Impact of gene polymorphism on the initiation and maintenance phases of warfarin therapy in Chinese patients undergoing heart valve replacement

摘要

Aim: To determine whether VKORC1 rs9923231, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650 genotypes contribute to warfarin therapy in patients during initiation and maintenance anticoagulation treatment after heart valve surgery. Methods: 287 Chinese patients with warfarin treatment more than three month after heart valve replacement operations were enrolled. Blood was collected from each subject for DNA extraction and genotyping. Analyzing the relationship between genotypes and warfarin curative effect. Results: Their mean age was 48.0 ± 10.5 years old. During the initiation phase, the growth rate of INR was partial correlated with VKORC1 rs9923231, CYP2C9 rs1057910 and ORM1 rs17650, respectively. Compared with AG or GG genotypes of VKORC1 c.-1639 carriers, patients with VKORC1 c.-1639AA reached target INR therapeutic range faster (P<0.001) and has a high risk of overanticoagulation (P<0.001). Carriers of at least one CYP2C9 *3 allele reached the target INR therapeutic range and supra-therapeutic INR were faster than CYP2C9 wild-type carriers (P=0.032, P=0.032, respectively). CYP4F2 rs2108622 could significantly influence on time to the target INR therapeutic range and time to INR above 3.0 after hierarchical analysis with VKORC1, CYP2C9 and ORM1 (P=0.011, P=0.044, respectively). VKORC1 rs9923231, CYP2C9 rs1057910 and ORM1 rs17650 were significantly influence the %TTR in three months (P=0.031, P=0.008, P=0.001, respectively). During the maintenance phase, VKORC1 c.-1639AA carriers spent more time at supra-therapeutic INRs (P<0.001). CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650 gene variants did not affect outcome parameters in maintenance phase. Conclusions: This study found that genetic factors could significantly affected on warfarin therapy in Chinese. Meanwhile, genetic variations play a more important role in the initial phase than did in maintenance phase of warfarin therapy.