Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups

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.

Figure 1. Variant CYP2C9 (combined *2, *3, *5, *6, *8 and *11), VKORC1 (g.-1639G>A) and CYP4F2 (*3 [rs2108622] and rs2189784) allele frequencies in various racial and ethnic populations

Wild-type and variant allele frequencies are represented by dark blue and light blue shading, respectively.

Figure 2. CYP2C9, VKORC1 and CYP4F2 genotype frequency profiles in various racial and ethnic populations

CYP2C9, VKORC1 and CYP4F2 genotype frequencies were combined for a subset of subjects with available data. Frequencies were subdivided based on variant CYP2C9 (*2, *3, *5, *6, *8 and *11), VKORC1 (g.-1639G>A) and CYP4F2 (*3; p.V433M) alleles. For each population studied, the frequency of homozygosity for a WT genotype at all three loci is highlighted by a dark blue bar, and a dotted line indicates the frequency profile trend. Note the high frequency (47.5%) of African–Americans with WT alleles compared with those in all other studied populations (p < 0.0001). n: Number of subjects; vt: Variant allele; WT: Wild-type allele (CYP2C9: *1; VKORC1: g.-1639G; CYP4F2: p.V433).