Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic 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 Židzik, Albert M Levin, L Keoki WilliamsTanja Dujic, Sabina Semiz, Michiaki Kubo, Huan-Chieh Chien, Shiro Maeda, John S Witte, Longyang Wu, Ivan Tkáč, 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 't Hart, Rury R Holman, Mark I McCarthy, Monique M Hedderson, Colin N A Palmer, Jose C Florez, Kathleen M Giacomini, Ewan R Pearson, MetGen Investigators

Research output: Contribution to journalLetter

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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
Early online date8 Aug 2016
DOIs
Publication statusPublished - Sep 2016

Keywords

  • Genetics research
  • Genome-wide association studies
  • Type 2 diabetes

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