title: Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients.
abstract: Warfarin is a commonly prescribed anticoagulant drug for the prevention of thromboembolic disorders. We investigated the contribution of genetic variations of four genes and clinical factors to warfarin dose requirement and provided a warfarin-dosing algorithm based on genetic and clinical variables in Korean patients. We recruited 564 Korean patients on stable anticoagulation. Single nucleotide polymorphisms (SNPs) for the VKORC1, CYP2C9, CYP4F2 and GGCX were analyzed. Using multiple regression analysis, we developed a model to predict the warfarin requirement. The SNPs of VKORC1, CYP2C9, CYP4F2 and GGCX showed significant correlation with warfarin dose. Patients with the 3730AA genotype received significantly higher doses of warfarin than those with the 3730GG (P=0.0001). For CYP2C9, the highest maintenance dose was observed in the patients with wild-type genotype compared with the variant allele carriers (P<0.0001). The multiple regression model including age, gender, body surface area (BSA), international normalized ratio (INR) and four genetic polymorphisms accounted for 35% of total variations in warfarin dose (R(2)=0.3499; P<0.0001). This study shows that age, gender, BSA, INR and VKORC1, CYP2C9 and CYP4F2 polymorphism affect warfarin dose requirements in Koreans. Translation of this knowledge into clinical guidelines for warfarin prescription may contribute to improve the efficacy and safety of warfarin treatment for Korean patients.
authors.affiliation: Laboratory of Medical Oncology, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Jung Ran
authors.initials: JR
authors.lastname: Choi
authors.forename: Jeong-Oh
authors.initials: JO
authors.lastname: Kim
authors.forename: Dae Ryong
authors.initials: DR
authors.lastname: Kang
authors.forename: Seong-Ae
authors.initials: SA
authors.lastname: Yoon
authors.forename: Jung-Young
authors.initials: JY
authors.lastname: Shin
authors.forename: XiangHua
authors.initials: X
authors.lastname: Zhang
authors.forename: Mee Ork
authors.initials: MO
authors.lastname: Roh
authors.forename: Hyung Joo
authors.initials: HJ
authors.lastname: Hong
authors.forename: Young-Pil
authors.initials: YP
authors.lastname: Wang
authors.forename: Keon-Hyon
authors.initials: KH
authors.lastname: Jo
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Lee
authors.forename: Ho-Jung
authors.initials: HJ
authors.lastname: Yun
authors.forename: Yong-Seog
authors.initials: YS
authors.lastname: Oh
authors.forename: Ki-Dong
authors.initials: KD
authors.lastname: Yoo
authors.forename: Hee-Gyeong
authors.initials: HG
authors.lastname: Jeon
authors.forename: Yoon Sook
authors.initials: YS
authors.lastname: Lee
authors.forename: Tae Sun
authors.initials: TS
authors.lastname: Kang
authors.forename: Hyun-Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Myeon Woo
authors.initials: MW
authors.lastname: Chung
authors.forename: Jin-Hyoung
authors.initials: JH
authors.lastname: Kang
mesh_terms: D000367:Age Factors; D000368:Aged; D000465:Algorithms; D000704:Analysis of Variance; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D049628:Body Size; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D008954:Models, Biological; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012044:Regression Analysis; D012737:Sex Factors; 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