Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin

S. Goswami, S. W. Yee, S. Stocker, J. D. Mosley, Michiaki Kubo, R. Castro, J. A. Mefford, C. Wen, X. Liang, J. Witte, C. Brett, S. Maeda, M. D. Simpson, M. M. Hedderson, R. L. Davis, D. M. Roden, K. M. Giacomini, R. M. Savic

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Abstract

One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator-activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.

Original languageEnglish
Pages (from-to)370-379
Number of pages10
JournalClinical Pharmacology and Therapeutics
Volume96
Issue number3
DOIs
Publication statusPublished - 01-01-2014

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Metformin
Transcription Factors
Pharmacokinetics
Hepatocyte Nuclear Factor 4
Sp1 Transcription Factor
Peroxisome Proliferator-Activated Receptors
Type 2 Diabetes Mellitus
Healthy Volunteers
Genome
Population

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Goswami, S. ; Yee, S. W. ; Stocker, S. ; Mosley, J. D. ; Kubo, Michiaki ; Castro, R. ; Mefford, J. A. ; Wen, C. ; Liang, X. ; Witte, J. ; Brett, C. ; Maeda, S. ; Simpson, M. D. ; Hedderson, M. M. ; Davis, R. L. ; Roden, D. M. ; Giacomini, K. M. ; Savic, R. M. / Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin. In: Clinical Pharmacology and Therapeutics. 2014 ; Vol. 96, No. 3. pp. 370-379.
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Goswami, S, Yee, SW, Stocker, S, Mosley, JD, Kubo, M, Castro, R, Mefford, JA, Wen, C, Liang, X, Witte, J, Brett, C, Maeda, S, Simpson, MD, Hedderson, MM, Davis, RL, Roden, DM, Giacomini, KM & Savic, RM 2014, 'Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin', Clinical Pharmacology and Therapeutics, vol. 96, no. 3, pp. 370-379. https://doi.org/10.1038/clpt.2014.109

Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin. / Goswami, S.; Yee, S. W.; Stocker, S.; Mosley, J. D.; Kubo, Michiaki; Castro, R.; Mefford, J. A.; Wen, C.; Liang, X.; Witte, J.; Brett, C.; Maeda, S.; Simpson, M. D.; Hedderson, M. M.; Davis, R. L.; Roden, D. M.; Giacomini, K. M.; Savic, R. M.

In: Clinical Pharmacology and Therapeutics, Vol. 96, No. 3, 01.01.2014, p. 370-379.

Research output: Contribution to journalArticle

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T1 - Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin

AU - Goswami, S.

AU - Yee, S. W.

AU - Stocker, S.

AU - Mosley, J. D.

AU - Kubo, Michiaki

AU - Castro, R.

AU - Mefford, J. A.

AU - Wen, C.

AU - Liang, X.

AU - Witte, J.

AU - Brett, C.

AU - Maeda, S.

AU - Simpson, M. D.

AU - Hedderson, M. M.

AU - Davis, R. L.

AU - Roden, D. M.

AU - Giacomini, K. M.

AU - Savic, R. M.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator-activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.

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