Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin

TY - JOUR

T1 - Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin

AU - Zhou, Kaixin

AU - Yee, Sook Wah

AU - Seiser, Eric L

AU - van Leeuwen, Nienke

AU - Tavendale, Roger

AU - Bennett, Amanda J

AU - Groves, Christopher J

AU - Coleman, Ruth L

AU - van der Heijden, Amber A

AU - Beulens, Joline W

AU - de Keyser, Catherine E

AU - Zaharenko, Linda

AU - Rotroff, Daniel M

AU - Out, Mattijs

AU - Jablonski, Kathleen A

AU - Chen, Ling

AU - Javorský, Martin

AU - Židzik, Jozef

AU - Levin, Albert M

AU - Williams, L Keoki

AU - Dujic, Tanja

AU - Semiz, Sabina

AU - Kubo, Michiaki

AU - Chien, Huan-Chieh

AU - Maeda, Shiro

AU - Witte, John S

AU - Wu, Longyang

AU - Tkáč, Ivan

AU - Kooy, Adriaan

AU - van Schaik, Ron H N

AU - Stehouwer, Coen D A

AU - Logie, Lisa

AU - Sutherland, Calum

AU - Klovins, Janis

AU - Pirags, Valdis

AU - Hofman, Albert

AU - Stricker, Bruno H

AU - Motsinger-Reif, Alison A

AU - Wagner, Michael J

AU - Innocenti, Federico

AU - Hart, Leen M 't

AU - Holman, Rury R

AU - McCarthy, Mark I

AU - Hedderson, Monique M

AU - Palmer, Colin N A

AU - Florez, Jose C

AU - Giacomini, Kathleen M

AU - Pearson, Ewan R

AU - MetGen Investigators

PY - 2016/9

Y1 - 2016/9

N2 - 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.

AB - 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.

KW - Genetics research

KW - Genome-wide association studies

KW - Type 2 diabetes

U2 - 10.1038/ng.3632

DO - 10.1038/ng.3632

M3 - Letter

C2 - 27500523

SN - 1061-4036

VL - 48

SP - 1055

EP - 1059

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -