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Effects of CYP4F2 gene polymorphisms on warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves

Title
 Effects of CYP4F2 gene polymorphisms on warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves
Authors
 Lee, Kyung-Eun; Chang, Byung-Chul; Gwak, Hye-Sun; Park, Hee-Yoon; Lee, Na-Ra; Yoon, In-Kyung; Kim, Han-Oll
Issue Date
2012
Journal Title
 Therapeutic Drug Monitoring
ISSN
 0163-4356
Citation
 Therapeutic Drug Monitoring, Vol.34(3) : 275~282, 2012
Abstract
BACKGROUND: Recently, a single nucleotide polymorphism of CYP4F2 (rs2108622) was reported to have a significant relationship with the stable warfarin dose. However, the underlying mechanism of CYP4F2 effects on the stable warfarin dose has not been studied. This study aimed to examine the effects of cytochrome P450 (CYP) 4F2 gene on warfarin clearance and sensitivity in Korean patients with mechanical heart valves. METHODS: One hundred ninety-one patients with mechanical heart valves who were on anticoagulation therapy with warfarin and maintained international normalized ratio levels of 2-3 for 3 consecutive times were followed up, retrospectively. Warfarin enantiomer concentrations were determined by a validated high-performance liquid chromatography method. Genotypes of vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP2C19, CYP4F2, human microsomal epoxide hydroxylase, calumenin, and γ-glutamyl carboxylase were determined. RESULTS: From multiple linear regression models, vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP4F2, and age were found to have significant effects on warfarin stable dose. The stable warfarin daily doses of patients with the CC, CT, and TT genotypes in the CYP4F2 gene were 5.34 ± 2.04, 5.33 ± 1.64, and 6.55 ± 2.12 mg, respectively. The higher dose requirements in patients with TT alleles in CYP4F2 were attributable to a low warfarin sensitivity (international normalized ratio/warfarin plasma concentration); the warfarin sensitivity in CC, CT, and TT genotypes was 2.1 ± 1.2, 1.0 ± 0.4, and 0.8 ± 0.6, respectively. The similarity between the dose requirements of patients with CT and CC alleles was explained through the combined result of warfarin sensitivity and clearance outcomes. Apparent plasma (S)- and (R)-warfarin clearances were found to be 37.7% and 34.1% lower in CT genotype patients than in CC genotype patients, respectively. CONCLUSIONS: The dose variability in CYP4F2 genotypes was attributable to both warfarin clearance and sensitivity differences.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/91914
DOI
10.1097/FTD.0b013e318256a77c
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Thoracic & Cardiovascular Surgery
Yonsei Authors
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 http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&AN=00007691-201206000-00007&LSLINK=80&D=ovft
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