Cytochrome P450 polymorphisms are associated with reduced warfarin dose.
BACKGROUND
Warfarin use is complicated by an erratic dose response. Interpatient variability associated with warfarin therapy may be partly attributable to polymorphisms of the cytochrome P450 (CYP) complex. The purpose of this study was to ascertain the frequency and influence of CYP polymorphisms on warfarin dosing in our patient population.


METHODS
Patients receiving warfarin therapy were recruited from the inpatient divisions of our hospital. Genotyping for known polymorphic alleles of the CYP subfamilies CYP2C9 (CYP2C9*1, CYP2C9*2, and CYP2C9*3) and CYP2A6 (CYP2A6*1, CYP2A6*2) with the use of standard methods of polymerase chain reaction amplification was performed. An unpaired t test was used to statistically compare genotypes.


RESULTS
Genotype frequency in 38 patients is as follows: CYP2C9*1/CYP2C9*1, 71%; CYP2C9*1/CYP2C9*2, 21%; CYP2C9*2/CYP2C9*2, 3%; CYP2C9*1/CYP2C9*3, 5%; CYP2A6*1/CYP2A6*1, 95%; CYP2A6*1/CYP2A6*2, 5%. Compared to a wild-type genotype, the presence of the CYP2C9*2, CYP2C9*3, or CYP2A6*2 allele was associated with a significant reduction in weekly warfarin dose (mean weekly warfarin dose [+/- SE] for wild-type genotype was 0.397 +/- 0.024 mg/kg/wk vs 0.307 +/- 0.03 mg/kg/wk for carriers of CYP2C9*2, CYP2C9*3, or CYP2A6*2 polymorphism; P =.03).


CONCLUSIONS
Polymorphisms that impair warfarin metabolism are common, occurring in 34% of patients, and are associated with increased warfarin sensitivity. The use of genotypic information to prescribe more accurate doses of warfarin may increase the safety and efficacy of this medication.
Freeman
B D
BD
Departments of Surgery, Pathology, and Biostatistics, Washington University School of Medicine, St Louis, MO 63110, USA.
Zehnbauer
B A
BA
McGrath
S
S
Borecki
I
I
Buchman
T G
TG
D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use*; D044383:Black People; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008923:Missouri; D017354:Point Mutation; D011110:Polymorphism, Genetic; D015183:Restriction Mapping; D014859:Warfarin / Q000008:administration & dosage / Q000627:therapeutic use*; D044465:White People; D001741:Black or African American
D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System