The pharmacogenetics of the response to warfarin in Chinese
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Abstract:
Warfarin is a commonly used oral anticoagulant with a narrow therapeutic range and large interindividual variability in daily dose. Compared with Caucasians, Chinese are known to require lower doses of warfarin. Differences between Caucasians and Chinese in the allelic frequencies of two genes, CYP2C9 and VKORC1 , largely explain the difference in dose requirement. There are other genetic polymorphisms that may further explain the response to warfarin. The VKORC1 genotype is an important determinant of response to warfarin in Chinese, but some genetic variants found in other ethnic groups that have a large effect on warfarin response and dosing are not commonly found in Chinese. Therefore, it is important to recognize and beware of ethnic differences in the pharmacogenetics of the response to warfarin, especially in the design of algorithms to aid dosing in clinical practice.Keywords:
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Objective To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase (VKOR) and CYP2C9. Methods Warfarin maintenance dose, unbound plasma S-warfarin concentration [Cu(S)] and INR were determined in 157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients. In a subset (n=166), fully carboxylated plasma normal prothrombin levels (NPT) were also measured. Genotyping for seven CYP2C9 (CYP2C9*1 through 6 and *11) and seven VKORC1 variants were performed in 115 Caucasians and 64 Japanese patients and 66 healthy African-Americans. Multivariate analysis was performed to identify covariates associated with warfarin requirement. Results The relationship between NPT and Cu(S) indicated Japanese are more susceptible to inhibition of NPT production by S-warfarin than the other two populations. VKORC1 1173 C>T had a greater frequency in Japanese (89.1%) than Caucasians (42.2%) and African-Americans (8.6%). CYP2C9 variants with reduced metabolizing ability were less frequent in Japanese compared to the other two populations. The median warfarin dose was significantly higher in Caucasians than Japanese patients (5.5 versus 3.5 mg/day), however, when matched for CYP2C9*1 homozygosity, no difference in dose was observed between VKORC1 genotype-matched groups. Furthermore, VKORC1 1173C>T and CYP2C9 (*2/*3/*11) genotypes, age and weight were identified as independent covariates contributing to interpatient variability in warfarin dosage. Conclusions Both VKORC1 and CYP2C9 polymorphisms contribute to inter-population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population.
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Pharmacogenetics of acenocoumarol: CYP2C9 *2 and VKORC1 c.-1639G>A, 497C>G, 1173C>T, and 3730G>A variants influence drug dose in anticoagulated patients -
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Genetic factors most correlated with warfarin dose requirements are variations in the genes encoding the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR). Patients receiving warfarin who possess one or more genetic variations in CYP2C9 and VKORC1 are at increased risk of adverse drug events and require significant dose reductions to achieve a therapeutic international normalized ratio (INR). A 74-year-old white female with atrial fibrillation was initiated on a warfarin dose of 2 mg PO daily, which resulted in multiple elevated INR measurements and three clinically significant hemorrhagic events and four vitamin K antidote treatments over a period of less than two weeks. Genetic analysis later revealed that she had the homozygous variant genotypes of CYP2C9*3*3 and VKORC1-1639 AA . Warfarin dosing was subsequently restarted and stabilized at 0.5 mg PO daily with therapeutic INRs. This is the first case report of a white female with these genotypes stabilized on warfarin, and it highlights the value of pharmacogenetic testing prior to the initiation of warfarin therapy to maximize efficacy and minimize the risk of adverse drug events.
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Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear.In 297 patients starting warfarin therapy, we assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement.As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range (P=0.02) and to the first INR of more than 4 (P=0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range (P=0.57) but was a significant predictor of the time to the first INR of more than 4 (P=0.03). Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy.Initial variability in the INR response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9.
