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

Kaixin Zhou; Sook Wah Yee; Eric L Seiser; Nienke van Leeuwen; Roger Tavendale; Amanda J Bennett; Christopher J Groves; Ruth L Coleman; Amber A van der Heijden; Joline W Beulens; Catherine E de Keyser; Linda Zaharenko; Daniel M Rotroff; Mattijs Out; Kathleen A Jablonski; Ling Chen; Martin Javorský; Jozef Židzik; Albert M Levin; L Keoki Williams; Tanja Dujic; Sabina Semiz; Michiaki Kubo; Huan-Chieh Chien; Shiro Maeda; John S Witte; Longyang Wu; Ivan Tkáč; Adriaan Kooy; Ron H N van Schaik; Coen D A Stehouwer; Lisa Logie; Calum Sutherland; Janis Klovins; Valdis Pirags; Albert Hofman; Bruno H Stricker; Alison A Motsinger-Reif; Michael J Wagner; Federico Innocenti; Leen M 't Hart; Rury R Holman; Mark I McCarthy; Monique M Hedderson; Colin N A Palmer; Jose C Florez; Kathleen M Giacomini; Ewan R Pearson; MetGen Investigators

doi:10.1038/ng.3632

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

Kaixin Zhou, Sook Wah Yee, Eric L Seiser, Nienke van Leeuwen, Roger Tavendale, Amanda J Bennett, Christopher J Groves, Ruth L Coleman, Amber A van der Heijden, Joline W Beulens, Catherine E de Keyser, Linda Zaharenko, Daniel M Rotroff, Mattijs Out, Kathleen A Jablonski, Ling Chen, Martin Javorský, Jozef Židzik, Albert M Levin, L Keoki WilliamsTanja Dujic, Sabina Semiz, Michiaki Kubo, Huan-Chieh Chien, Shiro Maeda, John S Witte, Longyang Wu, Ivan Tkáč, Adriaan Kooy, Ron H N van Schaik, Coen D A Stehouwer, Lisa Logie, Calum Sutherland, Janis Klovins, Valdis Pirags, Albert Hofman, Bruno H Stricker, Alison A Motsinger-Reif, Michael J Wagner, Federico Innocenti, Leen M 't Hart, Rury R Holman, Mark I McCarthy, Monique M Hedderson, Colin N A Palmer, Jose C Florez, Kathleen M Giacomini (Lead / Corresponding author), Ewan R Pearson (Lead / Corresponding author), MetGen Investigators

Postgraduate Medicine

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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.

Original language	English
Pages (from-to)	1055-1059
Number of pages	5
Journal	Nature Genetics
Volume	48
Issue number	9
Early online date	8 Aug 2016
DOIs	https://doi.org/10.1038/ng.3632
Publication status	Published - Sept 2016

Keywords

Genetics research
Genome-wide association studies
Type 2 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ng.3632

Author Accepted ManuscriptAccepted author manuscript, 985 KBLicence: Other
Author Accepted Manuscript - Supplementary MaterialAccepted author manuscript, 283 KBLicence: Other

Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)
Pearson, E. (Investigator)
16/02/15 → 15/08/21
Project: Research
Heritability and Pharmacogenetics in Patients with Type 2 Diabetes (Sir Henry Wellcome Postdoctoral Fellowship: Mr K Zhou)
Palmer, C. (Investigator), Pearson, E. (Investigator) & Zhou, K. (Investigator)
1/08/10 → 31/07/14
Project: Research

Combined GWAS of metaformin glycaemic reponse in 1372 GoDARTS patients
Zhou, K. (Creator), Pearson, E. (Contributor) & Palmer, C. (Contributor), University of Dundee, 7 Oct 2016
DOI: 10.15132/10000119, https://www.ebi.ac.uk/ega/datasets/EGAD00001002277
Dataset

File

Pearson, Ewan
- Diabetes Endocrinology and Reproductive Biology - Clinical Professor (Teaching and Research) of Diabetic Medicine
Person: Academic
Sutherland, Calum
- Diabetes Endocrinology and Reproductive Biology - Professor (Teaching and Research) of Molecular and Cellular Diabetes
Person: Academic

