Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.
Zhou K., Yee SW., 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 LK., Dujic T., Semiz S., Kubo M., Chien HC., Maeda S., Witte JS., Wu L., Tkáč I., Kooy A., van Schaik RHN., Stehouwer CDA., Logie L., MetGen Investigators None., DPP Investigators None., ACCORD Investigators None., Sutherland C., Klovins J., Pirags V., Hofman A., Stricker BH., Motsinger-Reif AA., Wagner MJ., Innocenti F., 't Hart LM., Holman RR., McCarthy MI., Hedderson MM., Palmer CNA., Florez JC., Giacomini KM., Pearson ER.
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.