Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

Kaixin Zhou, Sook Wah Yee, Eric L. Seiser, Nienke Van Leeuwen, Roger Tavendale, Amanda J. Bennett, Christopher J. Groves, Ruth L. Coleman, Amber A. Van Der Heijden, Joline W. Beulens, Catherine E. De Keyser, Linda Zaharenko, Daniel M. Rotroff, Mattijs Out, Kathleen A. Jablonski, Ling Chen, Martin Javorský, Jozef Zidzik, Albert M. Levin, L. Keoki WilliamsTanja Dujic, Sabina Semiz, Michiaki Kubo, Huan Chieh Chien, Shiro Maeda, John S. Witte, Longyang Wu, Ivan Tká, Adriaan Kooy, Ron H.N. Van Schaik, Coen D.A. Stehouwer, Lisa Logie, Calum Sutherland, Janis Klovins, Valdis Pirags, Albert Hofman, Bruno H. Stricker, Alison A. Motsinger-Reif, Michael J. Wagner, Federico Innocenti, Leen M. Hart, Rury R. Holman, Mark I. McCarthy, Monique M. Hedderson, Colin N.A. Palmer, Jose C. Florez, Kathleen M. Giacomini, Ewan R. Pearson

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10-14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Original languageEnglish
Pages (from-to)1055-1059
Number of pages5
JournalNature Genetics
Volume48
Issue number9
DOIs
Publication statusPublished - 01-09-2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics

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    Zhou, K., Yee, S. W., Seiser, E. L., Van Leeuwen, N., Tavendale, R., Bennett, A. J., Groves, C. J., Coleman, R. L., Van Der Heijden, A. A., Beulens, J. W., De Keyser, C. E., Zaharenko, L., Rotroff, D. M., Out, M., Jablonski, K. A., Chen, L., Javorský, M., Zidzik, J., Levin, A. M., ... Pearson, E. R. (2016). Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nature Genetics, 48(9), 1055-1059. https://doi.org/10.1038/ng.3632