Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes

Abstract

To determine CYP2C19 and CYP2C8 allele frequencies, 28 coding and/or functional variants were genotyped in 1250 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) individuals. The combined CYP2C19 variant allele frequencies ranged from ∼0.30 to 0.41; however, the CYP2C8 frequencies were much lower (∼0.04-0.13). After incorporating previously reported CYP2C9 genotyping results from these populations (36 total CYP2C variants), 16 multi-ethnic CYP2C haplotypes were inferred with frequencies >0.5%. Notably, the 2C19*17-2C9*1-2C8*2 haplotype was identified among African-Americans (8%) and Hispanics (2%), indicating that CYP2C19*17 does not always tag a CYP2C haplotype that encodes efficient CYP2C-substrate metabolism. The 2C19*1-2C9*2-2C8*3 haplotype was identified in all populations except African-Americans and additional novel haplotypes were identified in selected populations (for example, 2C19*2-2C9*1-2C8*4 and 2C19*4B-2C9*1-2C8*1), together indicating that both CYP2C19*17 and *2 can be linked with other CYP2C loss-of-function alleles. These results have important implications for pharmacogenomic association studies involving the CYP2C locus and are clinically relevant when administering CYP2C-substrate medications.

FIGURE 1

Linkage disequilibrium (LD) across the CYP2C locus (10q23.33) in each tested population using 13 polymorphic SNPs. Pairwise LD between polymorphisms is expressed as D'. Significant linkage (logarithm of the odds, LOD≥2) is illustrated by red shading depending on the magnitude of D' (from pink to bright red), and insignificant linkage (LOD<2) is illustrated by blue (if D'=1) or white (if D'<1) shading. Haplotype blocks were inferred using the `Four gamete of LD' method (Haploview).