Genetic determinants of warfarin dosing in the Han-Chinese population.
Warfarin, a widely prescribed oral anticoagulant, is used for the prevention of thromboembolism. Polymorphisms in CYP2C9 and VKORC1 have been shown to be associated with warfarin dose requirements. However, it is likely that other genes could also affect warfarin dose.


OBJECTIVE
In this study, we aimed to identify additional genes influencing warfarin dosing in the Han-Chinese population.


METHODS
In this study, we screened for SNPs in 13 genes (VKORC1, CYP2C9, CYP2C18, PROC, APOE, EPHX1, CALU, GGCX, ORM1, ORM2, factor II, factor VII and CYP4F2) and tested their associations with warfarin dosing with univariate and multiple regression analysis.


RESULTS
Polymorphisms in the VKORC1 gene have the strongest effects on warfarin dose, followed by CYP2C9*3. In addition, our results showed that CYP2C18, PROC and EPHX1 have small but significant associations with warfarin dose. In multiple regression analysis, PROC and EPHX1 explained 3% of the dose variation. The incorporation of these two genes into warfarin dosing algorithms could improve the accuracy of prediction in the Han-Chinese population.
Lee
M T Michael
MT
Institute of Biomedical Sciences, Academia Sinica, 128, Academia Road, Section 2, NanKang, Taipei, Taiwan.
Chen
Chien-Hsiun
CH
Chou
Ching-Heng
CH
Lu
Liang-Suei
LS
Chuang
Hui-Ping
HP
Chen
Ying-Ting
YT
Saleem
Amir N
AN
Wen
Ming-Shien
MS
Chen
Jin-Jer
JJ
Wu
Jer-Yuarn
JY
Chen
Yuan-Tsong
YT
D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013624:Taiwan; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases