title: Effect of CYP2C9, VKORC1, and CYP4F2 polymorphisms on warfarin maintenance dose in children aged less than 18 years: a protocol for systematic review and meta-analysis.
abstract: Despite its shortcomings, warfarin is still the most commonly prescribed anticoagulant to prevent thromboembolism in children. In adults, numerous studies confirmed the robust relationship between warfarin maintenance doses and single nucleotide polymorphisms of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase (VKORC1), and cytochrome P450 4F2 (CYP4F2). However, their effect in children still remains to be determined. The primary objective of the present systematic review and meta-analysis is to assess the effect of genotypes of CYP2C9, VKORC1, and CYP4F2 on warfarin maintenance dose in children.
  
  
  
  A comprehensive literature review search using the OVID platform will be conducted by a specialized librarian, without language restrictions (i.e., MEDLINE/EMBASE/Cochrane Central Register of Controlled Trials), and all abstracts will be reviewed by two authors. Data abstraction from each eligible study will be extracted individually by two authors (MT and TK), and disagreements will be resolved through discussion with a third person (SI). Critical appraisal of the included analysis of the primary objective will follow the Newcastle-Ottawa Scale, in addition to the Strengthening the Reporting of Genetic Association study (STREGA) statement, and data reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. For the meta-analysis, the presence vs. absence of each genetic polymorphism will be pursued, respectively, using a random effect model with effect size expressed as a mean difference plus 95 % confidence interval.
  
  
  
  Our study will provide a comprehensive systematic review and meta-analysis on the potential effects of CYP2C9, VKORC1, or CYP4F2 on the warfarin maintenance dose in children, exploring the feasibility of the development of pharmacogenetic-guided warfarin dosing algorithm for children on oral vitamin K antagonists.
  
  
  
  The review has been registered with PROSPERO (registration number CRD42015016172 ).
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Division of Pediatric Hematology/Oncology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada.
authors.forename: Leonardo R
authors.initials: LR
authors.lastname: Brandão
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada. shinya.ito@sickkids.ca.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ito
mesh_terms: D000293:Adolescent; D000925:Anticoagulants / Q000008:administration & dosage*; D002648:Child; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D000072470:Cytochrome P450 Family 4 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000078202:Systematic Reviews as Topic; D054556:Venous Thromboembolism / Q000235:genetics / Q000517:prevention & control*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*; D015201:Meta-Analysis as Topic
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: CYP2C9; CYP4F2; Children; Meta-analysis; Polymorphism; VKORC1; Warfarin