Genetic Determinants of Response to Warfarin in Thai Patients
Keywords:
Warfarin, VKORC1, CYP2C9, ThaiAbstract
Background: 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 in Thai patients has not been reported.
Objectives: To determine the influence of VKORC1 and CYP2C9 genetic variants on the maintenance therapeutic doses of warfarin that keep the international normalize ratios (INRs) between 2.0-3.0 and to assess the probability of over-anticoagulation (INR³4) by these genetic variants.
Methods: We studied 80 Thai warfarin-requiring patients who were treated at Ramathibodi Hospital. After informed consent, blood sampling was obtained from patients who had therapeutic INR and had stable maintenance warfarin dose. DNA was extracted from the white blood cells of the peripheral blood sample by conventional methods. CYP2C9 and VKORC1 genotypes were determined by the polymerase chain reaction (PCR) method. Warfarin dosage and clinical information were collected from the medical records.
Results: The frequencies of AA, GA, GG (wild type) polymorphisms at - 1639 of VKORC1 were 63.8, 28.7, and 7.5%, respectively. Regarding the CYP2C9 polymorphisms, 92.5% of all alleles were CYP2C9*1 (wild type) and 7.5% were CYP2C9*1/CYP2C9*3. The mean warfarin maintenance dose differed significantly among the three VKORC1 genotypes, at 3.3 mg/day for AA, 5.4 mg/day for AG, and 6.0 mg/day for GG (p < 0.001). Patients with CYP2C9 variants, compared to those without, had a statistically significant higher odds ratio (OR) of having an INR 24 in the first month of therapy (OR: 7.39, p = 0.045).
Conclusion: Genetic variation in VKORC1 and CYP2C9 appears to have a different influence on maintenance dose and anticoagulation related outcome such as the probability of over-anticoagulation.
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