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


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.

SUBMITTER: Zhou K 

PROVIDER: S-EPMC5007158 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Zhou Kaixin K   Yee Sook Wah SW   Seiser Eric L EL   van Leeuwen Nienke N   Tavendale Roger R   Bennett Amanda J AJ   Groves Christopher J CJ   Coleman Ruth L RL   van der Heijden Amber A AA   Beulens Joline W JW   de Keyser Catherine E CE   Zaharenko Linda L   Rotroff Daniel M DM   Out Mattijs M   Jablonski Kathleen A KA   Chen Ling L   Javorský Martin M   Židzik Jozef J   Levin Albert M AM   Williams L Keoki LK   Dujic Tanja T   Semiz Sabina S   Kubo Michiaki M   Chien Huan-Chieh HC   Maeda Shiro S   Witte John S JS   Wu Longyang L   Tkáč Ivan I   Kooy Adriaan A   van Schaik Ron H N RHN   Stehouwer Coen D A CDA   Logie Lisa L   Logie Lisa L   Sutherland Calum C   Klovins Janis J   Pirags Valdis V   Hofman Albert A   Stricker Bruno H BH   Motsinger-Reif Alison A AA   Wagner Michael J MJ   Innocenti Federico F   't Hart Leen M LM   Holman Rury R RR   McCarthy Mark I MI   Hedderson Monique M MM   Palmer Colin N A CNA   Florez Jose C JC   Giacomini Kathleen M KM   Pearson Ewan R ER  

Nature genetics 20160808 9


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 hemoglob  ...[more]

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