Factors influencing warfarin dose requirements in African-Americans.
BACKGROUND
African-Americans are under-represented in studies assessing contributors to warfarin response. Our primary objective was to determine whether the genes for cytochrome P450 (CYP) 2C9, nicotinamide adenine dinucleotide phosphate, reduced, quinone oxidoreductase (NQO1) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are associated with warfarin dose requirements in African-Americans.


METHODS
The following factors were assessed: demographics; clinical data; the CYP2C9 Arg144Cys (*2), Ile358Leu (*3) and Asp360Glu (*5); NQO1 Pro187Ser (*1/*2); and VKORC1 G6853C genotypes were analyzed in 115 African-Americans on stable warfarin doses.


RESULTS
Allele frequencies were 0.05 for the CYP2C9 *2, *3 or *5 alleles; 0.20 for NQO1 *2; and 0.25 for VKORC1 6853C. Possession of a CYP2C9*2, *3 or *5 allele was associated with a 38% lower warfarin dose compared with the *1/*1 genotype (30 +/- 13 vs 48 +/- 18 mg/week; p = 0.003). Neither the NQO1 *1/*2 nor VKORC1 G6853C genotype was associated with warfarin dose requirements in the population as a whole or in CYP2C9*1 allele homozygotes. Multiple regression analysis revealed that CYP2C9 genotype (p = 0.015), age (p < 0.001) and body surface area (p < 0.001) were jointly associated with warfarin dose requirements, and together explained 33% of the variability in warfarin dose requirements among African-Americans.


CONCLUSIONS
Our data suggest that CYP2C9 genotype, age and body size are important determinants of warfarin dose requirements in African-Americans. Our data further suggest that the VKORC1 G6853C polymorphism alone may not be useful for predicting warfarin dose requirements in this racial group.
Momary
Kathryn M
KM
Mercer University College of Pharmacy, 3001 Mercer University Dr., Atlanta, GA, 30341-4155, USA. MOMARY_KM@Mercer.edu
Shapiro
Nancy L
NL
Viana
Marlos Ag
MA
Nutescu
Edith A
EA
Helgason
Cathy M
CM
Cavallari
Larisa H
LH
D001741:Black or African American / Q000235:genetics*; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013923:Thromboembolism / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D014812:Vitamin K / Q000008:administration & dosage; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; D004247:DNA; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human