Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups.
OBJECTIVE
CYP4F2*3 (p.V433M) has been associated with higher warfarin dose requirements; however, its frequency, like other CYP2C9 and VKORC1 variants, has not been systematically assessed in major racial/ethnic populations. Thus, we determined the individual and combined frequencies of important CYP2C9, VKORC1 and CYP4F2 variants in several racial/ethnic groups.


METHODS
Healthy African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) blood donors were genotyped for CYP2C9 (*2, *3, *4, *5, *6, *8, *11 and *13), VKORC1 (g.-1639G>A) and CYP4F2 (*3 [p.V433M] and rs2189784).


RESULTS
The combined frequencies of variant CYP2C9 alleles were 0.133, 0.078, 0.212, 0.178 and 0.212 among African-American, Asian, Caucasian, Hispanic and AJ individuals, respectively. CYP4F2*3 frequencies were prevalent (0.233-0.342) among Asian, Caucasian, Hispanic and AJ individuals, while significantly less frequent among African-Americans (0.117; p < 0.0001). In addition, CYP4F2*3 was in linkage disequilibrium with rs2189784, an allele recently associated with time-to-therapeutic international normalized ratio, among all studied populations. Importantly, 87-95% of Asian, Caucasian, Hispanic and AJ individuals had a variant CYP2C9, VKORC1 and/or CYP4F2*3 allele, compared with only 53% of African-Americans (p < 0.0001).


CONCLUSIONS
Compared with other racial/ethnic populations studied, only approximately one in 80 African-Americans were CYP4F2*3 homozygous, indicating that this population would benefit less from dosing algorithms that include this variant. In addition, the unique allele frequency profiles identified among the different populations partly explain why genotype-guided warfarin dosing algorithms perform less well for African-Americans and suggest that other unidentified genetic and/or nongenetic factors that influence warfarin dosage may exist in this population.
Scott
Stuart A
SA
Department of Genetics & Genomic Sciences, Box 1498, Mount Sinai School of Medicine of New York University, Fifth Avenue at 100th Street, New York, NY 10029, USA.
Khasawneh
Rame
R
Peter
Inga
I
Kornreich
Ruth
R
Desnick
Robert J
RJ
D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004247:DNA / Q000235:genetics; D005006:Ethnicity / Q000235:genetics* / Q000706:statistics & numerical data; D005787:Gene Frequency; D005820:Genetic Testing; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D044469:Racial Groups / Q000235:genetics* / Q000706:statistics & numerical data; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics
D000925:Anticoagulants; D014859:Warfarin; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases