Key result
Patients with the CYP4F2 TT genotype required a higher stable warfarin daily dose (6.55 mg) compared to those with CC (5.34 mg) or CT (5.33 mg) genotypes, driven by lower warfarin sensitivity.
Why the study?
Do CYP4F2 gene polymorphisms affect warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves?
Cohort (n=191)
Do CYP4F2 gene polymorphisms affect warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves?
In Korean patients with mechanical heart valves, the CYP4F2 TT genotype is associated with higher warfarin dose requirements due to reduced warfarin sensitivity.
Answers are grounded in this paper and cite their sources.
CYP4F2 TT genotype was associated with higher warfarin doses in Korean mechanical valve patients; hypothesis-generating for pharmacogenetic algorithms, should not yet change practice.
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.
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Lee et al. (2012) conducted a cohort in Mechanical heart valves (n=191). CYP4F2 TT genotype vs. CYP4F2 CC and CT genotypes was evaluated on Stable warfarin daily dose. Patients with the CYP4F2 TT genotype required a higher stable warfarin daily dose (6.55 mg) compared to those with CC (5.34 mg) or CT (5.33 mg) genotypes, driven by lower warfarin sensitivity.
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