title: VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China.
abstract: OBJECTIVE
  To investigate the contribution of genetic polymorphisms of vitamin K epoxide reductase complex subunit 1 gene VKORC1-1639G>A, cytochrome P450 2C9 gene (CYP2C9), EPHXI, and clinical factors to warfarin sensitivity in southwest Chinese Han patients with mechanical heart valve prostheses.
  
  
  METHODS
  A total of 127 patients with mechanical heart valve prostheses who have been followed up at our department during the past 23 years were enrolled in this study and compared to a control group that consisted of 133 randomly selected healthy blood donors. These Chinese patients met stable warfarin dosage requirements and had reached the target international normalized ratio (INR) of 1.5-2.0. PCR and direct sequencing were carried out to identify the polymorphisms of VKORC1-1639G>A (rs9923231), CYP2C9*3 (rs1057910), CYP2C9 IVS3-65G>C (rs9332127), and EPHX1691A>G (rs4653436). In addition, total and free (non-protein-bound) warfarin concentrations were analyzed.
  
  
  CONCLUSIONS
  There were great interindividual differences in warfarin maintenance dosage (ranging from 0.6 to 8.4 mg/day) among the 127 patients with mechanical heart valve prostheses. VKORC1-1639G>A, CYP2C9, EPHX1691A>G polymorphism, body weight, and age were found to affect the dose demands. Multiple linear regression models incorporating genetic polymorphisms of VKORC1, CYP2C9, EPHX1691A>G, and the nongenetic factors of age and body weight were developed, and explained up to 76.8% of the total variation (adjusted R (2) of 0.743) in warfarin maintenance doses in southwest Chinese patients with mechanical heart valve prostheses.
authors.affiliation: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Chongqing, People's Republic of China. Qiang.gu@hotmail.com
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.forename: Jörn
authors.initials: J
authors.lastname: Schneede
authors.forename: Ying-Bin
authors.initials: YB
authors.lastname: Xiao
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Qian-Jin
authors.initials: QJ
authors.lastname: Zhong
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Wang
authors.forename: Jia
authors.initials: J
authors.lastname: Hao
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: Chen
authors.forename: Jing-Jin
authors.initials: JJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People / Q000235:genetics; D001835:Body Weight; D002681:China; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D004851:Epoxide Hydrolases / Q000235:genetics; D005260:Female; D005838:Genotype; D006350:Heart Valve Prosthesis; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human