Catalog of 605 single-nucleotide polymorphisms (snps) among 13 genes encoding human atp-binding cassette transporters: abca4, abca7, abca8, abcd1, abcd3, abcd4, abce1, abcf1, abcg1, abcg2, abcg4, abcg5, and abcg8

Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan Tel. +81-3-5449-5372
Journal of Human Genetics (Impact Factor: 2.46). 06/2002; 47(6). DOI: 10.1007/s100380200041


Single-nucleotide polymorphisms (SNPs) at some gene loci are useful as markers of individual risk for adverse drug reactions or susceptibility to complex diseases. We have been focusing on identifying SNPs in and around genes encoding drug-metabolizing enzymes and transporters, and have constructed several high-density SNP maps of such regions. Here we report SNPs at additional loci, specifically 13 genes belonging to the superfamily of ATP-binding cassette transporters (ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8). Sequencing a total of 416 kb of genomic DNA from 48 Japanese volunteers identified 605 SNPs among these 13 loci: 14 in 5′ flanking regions, 5 in 5′ untranslated regions, 37 within coding elements, 529 in introns, 8 in 3′ untranslated regions, and 12 in 3′ flanking regions. By comparing our data with SNPs deposited in the dbSNP database of the National Center for Biotechnology Information (US) and with published reports, we determined that 491 (81%) of the SNPs reported here were novel. We also detected 107 genetic variations of other types among the loci examined (insertion–deletions or mono- di-, or trinucleotide polymorphisms). The high-density SNP maps we constructed on the basis of these data should provide useful information for investigating associations between genetic variations and common diseases or responsiveness to drug therapy.

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    • "The ABCG2 gene is highly polymorphic. So far, over 40 single nucleotide polymorphisms (SNPs) have been found (Iida et al. 2002). SNPs may affect the level of mRNA expression , which leads to a change/loss of ABCG2 function. "
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    ABSTRACT: The aim of this study was to evaluate the participation of polymorphism at position C421A and mRNA expression of the ABCG2 gene in the development of peptic ulcers, which is a very common and severe disease. ABCG2, encoded by the ABCG2 gene, has been found inter alia in the gastrointestinal tract, where it plays a protective role eliminating xenobiotics from cells into the extracellular environment. The materials for the study were biopsies of gastric mucosa taken during a routine endoscopy. For genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) at position C421A, DNA was isolated from 201 samples, while for the mRNA expression level by real-time PCR, RNA was isolated from 60 patients. The control group of healthy individuals consisted of 97 blood donors. The dominant genotype in the group of peptic ulcer patients and healthy individuals was homozygous CC. No statistically significant differences between healthy individuals and the whole group of peptic ulcer patients and, likewise, between the subgroups of peptic ulcer patients (infected and uninfected with Helicobacter pylori) were found. ABCG2 expression relative to GAPDH expression was found in 38 of the 60 gastric mucosa samples. The expression level of the gene varies greatly among cases. The statistically significant differences between the intensity (p = 0.0375) of H. pylori infection and ABCG2 gene expression have been shown. It was observed that the more intense the infection, the higher the level of ABCG2 expression.
    Full-text · Article · Nov 2015 · Journal of applied genetics
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    • "ABBREVIATIONS: AUC, area under the curve; LDL-C, low-density lipoprotein cholesterol; PCR, polymerase chain reaction; SNP, singlenucleotide polymorphism; WT, wild type. populations (Iida et al., 2002; Bäckström et al., 2003; Zamber et al., 2003; Kobayashi et al., 2005). Previous studies have shown a significantly higher frequency of ABCG2 c.34G.A (rs2231137) and c.421C.A (rs2231142) variants in Asians when compared with Caucasians and African Americans (Kim et al., 2010). "
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    ABSTRACT: Rosuvastatin, a HMG-CoA reductase inhibitor used to lower blood LDL-C, is a substrate of the membrane ABCG2 exporter. ABCG2 variants have been shown to alter rosuvastatin disposition. The objective of this study is to determine the impact of ABCG2 34/421 compound haplotypes on rosuvastatin pharmacokinetics in healthy Chinese volunteer subjects. Eight-hundred healthy Chinese males were genotyped by PCR-Pyrosequencing for ABCG2 34G>A, ABCG2 421C>A, SLCO1B1 521T>C and CYP2C9*3 variants. Sixty-two male subjects with wild-type SLCO1B1 c.521TT and CYP2C9*3 were recruited for this pharmacokinetic study of rosuvastatin. A single oral dose of 10 mg rosuvastatin was administrated to each subject, and blood samples were collected before and at various time points after drug administration. Plasma concentration of rosuvastatin was determined by HPLC-MS/MS, and pharmacokinetic analysis was carried out using WinNonlin program. In Chinese males, high allele frequency of ABCG2 c.34G>A (0.275) and c.421C>A (0.282) was observed, resulting in a considerable portion (23.3%) of subjects being ABCG2 34/421 compound heterozygotes. Compared to subjects with ABCG2 wild-type (c.34GG/421CC), plasma rosuvastatin Cmax and AUC0-∞ were significantly higher, while CL/F was significantly lower in subjects with c.34AA, c.421AA, and c.34GA/421CA genotypes. Both T1/2 and Tmax were similar among subjects with different genotypes. A high frequency of ABCG2 c.34G>A and c.421C>A variants were present in Chinese males, and the disposition of rosuvastatin was significantly affected by both variants. This data suggests that it is advisable to genotype these variants when prescribing rosuvastatin to Chinese subjects, leading to a precise dose for each individual. The American Society for Pharmacology and Experimental Therapeutics.
    Full-text · Article · Jun 2015 · Journal of Pharmacology and Experimental Therapeutics
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    • "No genetic defect was reported on the human ABCA7 gene. A high-density single nucleotide polymorphism (SNP) map of ABC transporters in Japanese has been constructed and identified 67 SNPs at the ABCA7 locus [14]. No association has been indicated between variations and pathological phenotypes to date. "
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    ABSTRACT: Many ABC proteins are functional in cellular lipid transport in various different manners. ABCA7 is a full-size ABC transporter, the physiological function of which is unknown to date. This is a protein that shows the highest homology known to ABCA1, an essential molecule for producing of plasma high-density lipoprotein (HDL), and in fact it mimics ABCA1 to mediate the production of HDL from cellular lipid when transfected in vitro. It is therefore rational to assume that ABCA7 plays a relevant role in regulating of lipid metabolism. However, the ABCA7 expression profile is distinct from that of ABCA1, with respect to tissue-specific distribution and response to some reagents, presumably because of different transcriptional and posttranscriptional regulation. Potential roles and functions of ABCA7 in lipid homeostasis are discussed, especially in relation to HDL metabolism, based on available publications.
    Full-text · Article · Mar 2006 · FEBS Letters
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