A common 5′-UTR variant in MATE2-K is associated with poor response to metformin

J. H. Choi; S. W. Yee; A. H. Ramirez; K. M. Morrissey; G. H. Jang; P. J. Joski; J. A. Mefford; S. E. Hesselson; A. Schlessinger; G. Jenkins; R. A. Castro; S. J. Johns; D. Stryke; A. Sali; T. E. Ferrin; J. S. Witte; P. Y. Kwok; D. M. Roden; R. A. Wilke; C. A. McCarty; R. L. Davis; K. M. Giacomini

doi:10.1038/clpt.2011.165

A common 5′-UTR variant in MATE2-K is associated with poor response to metformin

J. H. Choi
, S. W. Yee
, A. H. Ramirez
, K. M. Morrissey
, G. H. Jang
, P. J. Joski
, J. A. Mefford
, S. E. Hesselson
, A. Schlessinger
, G. Jenkins
, R. A. Castro
, S. J. Johns
, D. Stryke
, A. Sali
, T. E. Ferrin
, J. S. Witte
, P. Y. Kwok
, D. M. Roden
, R. A. Wilke
, C. A. McCarty

R. L. Davis, K. M. Giacomini

Department of Pharmacology

Research output: Contribution to journal › Review article › peer-review

150 Scopus citations

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 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 (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.

Original language	English
Pages (from-to)	674-684
Number of pages	11
Journal	Clinical Pharmacology and Therapeutics
Volume	90
Issue number	5
DOIs	https://doi.org/10.1038/clpt.2011.165
State	Published - Nov 2011

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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., ... Giacomini, K. M. (2011). A common 5′-UTR variant in MATE2-K is associated with poor response to metformin. Clinical Pharmacology and Therapeutics, 90(5), 674-684. https://doi.org/10.1038/clpt.2011.165

@article{89f1b9cbd0ac4d3bb31def4b49df2c1b,

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 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.",

author = "Choi, \{J. H.\} and Yee, \{S. W.\} and Ramirez, \{A. H.\} and Morrissey, \{K. M.\} and Jang, \{G. H.\} and Joski, \{P. J.\} and Mefford, \{J. A.\} and Hesselson, \{S. E.\} and A. Schlessinger and G. Jenkins and Castro, \{R. A.\} and Johns, \{S. J.\} and D. Stryke and A. Sali and Ferrin, \{T. E.\} and Witte, \{J. S.\} and Kwok, \{P. Y.\} and Roden, \{D. M.\} and Wilke, \{R. A.\} and McCarty, \{C. A.\} and Davis, \{R. L.\} and Giacomini, \{K. M.\}",

year = "2011",

month = nov,

doi = "10.1038/clpt.2011.165",

language = "English",

volume = "90",

pages = "674--684",

journal = "Clinical Pharmacology and Therapeutics",

issn = "0009-9236",

publisher = "Wiley-Blackwell",

number = "5",

}

Choi, JH, Yee, SW, Ramirez, AH, Morrissey, KM, Jang, GH, Joski, PJ, Mefford, JA, Hesselson, SE, Schlessinger, A, Jenkins, G, Castro, RA, Johns, SJ, Stryke, D, Sali, A, Ferrin, TE, Witte, JS, Kwok, PY, Roden, DM, Wilke, RA, McCarty, CA, Davis, RL & Giacomini, KM 2011, 'A common 5′-UTR variant in MATE2-K is associated with poor response to metformin', Clinical Pharmacology and Therapeutics, vol. 90, no. 5, pp. 674-684. https://doi.org/10.1038/clpt.2011.165

TY - JOUR

T1 - A common 5′-UTR variant in MATE2-K is associated with poor response to metformin

AU - Choi, J. H.

AU - Yee, S. W.

AU - Ramirez, A. H.

AU - Morrissey, K. M.

AU - Jang, G. H.

AU - Joski, P. J.

AU - Mefford, J. A.

AU - Hesselson, S. E.

AU - Schlessinger, A.

AU - Jenkins, G.

AU - Castro, R. A.

AU - Johns, S. J.

AU - Stryke, D.

AU - Sali, A.

AU - Ferrin, T. E.

AU - Witte, J. S.

AU - Kwok, P. Y.

AU - Roden, D. M.

AU - Wilke, R. A.

AU - McCarty, C. A.

AU - Davis, R. L.

AU - Giacomini, K. M.

PY - 2011/11

Y1 - 2011/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/80054970528

U2 - 10.1038/clpt.2011.165

DO - 10.1038/clpt.2011.165

M3 - Review article

C2 - 21956618

AN - SCOPUS:80054970528

SN - 0009-9236

VL - 90

SP - 674

EP - 684

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 5

ER -

A common 5′-UTR variant in MATE2-K is associated with poor response to metformin

Abstract

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