title: Integrating interacting drugs and genetic variations to improve the predictability of warfarin maintenance dose in Chinese patients.
abstract: OBJECTIVE
  Compared with genetic factors, drug interactions are largely unexplored in pharmacogenetic studies. This study sought to systematically investigate the effects of VKORC1, STX4A, CYP2C9, CYP4F2, CYP3A4, and GGCX gene polymorphisms and interacting drugs on warfarin maintenance dose.
  
  
  METHODS
  A retrospective study of 845 Chinese patients after heart valve replacement receiving long-term warfarin maintenance therapy was conducted. Thirteen polymorphisms in the six genes were genotyped, and 36 drugs that may interact with warfarin were investigated.
  
  
  RESULTS
  Single-nucleotide polymorphism association analysis showed that VKORC1, CYP2C9 and CYP4F2 variations were highly associated with the warfarin maintenance dose. Among 36 drugs that may interact with warfarin, fluconazole, amiodarone, and omeprazole were associated with the requirement for 45.8, 16.7, and 16.7% lower median warfarin dose (all P<0.05 with a false discovery rate <0.05). The final pharmacogenetic equation explained 43.65% of interindividual variation of warfarin maintenance dose with age, body surface area, VKORC1 g.3588G>A, CYP2C9*3, CYP4F2 c.1297G>A, amiodarone, fluconazole, and diltiazem accounting for 1.97, 2.74, 24.12, 3.94, 1.64, 5.92, 2.47, and 0.84% of variation.
  
  
  CONCLUSIONS
  The present study indicated that VKORC1, CYP4F2, and CYP2C9 genotypes and interacting drugs had a significant impact on the warfarin maintenance dose in Chinese patients with heart valve replacement and demonstrated that integrating interacting drugs can largely improve the predictability of the dose algorithm.
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Institute of Clinical Pharmacology, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Zhong
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Mai
authors.forename: Hong-Hong
authors.initials: HH
authors.lastname: Tan
authors.forename: Qiu-Xiong
authors.initials: QX
authors.lastname: Lin
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Lin
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002681:China; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D019918:Heart Valve Prosthesis Implantation / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011184:Postoperative Period; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; 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