Cite this

Zhou, K., Yee, S. W., Seiser, E. L., van Leeuwen, N., Tavendale, R., Bennett, A. J., Groves, C. J., Coleman, R. L., van der Heijden, A. A., Beulens, J. W., de Keyser, C. E., Zaharenko, L., Rotroff, D. M., Out, M., Jablonski, K. A., Chen, L., Javorský, M., Židzik, J., Levin, A. M., ... MetGen Investigators (2016). Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin. Nature Genetics, 48(9), 1055-1059. https://doi.org/10.1038/ng.3632

@article{94d0dfd42d484e7496b6c2225fe83b47,

title = "Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic 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.",

keywords = "Genetics research, Genome-wide association studies, Type 2 diabetes",

author = "Kaixin Zhou and Yee, {Sook Wah} and Seiser, {Eric L} and {van Leeuwen}, Nienke and Roger Tavendale and Bennett, {Amanda J} and Groves, {Christopher J} and Coleman, {Ruth L} and {van der Heijden}, {Amber A} and Beulens, {Joline W} and {de Keyser}, {Catherine E} and Linda Zaharenko and Rotroff, {Daniel M} and Mattijs Out and Jablonski, {Kathleen A} and Ling Chen and Martin Javorsk{\'y} and Jozef {\v Z}idzik and Levin, {Albert M} and Williams, {L Keoki} and Tanja Dujic and Sabina Semiz and Michiaki Kubo and Huan-Chieh Chien and Shiro Maeda and Witte, {John S} and Longyang Wu and Ivan Tk{\'a}{\v c} and Adriaan Kooy and {van Schaik}, {Ron H N} and Stehouwer, {Coen D A} and Lisa Logie and Calum Sutherland and Janis Klovins and Valdis Pirags and Albert Hofman and Stricker, {Bruno H} and Motsinger-Reif, {Alison A} and Wagner, {Michael J} and Federico Innocenti and Hart, {Leen M 't} and Holman, {Rury R} and McCarthy, {Mark I} and Hedderson, {Monique M} and Palmer, {Colin N A} and Florez, {Jose C} and Giacomini, {Kathleen M} and Pearson, {Ewan R} and {MetGen Investigators}",

year = "2016",

month = sep,

doi = "10.1038/ng.3632",

language = "English",

volume = "48",

pages = "1055--1059",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

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Zhou, K, Yee, SW, Seiser, EL, van Leeuwen, N, Tavendale, R, Bennett, AJ, Groves, CJ, Coleman, RL, van der Heijden, AA, Beulens, JW, de Keyser, CE, Zaharenko, L, Rotroff, DM, Out, M, Jablonski, KA, Chen, L, Javorský, M, Židzik, J, Levin, AM, Williams, LK, Dujic, T, Semiz, S, Kubo, M, Chien, H-C, Maeda, S, Witte, JS, Wu, L, Tkáč, I, Kooy, A, van Schaik, RHN, Stehouwer, CDA, Logie, L, Sutherland, C, Klovins, J, Pirags, V, Hofman, A, Stricker, BH, Motsinger-Reif, AA, Wagner, MJ, Innocenti, F, Hart, LM, Holman, RR, McCarthy, MI, Hedderson, MM, Palmer, CNA, Florez, JC, Giacomini, KM, Pearson, ER & MetGen Investigators 2016, 'Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin', Nature Genetics, vol. 48, no. 9, pp. 1055-1059. https://doi.org/10.1038/ng.3632

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 -

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Projects

Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)

Heritability and Pharmacogenetics in Patients with Type 2 Diabetes (Sir Henry Wellcome Postdoctoral Fellowship: Mr K Zhou)

Datasets

Combined GWAS of metaformin glycaemic reponse in 1372 GoDARTS patients

Profiles

Pearson, Ewan

Sutherland, Calum

Cite this