Affiliation:
1. 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
Abstract
Aims: 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. Materials & 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.
Subject
Pharmacology,Genetics,Molecular Medicine
Cited by
145 articles.
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