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

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 variantsc.485CT and c.1177GAwere 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.130GA (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. © 2011 American Society for Clinical Pharmacology and Therapeutics.