Diverse Structures of Chimeric CYP-REP7/6-Containing CYP2D6 and a Novel Defective CYP2D6 Haplotype Harboring Single-type 36 and CYP-REP7/6 in Japanese

• Published in: DRUG METABOLISM AND PHARMACOKINETICS 2006, Vol.21 (5), p.395-405
• Main Authors: Soyama, Akiko, Saito, Yoshiro, Ohno, Yasuo, Komamura, Kazuo, Kamakura, Shiro, Kitakaze, Masafumi, Tomoike, Hitonobu, Ozawa, Shogo, Sawada, Jun-ichi
• Format: Article
• Language: English
• Subjects: Asian Continental Ancestry Group - genetics; Base Sequence; CYP-REP diversity; CYP2D610D; Cytochrome P-450 CYP2D6 - genetics; DNA - chemistry; DNA - genetics; Gene Deletion; Gene Frequency; Genetic Variation - genetics; Genetics, Population; Genotype; Haplotypes - genetics; Humans; Japan; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic - genetics; Polymorphism, Single Nucleotide - genetics; REP7/6 with CYP2D6; Repetitive Sequences, Nucleic Acid - genetics; Sequence Analysis, DNA; single-type CYP2D636; tandem-type 36-10D
• ISSN: 1347-4367; 1880-0920
• DOI: 10.2133/dmpk.21.395

Chimeric REP7/6 has been used as a marker of CYP2D6 deletion, such as for CYP2D6*5. However, the CYP2D6*10D (*10D) haplotype found in a Japanese population consist of CYP2D6*10B, CYP2D7P-derived 3′-flanking region, and a chimeric repetitive sequence, CYP-REP7/6 (REP7/6) (Ishiguro et al. Clin. Chim. Acta. 2004: 347, 217–221). From our analysis, REP7/6 was found in 26 out of 254 Japanese subjects. Thus, the REP7/6-containing CYP2D6 genes (2D6-REP7/6) were analyzed in detail. In order to specifically detect the 2D6-REP7/6 structure, primers were designed in CYP2D6 intron 6 and the REP7/6 3′-flanking region. Among 26 subjects analyzed by PCR, 5 had 2D6-REP7/6. The other 21 subjects were confirmed to have *5 by another *5-specific primer set. Three out of five subjects with 2D6-REP7/6 had the *10D structure. However, further analysis by PCR and sequencing revealed that their haplotypes were further divided into tandem-type *36-*10D (n = 2) and single-type *10D (n = 1). The remaining two subjects had a novel type of a *36-containing defective structure that consists of CYP2D6*36 and 3′-flanking REP7/6 (single-type *36-REP7/6). Then, REP7/6 sequences in *5, *10D, *36-*10D, and single-type *36 were determined and classified into 5 types: types A to D for *5, type E for *10D and *36-*10D, and type F for *36. These findings could be useful for accurate determination of *5 and REP7/6-harboring aberrant CYP2D6 haplotypes.