Genetic Variation and Haplotype Structure of the ABC Transporter Gene ABCG2 in a Japanese Population

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Author(s)

    • MAEKAWA Keiko
    • Project team for Pharmacogenetics, National Institute of Health Sciences
    • ITODA Masaya
    • Project team for Pharmacogenetics, National Institute of Health Sciences
    • SAI Kimie
    • Project team for Pharmacogenetics, National Institute of Health Sciences
    • SAITO Yoshiro
    • Project team for Pharmacogenetics, National Institute of Health Sciences
    • KANIWA Nahoko
    • Project team for Pharmacogenetics, National Institute of Health Sciences
    • SHIRAO Kuniaki
    • Gastrointestinal Oncology Division, National Cancer Center Hospital
    • KUNITOH Hideo
    • Thoracic Oncology Division, National Cancer Center Hospital
    • MINAMI Hironobu
    • Division of Oncology/Hematology, National Cancer Center Hospital East
    • KUBOTA Kaoru
    • Thoracic Oncology Division, National Cancer Center Hospital East
    • OHTSU Atsushi
    • Division of GI Oncology/Digestive Endoscopy, National Cancer Center Hospital East
    • YOSHIDA Teruhiko
    • Genetics Division, National Cancer Center Research Institute, National Cancer Center
    • KAMATANI Naoyuki
    • Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University
    • OZAWA Shogo
    • Project team for Pharmacogenetics, National Institute of Health Sciences
    • SAWADA Jun-ichi
    • Project team for Pharmacogenetics, National Institute of Health Sciences

Abstract

  The ATP-binding cassette transporter, ABCG2, which is expressed at high levels in the intestine and liver, functions as an efflux transporter for many drugs, including clinically used anticancer agents such as topotecan and the active metabolite of irinotecan (SN-38). In this study, to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of <i>ABCG2</i>, we have comprehensively searched for genetic variations in the putative promoter region, all the exons, and their flanking introns of <i>ABCG2</i> from 177 Japanese cancer patients treated with irinotecan. Forty-three genetic variations, including 11 novel ones, were found: 5 in the 5′-flanking region, 13 in the coding exons, and 25 in the introns. In addition to 9 previously reported nonsynonymous single nucleotide polymorphisms (SNPs), 2 novel nonsynonymous SNPs, 38C>T (Ser13Leu) and 1060G>A (Gly354Arg), were found with minor allele frequencies of 0.3%. Based on the LD profiles between the SNPs and the estimated past recombination events, the region analyzed was divided into three blocks (Block -1, 1, and 2), each of which spans at least 0.2 kb, 46 kb, and 13 kb and contains 2, 24, and 17 variations, respectively. The two, eight, and five common haplotypes detected in 10 or more patients accounted for most (>90%) of the haplotypes inferred in Block -1, Block 1, and Block 2, respectively. The SNP and haplotype distributions in Japanese were different from those reported previously in Caucasians. This study provides fundamental information for the pharmacogenetic studies investigating the relationship between the genetic variations in <i>ABCG2</i> and pharmacokinetic/pharmacodynamic parameters.<br>

Journal

  • Drug Metabolism and Pharmacokinetics

    Drug Metabolism and Pharmacokinetics 21(2), 109-121, 2006-04-27

    The Japanese Society for the Study of Xenobiotics

References:  35

Cited by:  2

Codes

  • NII Article ID (NAID)
    10017423120
  • NII NACSIS-CAT ID (NCID)
    AA1162652X
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    13474367
  • Data Source
    CJP  CJPref  J-STAGE 
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