Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin
Zhou K, Yee S, 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, Williams KL, Dujic T, Semiz S, Kubo M, Chien H, Maeda S, Witte JS, Wu L, Tkáč I, Kooy A, van Schaik RH, Stehouwer CD, Logie L, Sutherland C, Klovins J, Pirags V, Hofman A, Stricker B, Motsinger-Reif A, Wagner M, Innocenti F, 't Hart L, Holman R, McCarthy M, Hedderson M, Palmer C, Florez J, Giacomini K, Pearson E. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nature Genetics 2016; 48(9):1055-1059.
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.
Medical Subject Headings
Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Genome-Wide Association Study; Glucose Transporter Type 2; Glycated Hemoglobin A; Humans; Hypoglycemic Agents; Metformin; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable