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A Common 5′‐UTR Variant in MATE2‐K Is Associated With Poor Response to Metformin
Author(s) -
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 PY,
Roden D M,
Wilke R A,
McCarty C A,
Davis R L,
Giacomini K M
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.165
Subject(s) - metformin , medicine , pharmacology , biology , genetics , insulin
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 (HbA 1c ) (−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. Clinical Pharmacology & Therapeutics (2011); 90 5, 674–684. doi: 10.1038/clpt.2011.165