, UK [2] Department of Research, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors.forename: D B
authors.initials: DB
authors.lastname: Hawcutt
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Ghani
authors.affiliation: Department of Biostatistics, University of Liverpool, Liverpool, UK.
authors.forename: L
authors.initials: L
authors.lastname: Sutton
authors.affiliation: Department of Biostatistics, University of Liverpool, Liverpool, UK.
authors.forename: A
authors.initials: A
authors.lastname: Jorgensen
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: E
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors.forename: M
authors.initials: M
authors.lastname: Murray
authors.affiliation: Department of Cardiology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors.forename: H
authors.initials: H
authors.lastname: Michael
authors.affiliation: Department of Cardiology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors.forename: I
authors.initials: I
authors.lastname: Peart
authors.affiliation: Institute of Child Health, University College London (UCL), London, UK.
authors.forename: R L
authors.initials: RL
authors.lastname: Smyth
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007223:Infant; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000378:metabolism; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D014859:Warfarin; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases