title: 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.
authors: School of Medicine, University of Dundee, Dundee, UK.
authors: Kaixin
authors: K
authors: Zhou
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors: Sook Wah
authors: SW
authors: Yee
authors: Division of Pharmacotherapy and Experimental Therapeutics, Center for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors: Eric L
authors: EL
authors: Seiser
authors: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Nienke
authors: N
authors: van Leeuwen
authors: School of Medicine, University of Dundee, Dundee, UK.
authors: Roger
authors: R
authors: Tavendale
authors: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors: Amanda J
authors: AJ
authors: Bennett
authors: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors: Christopher J
authors: CJ
authors: Groves
authors: Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors: Ruth L
authors: RL
authors: Coleman
authors: Department of General Practice, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
authors: Amber A
authors: AA
authors: van der Heijden
authors: Department of Epidemiology and Biostatistics, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Joline W
authors: JW
authors: Beulens
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors: Catherine E
authors: CE
authors: de Keyser
authors: Latvian Genome Data Base (LGDB), Riga, Latvia.|Latvian Biomedical Research and Study Centre, Riga, Latvia.
authors: Linda
authors: L
authors: Zaharenko
authors: Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.|Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA.
authors: Daniel M
authors: DM
authors: Rotroff
authors: Treant Zorggroep, Location Bethesda, Hoogeveen, the Netherlands.|Bethesda Diabetes Research Centre, Hoogeveen, the Netherlands.
authors: Mattijs
authors: M
authors: Out
authors: Biostatistics Center, George Washington University, Rockville, Maryland, USA.
authors: Kathleen A
authors: KA
authors: Jablonski
authors: Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Ling
authors: L
authors: Chen
authors: Faculty of Medicine, Šafárik University, Košice, Slovakia.
authors: Martin
authors: M
authors: Javorský
authors: Faculty of Medicine, Šafárik University, Košice, Slovakia.
authors: Jozef
authors: J
authors: Židzik
authors: Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, USA.
authors: Albert M
authors: AM
authors: Levin
authors: Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan, USA.|Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan, USA.
authors: L Keoki
authors: LK
authors: Williams
authors: School of Medicine, University of Dundee, Dundee, UK.|Faculty of Pharmacy, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors: Tanja
authors: T
authors: Dujic
authors: Faculty of Pharmacy, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.|Faculty of Engineering and Natural Sciences, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors: Sabina
authors: S
authors: Semiz
authors: RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan.
authors: Michiaki
authors: M
authors: Kubo
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors: Huan-Chieh
authors: HC
authors: Chien
authors: Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.|Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan.
authors: Shiro
authors: S
authors: Maeda
authors: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.|Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.|Department of Urology, University of California, San Francisco, San Francisco, California, USA.|UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors: John S
authors: JS
authors: Witte
authors: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
authors: Longyang
authors: L
authors: Wu
authors: Faculty of Medicine, Šafárik University, Košice, Slovakia.
authors: Ivan
authors: I
authors: Tkáč
authors: Treant Zorggroep, Location Bethesda, Hoogeveen, the Netherlands.|Bethesda Diabetes Research Centre, Hoogeveen, the Netherlands.
authors: Adriaan
authors: A
authors: Kooy
authors: Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Ron H N
authors: RHN
authors: van Schaik
authors: Department of Internal Medicine and Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands.
authors: Coen D A
authors: CDA
authors: Stehouwer
authors: School of Medicine, University of Dundee, Dundee, UK.
authors: Lisa
authors: L
authors: Logie
authors: School of Medicine, University of Dundee, Dundee, UK.
authors: Calum
authors: C
authors: Sutherland
authors: Latvian Genome Data Base (LGDB), Riga, Latvia.|Latvian Biomedical Research and Study Centre, Riga, Latvia.
authors: Janis
authors: J
authors: Klovins
authors: Latvian Biomedical Research and Study Centre, Riga, Latvia.|Faculty of Medicine, University of Latvia, Riga, Latvia.|Department of Endocrinology, Pauls Stradins Clinical University Hospital, Riga, Latvia.
authors: Valdis
authors: V
authors: Pirags
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Inspectorate of Healthcare, Heerlen, the Netherlands.
authors: Bruno H
authors: BH
authors: Stricker
authors: Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.
authors: Alison A
authors: AA
authors: Motsinger-Reif
authors: Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Michael J
authors: MJ
authors: Wagner
authors: Division of Pharmacotherapy and Experimental Therapeutics, Center for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors: Federico
authors: F
authors: Innocenti
authors: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.|Department of Epidemiology and Biostatistics, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.|Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Leen M
authors: LM
authors: 't Hart
authors: Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors: Rury R
authors: RR
authors: Holman
authors: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
authors: Mark I
authors: MI
authors: McCarthy
authors: Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
authors: Monique M
authors: MM
authors: Hedderson
authors: School of Medicine, University of Dundee, Dundee, UK.
authors: Colin N A
authors: CNA
authors: Palmer
authors: Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Metabolism, Broad Institute, Cambridge, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors: Jose C
authors: JC
authors: Florez
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.|Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.
authors: Kathleen M
authors: KM
authors: Giacomini
authors: School of Medicine, University of Dundee, Dundee, UK.
authors: Ewan R
authors: ER
authors: Pearson
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics*; D055106:Genome-Wide Association Study; D051273:Glucose Transporter Type 2 / Q000235:genetics*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D044465:White People
chemical_list: D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; C495680:SLC2A2 protein, human; C517652:hemoglobin A1c protein, human