A Common 5′-UTR Variant in MATE2-K Is Associated With Poor Response to Metformin
| العنوان: | A Common 5′-UTR Variant in MATE2-K Is Associated With Poor Response to Metformin |
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| المؤلفون: | Andrej Sali, Sj J. Johns, Js S. Witte, Te E. Ferrin, Doug Stryke, Rl L. Davis, Sw W. Yee, Avner Schlessinger, Ah H. Ramirez, Ra A. Castro, Km M. Morrissey, Pui-Yan Kwok, Km M. Giacomini, Dm M. Roden, Gh H. Jang, Ca A. McCarty, Se E. Hesselson, G. Jenkins, Jh H. Choi, Ra A. Wilke, Pj J. Joski, Ja A. Mefford |
| المصدر: | Clinical Pharmacology & Therapeutics. 90:674-684 |
| بيانات النشر: | Springer Science and Business Media LLC, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Adult, Male, Nonsynonymous substitution, medicine.medical_specialty, Organic Cation Transport Proteins, Swine, Biology, Article, chemistry.chemical_compound, Basal (phylogenetics), Internal medicine, medicine, Animals, Humans, Hypoglycemic Agents, Pharmacology (medical), Allele, Luciferases, Promoter Regions, Genetic, Allele frequency, Alleles, Aged, Retrospective Studies, Glycated Hemoglobin, Pharmacology, Polymorphism, Genetic, Racial Groups, Genetic Variation, Myeloid zinc finger 1, Promoter, Middle Aged, HCT116 Cells, Metformin, HEK293 Cells, Treatment Outcome, Endocrinology, Diabetes Mellitus, Type 2, Haplotypes, chemistry, LLC-PK1 Cells, Female, Glycated hemoglobin, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1532-6535 0009-9236 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2658434e1cc1ba42cfcd3c446fa3b80cTest https://doi.org/10.1038/clpt.2011.165Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2658434e1cc1ba42cfcd3c446fa3b80c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15326535 00099236 |
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