title: 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 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.
authors.affiliation: Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Choi
authors.forename: S W
authors.initials: SW
authors.lastname: Yee
authors.forename: A H
authors.initials: AH
authors.lastname: Ramirez
authors.forename: K M
authors.initials: KM
authors.lastname: Morrissey
authors.forename: G H
authors.initials: GH
authors.lastname: Jang
authors.forename: P J
authors.initials: PJ
authors.lastname: Joski
authors.forename: J A
authors.initials: JA
authors.lastname: Mefford
authors.forename: S E
authors.initials: SE
authors.lastname: Hesselson
authors.forename: A
authors.initials: A
authors.lastname: Schlessinger
authors.forename: G
authors.initials: G
authors.lastname: Jenkins
authors.forename: R A
authors.initials: RA
authors.lastname: Castro
authors.forename: S J
authors.initials: SJ
authors.lastname: Johns
authors.forename: D
authors.initials: D
authors.lastname: Stryke
authors.forename: A
authors.initials: A
authors.lastname: Sali
authors.forename: T E
authors.initials: TE
authors.lastname: Ferrin
authors.forename: J S
authors.initials: JS
authors.lastname: Witte
authors.forename: P-Y
authors.initials: PY
authors.lastname: Kwok
authors.forename: D M
authors.initials: DM
authors.lastname: Roden
authors.forename: R A
authors.initials: RA
authors.lastname: Wilke
authors.forename: C A
authors.initials: CA
authors.lastname: McCarty
authors.forename: R L
authors.initials: RL
authors.lastname: Davis
authors.forename: K M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D014644:Genetic Variation; D006442:Glycated Hemoglobin / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D018374:LLC-PK1 Cells; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics* / Q000494:pharmacology; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D044469:Racial Groups / Q000235:genetics; D012189:Retrospective Studies; D013552:Swine; D016896:Treatment Outcome
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008156:Luciferases; D008687:Metformin; D027701:Organic Cation Transport Proteins; C521870:SLC47A2 protein, human