Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy. Issue 5 (May 2015)

• Record Type: Journal Article
• Authors: Hirai, Keita; Yamada, Yuto; Hayashi, Hideki; Tanaka, Masaki; Izumiya, Kohei; Suzuki, Masayuki; Yoshizawa, Misa; Moriwaki, Hideaki; Akimoto, Takehide; Tsuji, Daiki; Inoue, Kazuyuki; Itoh, Kunihiko
• Is Part Of: Thrombosis research. Volume 135:Issue 5(2015)
• Page Start: 861
• Page End: 866
• Publication Date: 2015-05
• Subjects: Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2015.02.019
• Languages: English
• ISSNs: 0049-3848

Abstract

<abstract abstract-type="author" id="ab0005"> <title id="st0005">Abstract</title> <sec> <title id="st0010">Introduction</title> <p id="sp0005">Warfarin is characterized by a large inter-individual variability in dosage requirement. This study aimed to analyze the contribution of the <italic>CYP4F2</italic> genetic polymorphism and plasma vitamin K concentration on the warfarin pharmacodynamics in patients and to clarify the plasma vitamin K concentration affecting warfarin sensitivity index in rats.</p> </sec> <sec> <title id="st0015">Materials and Methods</title> <p id="sp0010">Genetic analyses of selected genes were performed and plasma concentrations of warfarin, vitamin K1 (VK1) and menaquinone-4 (MK-4) were measured in 217 Japanese patients. We also assessed the association of plasma VK1 and MK-4 concentrations with the warfarin sensitivity index (INR/Cp) in rats.</p> </sec> <sec> <title id="st0020">Results</title> <p id="sp0015">Patients with the <italic>CYP4F2</italic> (rs2108622) TT genotype had significantly higher plasma VK1 and MK-4 concentrations than those with CC and CT genotypes. The multiple linear regression model including <italic>VKORC1</italic>, <italic>CYP4F2</italic>, and <italic>CYP2C9</italic> genetic variants, age, and weight could explain 42% of the variability in warfarin dosage. The contribution of <italic>CYP4F2</italic> polymorphism was estimated to be 2.2%. In contrast, plasma VK1 and MK-4 concentrations were not significantly associated with warfarin dosage in patients. Nevertheless, we were able to demonstrate that the warfarin sensitivity index was attenuated and negatively correlated with plasma VK1 concentration by the oral administration of VK1 in rats, as it resulted in a higher VK1 concentration than that in patients.</p> </sec> <sec> <title id="st0025">Conclusions</title> <p id="sp0020">The plasma VK1 and MK-4 concentrations are significantly influenced by <italic>CYP4F2</italic> genetic polymorphism but not associated with warfarin therapy at the observed concentration in Japanese patients. The <italic>CYP4F2</italic> polymorphism is poorly associated with inter-individual variability of warfarin dosage requirement.</p> </sec> </abstract>