Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement.
OBJECTIVE
The effect of CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes was evaluated for the early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement.


METHODS
The genotypes of CYP2C9 variants including CYP2C9*3, CYP2C9*13, and CYP2C9*14, and VKORC1 1173C>T were assessed for the association with warfarin dosing in 265 patients whose data were collected for warfarin dose; international normalized ratio (INR), comedication, comorbidity, and other clinical characteristics.


RESULTS
In the early phase of warfarin therapy, the combined genotypes of CYP2C9 and VKORC1 caused statistically significant difference in warfarin dose from day 7 of warfarin dosing and the subsequent time course of dose increase showed significant difference among the three different genotypes (P<0.001). Compared with patients with CYP2C9 wild type, the patients with heterozygous CYP2C9 variants have delayed time to reach stable dose [adjusted hazard ratio (HRadj): 0.48; 95% confidence interval (CI): 0.27-0.85] and tended to have high risk for the first INR greater than 3.5 (HRadj: 1.64; 95% CI: 0.98-2.75). The patients with the VKORC1 CT genotype showed no significant difference in the time to reach stable dose but statistically significant low HR for time to first INR greater than 3.5 compared with those with VKORC1 TT genotype (HRadj: 0.25; 95% CI: 0.13-0.51). The observed warfarin maintenance dose was best explained by a model including covariates of age, weight, concurrent congestive heart failure/cardiomyopathy, INR-increasing drugs, aspirin, dietary supplements, and CYP2C9 and VKORC1 genotypes (R=0.56).


CONCLUSIONS
The heterozygous CYP2C9 and VKORC1 genotypes influence warfarin dosing in an early phase as well as steady state of warfarin therapy in Korean patients with mechanical heart valve replacement.
Kim
Ho-Sook
HS
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
Lee
Sang Seop
SS
Oh
Minkyung
M
Jang
Yin-Jin
YJ
Kim
Eun-Young
EY
Han
Ii Yong
IY
Cho
Kwang-Hyun
KH
Shin
Jae-Gook
JG
D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D001777:Blood Coagulation / Q000235:genetics; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D019918:Heart Valve Prosthesis Implantation; D006351:Heart Valves / Q000601:surgery; D006579:Heterozygote; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
D000925:Anticoagulants; 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