Dan Roden
Faculty Member
Last active: 2/8/2016

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

Choi JH, Yee SW, Ramirez AH, Morrissey KM, Jang GH, Joski PJ, Mefford JA, Hesselson SE, Schlessinger A, Jenkins G, Castro RA, Johns SJ, Stryke D, Sali A, Ferrin TE, Witte JS, Kwok PY, Roden DM, Wilke RA, McCarty CA, Davis RL, Giacomini KM
Clin Pharmacol Ther. 2011 90 (5): 674-84

PMID: 21956618 · PMCID: PMC3329222 · 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.

MeSH Terms (25)

Adult Aged Alleles Animals Continental Population Groups Diabetes Mellitus, Type 2 Female Genetic Variation Glycated Hemoglobin A Haplotypes HCT116 Cells HEK293 Cells Humans Hypoglycemic Agents LLC-PK1 Cells Luciferases Male Metformin Middle Aged Organic Cation Transport Proteins Polymorphism, Genetic Promoter Regions, Genetic Retrospective Studies Swine Treatment Outcome

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