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

• Published in: Nature genetics Vol. 48; no. 9; pp. 1055 - 1059
• Main Authors: Zhou, Kaixin, Yee, Sook Wah, Seiser, Eric L, van Leeuwen, Nienke, Tavendale, Roger, Bennett, Amanda J, Groves, Christopher J, Coleman, Ruth L, van der Heijden, Amber A, Beulens, Joline W, de Keyser, Catherine E, Zaharenko, Linda, Rotroff, Daniel M, Out, Mattijs, Jablonski, Kathleen A, Chen, Ling, Javorský, Martin, Židzik, Jozef, Levin, Albert M, Williams, L Keoki, Dujic, Tanja, Semiz, Sabina, Kubo, Michiaki, Chien, Huan-Chieh, Maeda, Shiro, Witte, John S, Wu, Longyang, Tkáč, Ivan, Kooy, Adriaan, van Schaik, Ron H N, Stehouwer, Coen D A, Logie, Lisa, Sutherland, Calum, Klovins, Janis, Pirags, Valdis, Hofman, Albert, Stricker, Bruno H, Motsinger-Reif, Alison A, Wagner, Michael J, Innocenti, Federico, 't Hart, Leen M, Holman, Rury R, McCarthy, Mark I, Hedderson, Monique M, Palmer, Colin N A, Florez, Jose C, Giacomini, Kathleen M, Pearson, Ewan R
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.09.2016
• Subjects: Blood Glucose - analysis; Body Mass Index; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Drug metabolism; Genealogy; Genes; Genetic aspects; Genetic variation; Genome-Wide Association Study; Genomes; Glucose Transporter Type 2 - genetics; Glycated Hemoglobin A - analysis; Humans; Hypoglycemic Agents - therapeutic use; Identification and classification; Meta-analysis; Metformin; Metformin - therapeutic use; Minority & ethnic groups; Patient outcomes; Polymorphism, Single Nucleotide - genetics; Properties; Quantitative Trait, Heritable; Transport proteins; Whites
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3632

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.