Effect Of Cytochrome P-450 2C9 Gene Polymorphism On Steady-state Warfarin Dose In Patients With Atrial Fibrillation

Objective:The genetic polymorphism of CYP2C9 gene in Chinese Han patients with atrial fibrillation was analyzed to explore the influence of rare CYP2C9 alleles other than common 2C9 on the steady-state dose of warfarin in patients.Based on genetic factors such as non-genetic factors and rare mutations,a prediction algorithm was constructed and verified.Methods:A total of 1814 patients with atrial fibrillation admitted to the Department of Cardiology of Beijing Hospital and receiving warfarin anticoagulant therapy from January 2015 to December 2019 were selected.The CYP2C9 and VKORC1 genotypes of these patients were sequenced by PCR technology to analyze the gene polymorphisms.After complete follow-up,clinical information and steady-state warfarin dose of 675 patients were obtained,and they were randomly divided into model group(n=283)and validation group(n=392).Single factor correlation analysis was used to select variables related to warfarin steady dose,and multivariate linear regression analysis was used to establish a prediction algorithm for warfarin administration.Results:1.Eleven rare CYP2C9alleles were found after screening,and complete clinical information of patients carrying four rare mutations was obtained after follow-up(CYP2C9*13,*16,*60,and*62).In combination with these four rare genotypes,non-CYP2C9*3 minor allele was defined as variable,and the steady-state dose of warfarin was found to be significantly lower than that of CYP2C9*1/*1(p<0.01)and CYP2C9*1/*3(p<0.01).2.A steady-state dose prediction algorithm for warfarin was established,including other non-CYP2C9*3 minor allele variables,which accounted for 6.0%of the inter-individual variation in warfarin dose.Then the model was applied to the validation group,and the correlation coefficient reached 33.5%.3.According to the factors including race,region and genetic variables,a total of 7 different warfarin dose prediction algorithms were selected and compared with the algorithm in this study,and the prediction algorithm in this study showed good performance in terms of accuracy,practicability and safety.Conclusion:There are abundant CYP2C9 gene polymorphisms in Chinese Han population.The rare CYP2C9 allele is associated with lower steady-state dose of warfarin,and the drug dose prediction algorithm that includes the rare CYP2C9 allele variable can better predict the steady-state dose of warfarin in the Chinese population.