title: The influence of genetic polymorphisms and interacting drugs on initial response to warfarin in Chinese patients with heart valve replacement.
abstract: OBJECTIVE
  Compared with genetic factors, drug interactions were largely unexplored in warfarin pharmacogenetic studies. This study sought to systematically investigate the effects of genetic polymorphisms of VKORC1, STX4A, CYP2C9, CYP3A4, and GGCX and interacting drugs on the initial responses to warfarin in Chinese patients with heart valve replacement (HVR).
  
  
  METHODS
  A retrospective study was conducted in 809 patients starting warfarin therapy after HVR. The relationships between 12 polymorphisms plus 47 drugs and primary outcomes of the time to the first international normalized ratio (INR) ≥ 1.8 and the time to the first INR > 3.5 and the secondary outcomes of the proportion of time INR < 1.8, the proportion of time INR > 3.5, and the daily warfarin dose in the first 28 days after the initiation of warfarin treatment were analyzed.
  
  
  RESULTS
  Genetic polymorphisms and interacting drugs could significantly affect the primary and secondary outcomes. The time to the first INR ≥ 1.8 was significantly influenced by the body surface area (BSA), VKORC1 g.3588G > A allele, and CYP2C9*3 allele, with hazard ratio (HR; 95% confidence interval [CI]) of 0.34 (0.17-0.66), 2.71 (2.2-3.35) and 1.43 (1.07-1.93) respectively. The time to the first INR > 3.5 was affected not only by BSA, VKORC1 g.3588G > A allele, and CYP2C9*3 allele with HR (95%CI) of 0.26 (0.07-0.99), 2.76 (1.61-4.72), and 3.09 (2.02-4.74) respectively, but also by age and interacting drugs, including fluconazole, amiodarone, and simvastatin with HR (95%CI) of 1.02 (1.01-1.04), 2.66 (1.16-6.08), 1.78 (1.17-2.73), and 5.33 (1.67-16.96) respectively.
  
  
  CONCLUSIONS
  Not only VKORC1 and CYP2C9 genotypes, but also interacting drugs, had a significant impact on the variability of the initial response to warfarin.
authors.affiliation: Guangdong Provincial Cardiovascular Institute, Medical Research Center of Guangdong General Hospital, Guangdong Institute of Clinical Pharmacology, Guangdong Academy of Medical Sciences, 96 Dongchuan Road, Guangzhou, GD 510080, People's Republic of China.
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Zhong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
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: Hai-Yan
authors.initials: HY
authors.lastname: Lao
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; D044466:Asian People / Q000235:genetics; D058385:Cardiac Valve Annuloplasty; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006351:Heart Valves / Q000187:drug effects / Q000601:surgery*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; C400322:cytochrome P-450 CYP2C subfamily; 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