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The aims of the study were to explore the genotype and allele frequency of CYP2C9 and VKORC1 in Shaanxi Han nationality, to observe the effect of gene polymorphism and clinical features on warfarin steady-state therapeutic dose and the relationship between individualized recommended treatment dose and steady-state therapeutic dose of warfarin.
The subjects with non-valvular atrial fibrillation were enrolled from cardiovascular clinic and in-patient wards between June 2015 and March 2017. After using the CHA2DS2-VASc and HAS-BLED system to evaluate the stroke and bleeding risks, the patients with oral anticoagulant therapy were divided with conventional (initial dose with 1.5-3.0 mg/d) and individual groups (calculate the individualized recommended treatment dose of warfarin based on CYP2C9 and VKORC1 genotyping). The genotype and allele frequency of CYP2C9 and VKORC1, the time required for INR 2.0-3.0 after taking warfarin, association between individualized recommended treatment dose and warfarin steady-state therapeutic dose and safety of individual and conventional groups were explored in the clinical study. All data were analyzed using SPSS 13.0 software.
A total of 678 participants were enrolled into the study and 134 patients were receiving the oral anticoagulant therapy finally. The significant differences of age (P=0.016), individualized recommended treatment dose (P<0.001) and the time required for INR 2.0-3.0 after taking warfarin (P<0.001) were observed between individual and conventional groups. The CYP2C9*2 (R144C, C>T) genotyping showed that the allele frequencies of CC, CT and TT were 100%, 0% and 0%, CYP2C9*3 (I359L, A>C) genotyping of AA, AC and CC were 95.7%, 4.3% and 0%, and VKORC1 (1639, G>A), genotyping of GG, GA and AA were 0%, 17.4% and 82.6%, respectively. The warfarin dose in CYP2C9*2- R144C CC was 3.24 mg/d, in CYP2C9*3- I359L AA and AC were 3.31 mg/d and 2.24 mg/d, and in VKORC1-1639 GA and AA were 3.81 mg/d and 3.10 mg/d, respectively. There was no statistical difference between the inter-groups (P>0.05). The negative correlation between warfarin steady-state therapeutic dose and age (r=-0.589, P<0.001), and the positive associations between warfarin steady-state therapeutic dose and height (r=0.384, P=0.033), individualized recommended treatment dose (r=0.935, P<0.001) were observed. After adjusting for confounders via multivariate linear regression, the age, genotype of CYP2C9*3 and VKORC1 values remained independently associated with warfarin steady-state therapeutic dose for patients receiving oral anticoagulation.
CYP2C9 and VKORC1 gene polymorphism can accurately predict the warfarin steady-state treatment dose, which could reduce the occurrence of drug-related adverse events and optimize the therapeutic strategies of oral anticoagulant therapy.