University of Dundee Variation in the Glucose Transporter gene SLC 2 A 2 is associated with glycaemic response to metformin
67 68 Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its 69 mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium 70 reports a three-stage genome wide association study (GWAS), consisting of 13,123 participants of 71 different ancestries. The C-allele of rs8192675 in the intron of SLC2A2, which encodes the 72 facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6x10) greater 73 metformin induced HbA1c reduction in 10,577 participants of European ancestry. rs8192675 is the 74 top cis-eQTL for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in 75 regulation of metformin action. In obese individuals C-allele homozygotes at rs8192675 had a 0.33% 76 (3.6mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes.This is about half the 77 effect seen with the addition of a DPP-4 inhibitor, and equates to a dose difference of 550mg of 78 metformin, suggesting rs8192675 as a potential biomarker for stratified medicine. 79