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 & 2 others Robert Davis, K. M. Giacomini

Research output: Contribution to journalReview article

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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.

Original languageEnglish (US)
Pages (from-to)674-684
Number of pages11
JournalClinical Pharmacology and Therapeutics
Volume90
Issue number5
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

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5' Untranslated Regions
Metformin
Zinc Fingers
Glycosylated Hemoglobin A
Luciferases
Genetic Promoter Regions
Gene Frequency
Haplotypes
Cations
Proteins
Alleles
Pharmaceutical Preparations
Population

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Choi, J. H., Yee, S. W., Ramirez, A. H., Morrissey, K. M., Jang, G. H., Joski, P. J., ... 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

A common 5′-UTR variant in MATE2-K is associated with poor response to metformin. / 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.; McCarty, C. A.; Davis, Robert; Giacomini, K. M.

In: Clinical Pharmacology and Therapeutics, Vol. 90, No. 5, 01.11.2011, p. 674-684.

Research output: Contribution to journalReview article

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, R & 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
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. ; McCarty, C. A. ; Davis, Robert ; Giacomini, K. M. / A common 5′-UTR variant in MATE2-K is associated with poor response to metformin. In: Clinical Pharmacology and Therapeutics. 2011 ; Vol. 90, No. 5. pp. 674-684.
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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.",
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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, Robert

AU - Giacomini, K. M.

PY - 2011/11/1

Y1 - 2011/11/1

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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