Effects of CYP4F2 Polymorphism on Response to Warfarin During Induction Phase: A Prospective, Open-Label, Observational Cohort Study

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• 作者：Idit Bejarano-Achache ; PhD¹ ; ² ; Liran Levy ; MD¹ ; Liat Mlynarsky ; MD¹ ; Meir Bialer ; PhD² ; Mordechai Muszkat ; MD¹ ; Yoseph Caraco ; MD¹ ; ^{caraco@hadassah.org.il}
• 关键词：3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors ; CYP4F2 ; pharmacogenetics ; statin ; variability ; warfarin
• 刊名：Clinical Therapeutics
• 出版年：2012
• 期刊代码：65_01492918
• 类别：med
• 出版时间：April, 2012
• 卷：34
• 期：4
• 页码：811-823
• 文件大小：513 K

摘要

Background

The cytochrome P450 (CYP) 4F2 isozyme has been reported to metabolize vitamin K₁ in vitro, and the V433M polymorphism in the CYP4F2 gene has been associated with reduced vitamin K₁ metabolism and the need for a higher maintenance dosage in patients receiving warfarin.

Objective

The purpose of the present study was to evaluate the effects of V433M polymorphism on warfarin response during the induction phase.

Methods

Warfarin-naive white patients in whom warfarin was scheduled to be initiated with a target INR of 2 to 3 were enrolled into the study. On enrollment, a single blood sample for the genotyping of CYP4F2, CYP2C9, and VKORC1 was drawn. The international normalized ratio (INR) was followed daily during induction and twice weekly until stable anticoagulation was reached. The relationships between several markers of warfarin response during induction and CYP4F2 polymorphism were determined.

Results

The cohort consisted of 241 patients (115 men; mean [SD] age, 55.2 [19.4] years; weight, 79.5 [18.3] kg). Most of the patients were carriers of the CYP4F2 CC genotype (112 patients) or the CT genotype (104 patients). In carriers of the TT genotype (25 patients), INR >3 was >4-fold lower compared with that in carriers of the CC or CT genotype, suggesting that patients with the TT genotype were less sensitive to warfarin during induction. Also in TT carriers, the extent of excessive anticoagulation was >10-fold lower than in the other carriers. Both of these findings had a nominal P value of <0.05. After adjustment for false discovery rate, none of the findings remained significant at a threshold q value of <0.05. Among CC carriers, the concurrent use of a statin was associated with a 1-mg/d reduction in warfarin maintenance dosage. No similar effect was noted in the CT or TT carriers, suggesting a possible genetic influence on warfarin-statin interaction.

Conclusions

These preliminary findings suggest that among white patients treated with warfarin, CYP4F2 polymorphism had a measurable effect on warfarin responsiveness during induction; however, the observed differences failed to reach the level of statistical significance. The possibility that the effect of statins on warfarin anticoagulation varies among carriers of different CYP4F2 genotypes could not be excluded and should be evaluated further in a larger patient sample.