Journal
CLINICAL PHARMACOLOGY & THERAPEUTICS
Volume 90, Issue 5, Pages 674-684Publisher
WILEY
DOI: 10.1038/clpt.2011.165
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Funding
- National Institutes of Health [GM61390, GM36780, GM74929, DK080007, HL65962, F32 GM088991]
- Agency for Healthcare Research and Quality
- National Research Foundation of Korea
- Korean government (MEST) [2010-0029353]
- Institute for Human Genetics, UCSF
- Grants-in-Aid for Scientific Research [23590646] Funding Source: KAKEN
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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.
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