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A common 5′-UTR variant in MATE2-K is associated with poor response to metformin
- A common 5′-UTR variant in MATE2-K is associated with poor response to metformin
- 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.
- Ewha Authors
- SCOPUS Author ID
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- Journal Title
- Clinical Pharmacology and Therapeutics
- vol. 90, no. 5, pp. 674 - 684
- SCI; SCIE; SCOPUS
- 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.
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