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Nat Genet. 2016 Sep;48(9):1055-1059. doi: 10.1038/ng.3632. Epub 2016 Aug 8.

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

Author information

1
School of Medicine, University of Dundee, Dundee, UK.
2
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
3
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.
4
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
5
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
6
Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
7
Department of General Practice, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
8
Department of Epidemiology and Biostatistics, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
9
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
10
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
11
Latvian Genome Data Base (LGDB), Riga, Latvia.
12
Latvian Biomedical Research and Study Centre, Riga, Latvia.
13
Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.
14
Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA.
15
Treant Zorggroep, Location Bethesda, Hoogeveen, the Netherlands.
16
Bethesda Diabetes Research Centre, Hoogeveen, the Netherlands.
17
Biostatistics Center, George Washington University, Rockville, Maryland, USA.
18
Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
19
Faculty of Medicine, Šafárik University, Košice, Slovakia.
20
Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, USA.
21
Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan, USA.
22
Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan, USA.
23
Faculty of Pharmacy, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
24
Faculty of Engineering and Natural Sciences, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
25
RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan.
26
Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
27
Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan.
28
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
29
Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.
30
Department of Urology, University of California, San Francisco, San Francisco, California, USA.
31
UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
32
Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands.
33
Department of Internal Medicine and Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands.
34
Faculty of Medicine, University of Latvia, Riga, Latvia.
35
Department of Endocrinology, Pauls Stradins Clinical University Hospital, Riga, Latvia.
36
Inspectorate of Healthcare, Heerlen, the Netherlands.
37
Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
38
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
39
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
40
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
41
Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
42
Program in Metabolism, Broad Institute, Cambridge, Massachusetts, USA.
43
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
44
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
#
Contributed equally

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.

PMID:
27500523
PMCID:
PMC5007158
DOI:
10.1038/ng.3632
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors have declared that no competing interests exist.

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