Race-Specific Influence of CYP4F2 on Dose and Risk of Hemorrhage Among Warfarin Users

• Authors: Aditi Shendre, University of Alabama Birmingham; Todd M. Brown, University of Alabama Birmingham; Nianjun Liu, University of Alabama Birmingham; Charles Hill, Emory University; T. Mark Beasley, University of Alabama Birmingham; Deborah A. Nickerson, University of Washington; Nita A. Limdi, University of Alabama Birmingham
• Journal Title: Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy
• Volume: Volume 36, Number 3
• Publisher: Wiley: 12 months | 2016-03-01, Pages 263-272
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/phar.1717
• Subjects: Health Sciences, Pharmacology; Health Sciences, Epidemiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Pharmacology & Pharmacy; CYP4F2; race; warfarin dose; PTTR; overanticoagulation; hemorrhage; AFRICAN-AMERICANS; DOSING ALGORITHMS; MAINTENANCE; CAUCASIANS; CYP2C9

Abstract

Objective: The p.V433M in cytochrome P450 4F2 (rs2108622, CYP4F2∗3) is associated with a higher warfarin dose and lower risk of hemorrhage among European Americans. We evaluate the influence of CYP4F2∗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: CYP4F2∗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 CYP4F2∗3 variant was 30.3% among European Americans and 8.4% among African Americans. CYP4F2∗3 was associated with higher dose among European Americans but not African Americans. Compared to CYP4F2∗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). CYP4F2 genotype did not influence time to target INR, time to stable dose, or PTTR in either race group. CYP4F2∗3/∗3 was associated with a 31% lower risk of over anticoagulation (p=0.06). Incidence of hemorrhage was lower among participants with CYP4F2∗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, CYP4F2∗3/∗3 was associated with a 52% lower risk of hemorrhage, although this was not statistically significant (p=0.24). Conclusion: Possession of CYP4F2∗3 variant influences warfarin dose among European Americans but not African Americans. The CYP4F2-dose, CYP4F2-overanticoagulation, and CYP4F2-hemorrhage association follows a recessive pattern with possession of CYP4F2∗3/∗3 genotype likely demonstrating a protective effect. These findings need further confirmation.