Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin.
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.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
S
S
Goswami
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
S W
SW
Yee
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
S
S
Stocker
Department of Pharmacology and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
J D
JD
Mosley
Center of Genomic Medicine, RIKEN, Yokohama City, Japan.
M
M
Kubo
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
R
R
Castro
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
J A
JA
Mefford
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
C
C
Wen
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
X
X
Liang
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
J
J
Witte
Department of Anesthesiology, University of California, San Francisco, San Francisco, California, USA.
C
C
Brett
Center of Genomic Medicine, RIKEN, Yokohama City, Japan.
S
S
Maeda
Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
M D
MD
Simpson
Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
M M
MM
Hedderson
Center for Health Research Southeast, Kaiser Permanente Georgia, Atlanta, Georgia, USA.
R L
RL
Davis
Department of Pharmacology and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
D M
DM
Roden
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
K M
KM
Giacomini
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
R M
RM
Savic
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006442:Glycated Hemoglobin / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D047493:PPAR alpha / Q000235:genetics; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D016329:Sp1 Transcription Factor / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
D015415:Biomarkers; D006442:Glycated Hemoglobin; D051557:Hepatocyte Nuclear Factor 4; D007004:Hypoglycemic Agents; D008687:Metformin; D047493:PPAR alpha; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C496592:HNF4A protein, human; C517652:hemoglobin A1c protein, human