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

TitleVariation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.
Publication TypeJournal Article
Year of Publication2016
AuthorsZhou, K, Yee, SWah, Seiser, EL, van Leeuwen, N, Tavendale, R, Bennett, AJ, Groves, CJ, Coleman, RL, van der Heijden, AA, Beulens, JW, de Keyser, CE, Zaharenko, L, Rotroff, DM, Out, M, Jablonski, KA, Chen, L, Javorský, M, Židzik, J, Levin, AM, L Williams, K, Dujić, T, Semiz, S, Kubo, M, Chien, H-C, Maeda, S, Witte, JS, Wu, L, Tkáč, I, Kooy, A, van Schaik, RHN, Stehouwer, CDA, Logie, L, Sutherland, C, Klovins, J, Pirags, V, Hofman, A, Stricker, BH, Motsinger-Reif, AA, Wagner, MJ, Innocenti, F, Hart, LM 't, Holman, RR, McCarthy, MI, Hedderson, MM, Palmer, CNA, Florez, JC, Giacomini, KM, Pearson, ER
Corporate AuthorsMetGen Investigators, DPP Investigators, ACCORD Investigators
JournalNat Genet
Volume48
Issue9
Pagination1055-9
Date Published2016 Sep
ISSN Number1546-1718
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.

DOI10.1038/ng.3632
Alternate JournalNat. Genet.