Genetic Variations and Haplotype Structures of the ABC Transporter Gene ABCC1 in a Japanese Population
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- FUKUSHIMA-UESAKA Hiromi
- Project Team for Pharmacogenetics, National Institute of Health Sciences
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- SAITO Yoshiro
- Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Biochemistry and Immunochemistry, National Institute of Health Sciences
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- TOHKIN Masahiro
- Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Medicinal Safety Science, National Institute of Health Sciences
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- MAEKAWA Keiko
- Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Biochemistry and Immunochemistry, National Institute of Health Sciences
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- HASEGAWA Ryuichi
- Division of Medicinal Safety Science, National Institute of Health Sciences
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- KAWAMOTO Manabu
- Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University
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- KAMATANI Naoyuki
- Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University
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- SUZUKI Kazuko
- Nerima General Hospital
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- YANAGAWA Tatsuo
- Nerima General Hospital
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- KAJIO Hiroshi
- Division of Endocrine and Metabolic Diseases, the Hospital, Research Institute, International Medical Center of Japan
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- KUZUYA Nobuaki
- Division of Endocrine and Metabolic Diseases, the Hospital, Research Institute, International Medical Center of Japan
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- YASUDA Kazuki
- Department of Metabolic Disorder, Research Institute, International Medical Center of Japan
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- 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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Abstract
Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5′-flanking region, 1 in the 5′-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3′-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5′-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on ≥10 chromosomes accounted for ≥91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese.<br>
Journal
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- Drug Metabolism and Pharmacokinetics
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Drug Metabolism and Pharmacokinetics 22 (1), 48-60, 2007
The Japanese Society for the Study of Xenobiotics
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Details 詳細情報について
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- CRID
- 1390282680155859840
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- NII Article ID
- 130004933403
- 10018733006
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- NII Book ID
- AA1162652X
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- ISSN
- 18800920
- 13474367
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- Text Lang
- en
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- Data Source
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- JaLC
- Crossref
- CiNii Articles
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- Abstract License Flag
- Disallowed