Pharmacogenetics of CYP2C8 and haplotypic associations in three distinct Asian populations

Abstract

CYP2C8 is a polymorphic enzyme involved in the metabolism of several clinically important drugs, e.g. paclitaxel, all‐trans retinoic acid and cerivastatin. The aim of the present study was to determine and compare allele frequencies of reported SNPs in the CYP2C8 gene among three distinct Asian populations and to investigate haplotypic associations among the SNPs. Seventeen SNPs were analysed: 3 in the 5′ UTR, 7 in the coding region, 6 in the intronic region, and 1 in the 3′UTR in a total of 280 healthy subjects (100 Chinese, 90 Malays and 90 Indians) using PCR‐RFLP and direct DNA sequencing. The distribution of allelic frequencies were high in the 5′UTR in all 3 ethnic groups (‐411C>T, range: 0.61‐0.79; ‐370T>G, range: 0.23‐0.33; ‐271C>A, range:0.10‐0.16). Similarly, interethnic difference in allelic frequencies were noted for the following intronic SNPs: IVS2‐64A>G, range: 0.40‐0.60; IVS2‐13Tins, range:0.34‐0.36, IVS7+49T>A, range: 0.43–0.66. The seven cSNPs (416G>A, 805A>T, 792C>G,1169T>C, 1196A>G, 1210C>G, 1230C>T and 1232A>T) and 3 intronic SNPs (IVS1 –37C>T, IVS2 –36G>A and IVS8 –92G>A) were very rare in all 3 ethnic groups. Marked interethnic variations in allele frequencies were apparent at 5′UTR (‐411T>C), intron 2 (IVS2 ‐64A>G) and intron 7 (IVS7 +49T>C) (P<0.05). Haplotype analysis revealed 8 hyplotypes in the Chinese, 8 in the Malays and 12 in the Indians. Future studies should aim to investigate the functional consequences of these haplotypic associations and their impact on the pharmacokinetics of CYP2C8 substrates. Clinical Pharmacology & Therapeutics (2004) 75, P16–P16; doi: