title: Impact of CYP2C9*3, VKORC1-1639, CYP4F2rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients.
abstract: To evaluate the impact of gene polymorphisms of Cytochrome P450 2C9 (CYP2C9), Vitamin K epoxide reductase complex subunit 1 (VKORC1) and Cytochrome P450 4F2 (CYP4F2) and clinical factors on warfarin maintenance dose in Han-Chinese patients from main land. DNA was extracted from 115 patients taking warfarin for more than 3 months with a stable international normalized ratio (INR) and genotyped for CYP2C9*3, VKORC1-1639 and CYP4F2 (rs2108622) polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Univariate analysis and multiple regression analysis were undertaken to assess the effect of genetic and clinical factors on the warfarin maintenance dose. Our study demonstrated that patients carrying CYP4F2 CT or TT allele needed a significantly higher warfarin dose compared to those carrying CC ((3.36 ± 0.14 mg/d vs. 2.77 ± 0.14 mg/d), P = 0.004). We also confirmed CYP2C9 *3 variant was related to lower warfarin dose (2.01 ± 0.23 mg/d) requirement compared to wild type (3.21 ± 0.11 mg/d) (P = 0.001). VKORC1-1639 AG genotype was associated with a higher maintenance dose compared to those with the AA genotype (4.06 ± 0.21 mg/d vs. 2.95 ± 0.11 mg/d, P < 0.001). The multiple linear regression model including VKORC1-1639G>A, CYP2C9, CYP4F2 and clinical factors (body surface area (BSA) and age) could explain 42 % of the variance in the warfarin maintenance dose. We developed a dose algorithm based on genetic polymorphism and clinical variables for Han-Chinese patients and evaluated its performance. CYP4F2 rs2108622 has a small but significant association with warfarin stable dose in Han-Chinese population.
authors.affiliation: Heart Center, Peking University People's Hospital, #11 Xizhimen South Street, Xichengqu, Beijing 100044, China.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Liang
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Cuilan
authors.initials: C
authors.lastname: Li
authors.forename: Yuanfeng
authors.initials: Y
authors.lastname: Gao
authors.forename: Wenling
authors.initials: W
authors.lastname: Liu
authors.forename: Dayi
authors.initials: D
authors.lastname: Hu
authors.forename: Yihong
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000368:Aged; D000465:Algorithms; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People; D002681:China; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio / Q000379:methods; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods; D016133:Polymerase Chain Reaction / Q000379:methods; D012150:Polymorphism, Restriction Fragment Length; 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