Race‐Specific Influence of CYP 4F2 on Dose and Risk of Hemorrhage Among Warfarin Users

Objective The p.V433M in cytochrome P450 4F2 (rs2108622, CYP 4F2*3 ) is associated with a higher warfarin dose and lower risk of hemorrhage among European Americans. We evaluate the influence of CYP 4F2*3 on warfarin dose, time to target international normalized ratio ( INR), and stable dose, proportion of time spent in target range ( PTTR ), as well as the risk of overanticoagulation and hemorrhage among European and African Americans. Design CYP 4F2*3 was genotyped in 1238 patients initiated on warfarin in a prospective inception cohort. Multivariable linear regression was used to assess warfarin dose and PTTR ; proportional hazards analysis was performed to evaluate time to target INR and stable dose, overanticoagulation, and hemorrhage. Setting Two outpatient anticoagulation clinics. Participants A total of 1238 anticoagulated patients. Outcomes Warfarin dose (mg/day), time to target INR and stable dose, PTTR , overanticoagulation ( INR more than 4), and major hemorrhage. Results Minor allele frequency for the CYP 4F2*3 variant was 30.3% among European Americans and 8.4% among African Americans. CYP 4F2*3 was associated with higher dose among European Americans but not African Americans. Compared to CYP 4F2*1 / *1 , *1 / *3 was associated with a statistically nonsignificant increase in dose (4.5%, p=0.22) and *3 / *3 was associated with a statistically significant increase in dose (13.2%, p=0.02). CYP 4F2 genotype did not influence time to target INR , time to stable dose, or PTTR in either race group. CYP 4F2*3 / *3 was associated with a 31% lower risk of over anticoagulation (p=0.06). Incidence of hemorrhage was lower among participants with CYP 4F2 *3 / *3 compared with *1 / *3 or *1 / *1 (incidence rate ratio = 0.45, 95% confidence interval 0.14–1.11, p=0.09). After controlling for covariates, CYP 4F2 *3 / *3 was associated with a 52% lower risk of hemorrhage, although this was not statistically significant (p=0.24). Conclusion Possession of CYP 4F2*3 variant influences warfarin dose among European Americans but not African Americans. The CYP 4F2‐ dose, CYP 4F2‐ overanticoagulation, and CYP 4F2‐ hemorrhage association follows a recessive pattern with possession of CYP 4F2*3 / *3 genotype likely demonstrating a protective effect. These findings need further confirmation.