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. McCartyR. L. Davis, K. M. Giacomini

Department of Pharmacology

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

140 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",

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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.

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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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