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

• Published in: Clinical pharmacology and therapeutics Vol. 90; no. 5; p. 674
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 01.11.2011
• Subjects: Adult; Aged; Alleles; Animals; Continental Population Groups - genetics; Diabetes Mellitus, Type 2 - drug therapy; Female; Genetic Variation; Glycated Hemoglobin A - metabolism; Haplotypes; HCT116 Cells; HEK293 Cells; Humans; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; LLC-PK1 Cells; Luciferases - metabolism; Male; Metformin - pharmacokinetics; Metformin - pharmacology; Middle Aged; Organic Cation Transport Proteins - genetics; Polymorphism, Genetic; Promoter Regions, Genetic; Retrospective Studies; Swine; Treatment Outcome
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2011.165

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.