NDLI: A common 5'-UTR variant in MATE2-K is associated with poor response to metformin.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Choi, J. H. Yee, S. W. Ramirez, A. H. Morrissey, K. M. Jang, G. H. Joski, P. J. Mefford, J. A. Hesselson, S. E. Schlessinger, A. Jenkins, G. Castro, R. A. Johns, S. J. Stryke, D. Sali, A. Ferrin, T. E. Witte, J. S. Kwok, P-Y Roden, D. M. Wilke, R. A. McCarty, C. A. Davis, R. L. Giacomini, K. M.
Description	Author Affiliation: Choi JH ( Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Korea.)
Abstract	Multidrug and toxin extrusion 2 (MATE2-K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2-K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2-K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants-c.485C>T and c.1177G>A-were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2-K basal promoter haplotypes containing the most common variant, g.-130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF-1). Patients with diabetes who were homozygous for g.-130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (-0.027 (-0.076, 0.033)), as compared with carriers of the reference allele, g.-130G (-0.15 (-0.17, -0.13)) (P=0.002). Our study showed that MATE2-K plays a role in the antidiabetes response to metformin.
File Format	HTM / HTML
ISSN	00099236
e-ISSN	15326535
DOI	10.1038/clpt.2011.165
Journal	Clinical Pharmacology & Therapeutics
Issue Number	5
Volume Number	90
Language	English
Publisher	Wiley
Publisher Date	2011-11-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Pharmacology Diabetes Mellitus, Type 2 Drug Therapy Hypoglycemic Agents Pharmacokinetics Metformin Organic Cation Transport Proteins Genetics Alleles Animals Continental Population Groups Genetic Variation Hct116 Cells Hek293 Cells Haplotypes Hemoglobin A, Glycosylated Metabolism Pharmacology Llc-pk1 Cells Luciferases Polymorphism, Genetic Promoter Regions, Genetic Retrospective Studies Swine Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)

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