Warfarin and cytochrome P450 2C9 genotype: possible ethnic variation in warfarin sensitivity.
BACKGROUND
Warfarin is a widely prescribed, efficacious oral anticoagulant. S-warfarin, the more active form, is metabolized by the cytochrome P450 (CYP)2C9 enzyme. The aim was to evaluate the influence of two CYP2C9 functional polymorphisms (*2 and *3) on warfarin dose in African-Americans, an unstudied population and Caucasians, and also to assess the effect of these polymorphisms on anticoagulation response after accounting for nongenetic factors and genetic factors that might also impact the dose-response relationship of warfarin.


METHODS
A prospective cohort of 362 patients with a target international normalized ratio of between 2.0 and 3.0 were genotyped. Warfarin sensitivity stratified by genotype was investigated using univariate and multivariate analyses.


RESULTS
The maintenance dose of warfarin was significantly related to genotype (p < 0.01) (variant carriers: 31.25 mg/week; wild-type: 37.5 mg/week), even after adjustment for possible confounding factors (p = 0.046). However, the effect of genotype was restricted to Caucasians, in whom variant carriers had a significantly lower maintenance dose compared with wild-type homozygotes (unadjusted: p < 0.01; adjusted: p = 0.02). There was a greater risk of over-anticoagulation among Caucasian variant carriers, although this was only observed prior to reaching maintenance dose. For African-American variant carriers, there was no difference in warfarin response based on CYP2C9 genotype.


CONCLUSIONS
CYP2C9 *2 and *3 variants provide predictive information in anticoagulation response. However, these variants may not be useful in African-Americans or as a marker of long-term over-anticoagulation once a stable dose is reached.
Kealey
Carmel
C
University of Pennsylvania, Department of Pharmacology and Center for Pharmacogenetics, School of Medicine, Philadelphia, PA, USA.
Chen
Zhen
Z
Christie
Jason
J
Thorn
Caroline F
CF
Whitehead
Alexander S
AS
Price
Maureen
M
Samaha
Frederick F
FF
Kimmel
Stephen E
SE
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*; D044465:White People / Q000235:genetics*
D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases