Genetic variations and haplotype structures of the ABC transporter gene ABCC1 in a Japanese population

作者：Fukushima Uesaka Hiromi; Saito Yoshiro^*; Tohkin Masahiro; Maekawa Keiko; Hasegawa Ryuichi; Kawamoto Manabu; Kamatani Naoyuki; Suzuki Kazuko; Yanagawa Tatsuo; Kajio Hiroshi; Kuzuya Nobuaki; Yasuda Kazuki; Sawalda Jun ichi

来源：Drug Metabolism and Pharmacokinetics, 2007, 22(1): 48-60.

DOI：10.2133/dmpk.22.48

• ABCC1
• genetic variation
• amino acid change
• haplotype
• haplotype tagging SNP

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'-flnking region, 1 in the 5'-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variation), 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 (Arg1301ys), and 4502A> G (Asp1501Gly), were detected with an allele frequency of 0.003. Base 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.

• 出版日期2007