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

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
Clin Pharmacol Ther. 2014 96 (3): 370-9

PMID: 24853734 · PMCID: PMC4171106 · DOI:10.1038/clpt.2014.109

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.

MeSH Terms (27)

Adult Aged Aged, 80 and over Biomarkers Diabetes Mellitus, Type 2 Female Genome-Wide Association Study Glycated Hemoglobin A Hepatocyte Nuclear Factor 4 Homozygote Humans Hypoglycemic Agents Male Metformin Middle Aged Models, Biological Multivariate Analysis Pharmacogenetics Phenotype Polymorphism, Single Nucleotide PPAR alpha Retrospective Studies Sp1 Transcription Factor Transcription Factors Treatment Outcome United States Young Adult

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