Abstract

Background: CYP2D6 is one of the most significant polymorphic genes of drugmetabolizing enzymes due to its association with different metabolic activities and the pharmacokinetics of CYP2D6 substrates.

Objective: The objective of this study was to explore for a novel haplotype of CYP2D6 in the Japanese population by using a large database of previous clinical studies.

Methods: We analyzed CYP2D6 genotype data from a total of 723 Japanese individuals for 8 loci (100C>T, 1758G>A, 1846G>A, 2573 insertion of C, 2850C>T, 2988G>A, 4125 insertion of 9bp, and 4180G>C) and gene deletion. Genotypes were determined by the designated alleles CYP2D6*2, *4, *5, *10, *14A, *14B, *18, *21, and *41.

Results: The frequencies of the common major haplotypes CYP2D6*1, *10, and *2 in the Japanese population were respectively 43.5%, 38.0%, and 11.3%. In 11 subjects, diplotypes of CYP2D6 were not identified and the genotypes at the 8 loci suggested that there were 2 minor haplotypes, one with only a variation at 4180G>C compared with the wild type CYP2D6*1 (Hap1, frequency: 0.4%) and one with only a variation at 100C>T (Hap2, frequency: 0.4%). The Hap1 haplotype is considered to have no effect on metabolic activity, while it is estimated that the Hap2 haplotype does have an effect on metabolic activity. By comparing with the allele nomenclature for CYP2D6, the Hap2 haplotype was considered to be a potentially novel haplotype involving 100C>T without 4180G>C.

Conclusion: Using a large database of CYP2D6 genotypes in the Japanese population, we found a novel haplotype which involves 100C>T without 4180G>C. Although the haplotype will need to be confirmed by full sequencing, it may be a unique haplotype with an exception to the strong linkage disequilibrium between 100C>T and 4180G>C.

Keywords: CYP2D6, haplotype, frequency, Japanese, allele, polymorphism.

Graphical Abstract