Global variation in CYP2C8-CYP2C9 functional haplotypes

Abstract

We have studied the global frequency distributions of 10 single nucleotide polymorphisms (SNPs) across 132 kb of CYP2C8 and CYP2C9 in approximately 2500 individuals representing 45 populations. Five of the SNPs were in noncoding sequences; the other five involved the more common missense variants (four in CYP2C8, one in CYP2C9) that change amino acids in the gene products. One haplotype containing two CYP2C8 coding variants and one CYP2C9 coding variant reaches an average frequency of 10% in Europe; a set of haplotypes with a different CYP2C8 coding variant reaches 17% in Africa. In both cases these haplotypes are found in other regions of the world at <1%. This considerable geographic variation in haplotype frequencies impacts the interpretation of CYP2C8/CYP2C9 association studies, and has pharmacogenomic implications for drug interactions.

Figure 1

A graphical depiction of the frequencies of the ancestral alleles at the 10 single nucleotide polymorphisms (SNPs) studied in the 45 populations. The figure illustrates the frequencies of these alleles in 45 different populations (listed across the bottom) from around the world. Populations are ordered generally as Africa, Europe, East Asia, Americas.

Figure 2

CYP2C9–CYP2C8 haplotype frequencies. The frequencies of the 17 common haplotypes of CYP2C8–C9 single nucleotide polymorphisms (SNPs). The figure illustrates the frequencies of these haplotypes in 45 different populations listed from top to bottom on the left side in the same order as in Figure 1. The length of each colored bar represents the frequency of the corresponding haplotype in that population. The allelic compositions for the haplotypes are given in Table 2; the frequencies are in ALFRED. Haplotypes that are rare (less than 5%) in all populations are combined into a residual class. Note that coding variants can occur in different combinations and as part of different haplotypes.