Mutation Analysis of CYP2D6 Locus in the Korean Population: Identification of Rare Poor Metabolizer Alleles at the Nucleotide Level

The CYP2D6 loci of one hundred and eight genetically unrelated Koreans were analyzed. The G1934A mutation which causes aberrant splicing, thereby producing nonfunctional enzymes and is responsible for 70% of poor metabolizer (PM) phenotype among Caucasians, was found in three heterozygous individuals. The mutation frequency of Koreans at 1934 (1.5%) was one thirteenth of that of Caucasians (20.7%). Such a low mutation frequency could be the major genetic explanation for rare PMs in Koreans. A substitution allele of Gly169-Arg(G1846A) which also produces a nonfunctional enzyme was detected in one heterozygous individual. This PM allele has been reported only in Chinese but not in Caucasians. This is the first report which demonstrates the presence of CYP2D6 PM alleles at the nucleotide level in Koreans. No base changes were detected at 1795, 2637, and 3023 whose mutations would also make nonfunctional enzymes. Individuals with two nonfunctional alleles are thereby expected to be PMs phenotypically and were not detected in this study. Mutant alleles with Arg296-Cys(C2938T) and Ser476-Thr(G4268C) substitutions known to reduce enzyme activity and with silent mutations at 1749 were studied; mutation frequencies were 17.9%, 64.7%, and 66%, respectively. The mutation frequency at 2938 was especially reduced by half when compared to that of Caucasians (32.4%).