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Warfarin is a commonly used oral anticoagulant with a narrow therapeutic range and large interindividual variability in daily dose. Compared with Caucasians, Chinese are known to require lower doses of warfarin. Differences between Caucasians and Chinese in the allelic frequencies of two genes, CYP2C9 and VKORC1 , largely explain the difference in dose requirement. There are other genetic polymorphisms that may further explain the response to warfarin. The VKORC1 genotype is an important determinant of response to warfarin in Chinese, but some genetic variants found in other ethnic groups that have a large effect on warfarin response and dosing are not commonly found in Chinese. Therefore, it is important to recognize and beware of ethnic differences in the pharmacogenetics of the response to warfarin, especially in the design of algorithms to aid dosing in clinical practice.
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Introduction: Warfarin, a commonly prescribed anticoagulant, exhibits large interindividual and interethnic differences in the dose required for its anticoagulation effect. Asian patients require a much lower maintenance dose compared with Caucasians; the explanation for these differences remains unknown. Methods: We analyzed five single nucleotide polymorphisms of the vitamin K epoxide reductase complex subunit 1 gene (VKORC1) and the *3 variant of cytochrome P450 (CYP)2C9, as well as the plasma warfarin concentration, in 108 Korean patients with atrial fibrillation. Results: Genotypic frequencies of VKORC1 +1173CT and CYP2C9*1/*3 were 17.6 and 10.2%, respectively, in the study population; VKORC1 +1173CC and CYP2C9*3/*4 were detected in one patient each. Patients carrying at least one copy of the VKORC1 +1173C allele, or the H7 (group B) haplotype, required a significantly higher warfarin dose (n = 20; 5.5 ± 1.7 mg/day) than those homozygous for the +1173T allele, or the H1 (group A) haplotype, (3.8 ± 1.2 mg/day; p < 0.001). There were statistically significant differences in warfarin dose between the CYP2C9*1/*1 (4.3 ± 1.6 mg/day; p < 0.001) and those with the other two genotypes including CYP2C9*1/*3 and CYP2C9*3/*4 (2.7 ± 0.9 mg/day). The multiple regression analysis revealed that the VKORC1 genotype (r2 = 0.197; p < 0.001), the age when warfarin started (r2 = 0.09; p < 0.001), body surface area (r2 = 0.041; p = 0.004) and CYP2C9 genotype (r2 = 0.029; p = 0.014) were factors associated with the daily dose of warfarin required. Conclusion: In the present study, we found that the VKORC1 polymorphism had a dominant genetic influence on interindividual variability for warfarin dose in Korean patients. It explained approximately 32% of the overall variability in warfarin dose requirements given all of the variables studied. Thus, analysis of the VKORC1 genotypes may be important to guide warfarin dose selection and allow personalized warfarin treatment.
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Warfarin therapy is complicated by a narrow therapeutic index and substantial interpatient variability in dose response. The cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genes have recently been determined to be associated with warfarin dose requirements, with reduced doses of this drug being required in patients with the variant CYP2C9*2, CYP2C9*3, or VKORC1 -1639A allele. The combination of genotype and clinical factors explains approximately 50 to 60% of the variance in warfarin dose requirements in Caucasians and Asians, but only 25 to 40% among African Americans. Racial differences in the association between genotype and a patient's response to warfarin treatment may be caused by racial differences in the frequencies of the variant CYP2C9*2, CYP2C9*3, and VKORC1 -1639A alleles or by the influence of non-genetic factors. Genotype also influences the time required to attain therapeutic anticoagulation and the risk for over-anticoagulation and hemorrhage. Although the incorporation of genotype information improves the accuracy of dose prediction, an improvement in anticoagulation control or a reduction in hemorrhagic complications has not been demonstrated. Therefore, the routine use of CYP2C9 and VKORC1 genotyping is not supported by currently available evidence. The results of ongoing or future multicenter clinical trials are expected to clarify the role of pharmacogenomics in the management of warfarin therapy.
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Warfarin is an oral anticoagulant that is widely prescribed to prevent thromboembolic events in persons at increased risk. The optimal dose is difficult to establish because it can vary 10-fold among individuals due to clinical and demographic factors. Testing for variants of the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes has been proposed for use in guiding the initial dose of warfarin, thus achieving optimal dosing more quickly and with lower risk of bleeding.
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