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Clin Pharmacol Ther. 2014 Sep;96(3):370-9. doi: 10.1038/clpt.2014.109. Epub 2014 May 22.

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

Author information

1
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
2
Department of Pharmacology and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
3
Center of Genomic Medicine, RIKEN, Yokohama City, Japan.
4
Department of Anesthesiology, University of California, San Francisco, San Francisco, California, USA.
5
Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
6
Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
7
Center for Health Research Southeast, Kaiser Permanente Georgia, Atlanta, Georgia, USA.

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.

PMID:
24853734
PMCID:
PMC4171106
DOI:
10.1038/clpt.2014.109
[Indexed for MEDLINE]
Free PMC Article

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