Genetic Variations and Haplotype Structures of the ABC Transporter Gene ABCC1 in a Japanese Population
| Autor: | Hiroshi Kajio, Kazuki Yasuda, Yoshiro Saito, Ryuichi Hasegawa, Hiromi Fukushima-Uesaka, Keiko Maekawa, Masahiro Tohkin, Nobuaki Kuzuya, Jun-ichi Sawada, Kazuko Suzuki, Tatsuo Yanagawa, Naoyuki Kamatani, Manabu Kawamoto |
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| Rok vydání: | 2007 |
| Předmět: |
Molecular Sequence Data
Pharmaceutical Science ATP-binding cassette transporter Polymorphism Single Nucleotide Linkage Disequilibrium Japan Genetic variation Diabetes Mellitus Humans SNP Pharmacology (medical) 3' Untranslated Regions Gene Pharmacology Genetics biology Reverse Transcriptase Polymerase Chain Reaction Haplotype Genetic Variation DNA Exons Japanese population Introns Haplotypes ABCC1 biology.protein Amino acid change Multidrug Resistance-Associated Proteins 5' Untranslated Regions |
| Zdroj: | Drug Metabolism and Pharmacokinetics. 22:48-60 |
| ISSN: | 1347-4367 |
| DOI: | 10.2133/dmpk.22.48 |
| Popis: | 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, 726GT (Trp242Cys), 1199TC (Ile400Thr), 1967GC (Ser656Thr), 2530GA (Gly844Ser), 3490GA (Val1164Ile), 3550GA (Glu1184Lys), 3901CT (Arg1301Cys), and 4502AG (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 onor = 10 chromosomes accounted foror = 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. |
| Databáze: | OpenAIRE |
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