Influence of CYP2C9*3 and CYP4F2 rs2108622 gene polymorphisms on over-anticoagulation and bleeding complications of warfarin therapy in Chinese patients: a cohort study

doi:10.5246/jcps.2021.06.037

Abstract

Abstract:

In this retrospective cohort study, we aimed to identify the influence of the CYP2C9*3 and CYP4F2 rs2108622 gene alleles on over-anticoagulation and bleeding complications associated with warfarin therapy. A total of 196 patients were included, including 80 males, the mean age was 50.8±10.7 years, and the average follow-up was 26.9±11.8 months. These patients underwent heart valve replacement surgery in the Cardiovascular Surgery of Fujian Provincial Hospital between January 2018 and August 2019, who took warfarin for at least 3 months and had target international normalized ratio (INR) between 1.8 and 2.5. Genotypes of CYP2C9*3 and CYP4F2 rs2108622 genes were tested by polymerase chain reaction (PCR)-gene sequencing technique. SPSS19.0 software was utilized to analyze the association between genotypes and warfarin-related over-anticoagulation and bleeding complications. Of the 434 patient-years, 18 severe bleedings and 59 mild ones occurred in 31 patients. Patients with CYP2C9 *1/*3 were associated with a higher over-anticoagulation risk compared with the *1/*1 carriers (hazard rate (HR) 7.10; 95% confidence interval (CI): 2.54–19.79, P < 0.001). The CYP4F2 rs2108622 mutant genotype did not cause significant increase in bleeding risk (HR 0.89; 95% CI: 0.43–1.82, P = 0.74) or over-anticoagulation (HR 0.43; 95% CI: 0.16–1.13, P = 0.09). Meanwhile, Kaplan-Meier survival curves showed that the time to over-anticoagulation in CYP2C9 *1/*3 carriers was significantly shorter compared with the *1/*1 carriers (log-rank test, P<0.001), while that in CYP4F2 rs2108622 mutant genotype patients was longer compared with the wild-type patients (P = 0.05). CYP2C9*3 and CYP4F2 rs2108622 might be major predictive factors of over-anticoagulation for warfarin therapy in Chinese patients.

Key words: Anticoagulation, Genetics, Bleeding disorders &, coagulopathies, Risk management

Supporting:

Yushan Wu, Limei Yang, Xuhui Huang, Feng Huang, Tao Han. Influence of CYP2C9*3 and CYP4F2 rs2108622 gene polymorphisms on over-anticoagulation and bleeding complications of warfarin therapy in Chinese patients: a cohort study[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(6): 484-494.

Figures/Tables 6

Table 1. Gene frequency and Hardy-Weinberg equilibrium test.

Table 2. Demographic characteristics and clinical features of patients.

Table 3. The incidence rate of over-anticoagulation and bleeding complications in CYP2C9*3 and CYP4F2 rs2108622 genotypes.

Table 4. HR and 95% CI of the influence of CYP2C9*3 heterozygous mutant on over-anticoagulation and bleeding complications.

Table 5. HR and 95% CI of the influence of CYP4F2 rs2108622 mutant type on over-anticoagulation and bleeding complications.

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