CYP4F2 and Hemorrhage Among Warfarin Users
What is the influence of the cytochrome P450 4F2 (CYP4F2) on warfarin dose, time to therapeutic international normalized ratio (INR) and stable dose, anticoagulation control, overanticoagulation (INR > 4.0), and major hemorrhage between European Americans and African Americans?
This was a prospective cohort study that genotyped patients newly initiated on warfarin therapy from two outpatient anticoagulation clinics. The single nucleotide polymorphisms assessed included CYP4F2, VKORC1, and CYP2C9. Patients were followed monthly for up to two years for INR monitoring, assessment of dietary and medication changes, alcohol intake, and additional factors that may have influenced the INR.
Genotyping was performed in 1,238 subjects, and the minor allele frequency for the CYP4F2*3 variant was 30.3% in European Americans and 8.4% among African Americans. Those with the CYP4F2*3 variant were typically older and had atrial fibrillation; other comorbidities and medications did not differ by genotype. Additionally, CYP2C9*2 and VKORC1 were more prevalent in subjects with the CYP4F2*3 variant. The presence of the CYP4F2*3 variant was associated with requiring a higher warfarin dose in European Americans but not African Americans. European Americans with the CYP4F2*3/*3 genotype required 13.2% higher warfarin doses (p = 0.02) compared with European Americans with the CYP4F2*1/*3 genotype. Regardless of ethnicity, the CYP4F2*3 genotype had no impact on time to target INR, stable dose, or proportion of time in therapeutic range. Subjects with the CYP4F2*3/*3 genotype had a 31% lower risk of over anticoagulation (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.47-1.01, p = 0.06) and a 55% lower incidence of hemorrhage in patients with the CYP4F2*3/*3 genotype (HR 0.45, 95% CI 0.14-1.11, p = 0.09), although neither was statistically significant. The most common hemorrhagic events by site were gastrointestinal (n = 84), genitourinary, hematomas (n = 16), and intracranial (n = 12). Ethnicity-specific differences between European Americans and African Americans for risk of hemorrhage could not be determined because only two African Americans were found to have the CYP4F2*3/*3 genotype.
The CYP4F2*3 variant influenced warfarin dosing in European Americans but not African Americans, resulting in higher warfarin doses to achieve the target INR. Those with the CYP4F2*3/*3 genotype may be less susceptible to overanticoagulation or hemorrhage compared with those with CYP4F2*1/*3 and CYP4F2*1/*1, which suggests a recessive pattern. This trend was not, however, statistically significant, which indicates the need for a larger study to fully determine the impact of the CYP4F2*3 variant on clinical outcomes.
This study provides further evidence supporting the effect of genotypes on individual warfarin dose requirements. Although the presence of CYP4F2*3 necessitates higher warfarin doses in European Americans, it plays a lesser role than VORC1 and CYP2C9 genotypes and is less commonly found in African Americans. Further study is needed to determine the clinical significance of CYP4F2*3 on the risk of hemorrhage associated with warfarin.
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