Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement

被引：57

作者：

Kim, Ho-Sook ^{[1
,2
]}

Lee, Sang Seop ^{[1
,2
]}

Oh, Minkyung ^{[3
]}

Jang, Yin-Jin ^{[1
,2
]}

Kim, Eun-Young ^{[3
]}

Han, Il Yong ^{[4
]}

Cho, Kwang-Hyun ^{[4
]}

Shin, Jae-Gook ^{[1
,2
,3
]}

机构：

[1] Inje Univ, Dept Pharmacol, Coll Med, Pusan 614735, South Korea

[2] Inje Univ, PharmacoGenom Res Ctr, Coll Med, Pusan 614735, South Korea

[3] Inje Univ, Dept Clin Pharmacol, Busan Paik Hosp, Pusan 614735, South Korea

[4] Inje Univ, Dept Thorac & Cardiovasc Surg, Coll Med, Pusan 614735, South Korea

来源：

PHARMACOGENETICS AND GENOMICS | 2009年 / 19卷 / 02期

关键词：

CYP2C9; Korean; mechanical heart valve replacement; vitamin K epoxide reductase complex subunit 1 (VKORC1); warfarin dose; K EPOXIDE REDUCTASE; CYTOCHROME P4502C9; INTERINDIVIDUAL VARIABILITY; ANTICOAGULATION STATUS; GENETIC-POLYMORPHISM; VARIANTS; DETERMINANTS; ASSOCIATION; SENSITIVITY; PROPOSAL;

D O I：

10.1097/FPC.0b013e32831a9ae3

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

Objectives 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 (Cl): 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% Cl: 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-2=0.56). Conclusion 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 Pharmacogenetics and Genomics 19:103-112 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

引用

页码：103 / 112

页数：10

共 36 条

[1]

Comparison of a daily fixed 2.5-mg warfarin dose with a 5-mg, international normalized ratio adjusted, warfarin dose initially following heart valve replacement [J].