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

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  • SOYAMA Akiko
    Project Team for Pharmacogenetics, National Institute of Health Sciences
  • SAITO Yoshiro
    Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Biochemistry and Immunochemistry, National Institute of Health Sciences
  • OHNO Yasuo
    Division of Pharmacology, National Institute of Health Sciences Deputy Director General, National Institute of Health Sciences
  • KOMAMURA Kazuo
    Department of Cardiology, National Cardiovascular Center Department of Cardiovascular Dynamics Research Institute, National Cardiovascular Center
  • KAMAKURA Shiro
    Department of Cardiology, National Cardiovascular Center
  • KITAKAZE Masafumi
    Department of Cardiology, National Cardiovascular Center
  • TOMOIKE Hitonobu
    Department of Cardiology, National Cardiovascular Center
  • OZAWA Shogo
    Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Pharmacology, National Institute of Health Sciences
  • SAWADA Jun-ichi
    Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Biochemistry and Immunochemistry, National Institute of Health Sciences

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  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.<br>

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