Variation in the glucose transporter gene SLC2A2 is associated with glycemic 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 Zidzik; Albert M. Levin; L. Keoki Williams; Tanja Dujic; Sabina Semiz; Michiaki Kubo; Huan Chieh Chien; Shiro Maeda; John S. Witte; Longyang Wu; Ivan Tká; 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. Hart; Rury R. Holman; Mark I. McCarthy; Monique M. Hedderson; Colin N.A. Palmer; Jose C. Florez; Kathleen M. Giacomini; Ewan R. Pearson

doi:10.1038/ng.3632

Variation in the glucose transporter gene SLC2A2 is associated with glycemic 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 Zidzik
, Albert M. Levin
, L. Keoki Williams

Tanja Dujic, Sabina Semiz, Michiaki Kubo, Huan Chieh Chien, Shiro Maeda, John S. Witte, Longyang Wu, Ivan Tká, 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. Hart, Rury R. Holman, Mark I. McCarthy, Monique M. Hedderson, Colin N.A. Palmer, Jose C. Florez, Kathleen M. Giacomini, Ewan R. Pearson^*

^*Corresponding author for this work

University of Dundee
University of California at San Francisco
University of North Carolina at Chapel Hill
Leiden University
University of Oxford
VU University Medical Center Amsterdam
Utrecht University
Erasmus University Rotterdam
Latvian Biomedical Research and Study Centre
Latvian Genome Data Base (LGDB)
North Carolina State University
Treant Zorggroep
Bethesda Diabetes Research Centre
George Washington University
Massachusetts General Hospital
P. J. Safarik University
Henry Ford Health System
University of Sarajevo
International University of Sarajevo
RIKEN
University of the Ryukyus
Maastricht University
University of Latvia
Paula Stradina Clinical University Hospital
Inspectorate of Healthcare
Oxford University Hospitals NHS Foundation Trust
Kaiser Permanente
Broad Institute
Harvard University

Research output: Contribution to journal › Article › peer-review

197 Citations (Scopus)

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
DOIs	https://doi.org/10.1038/ng.3632
Publication status	Published - 1 Sept 2016
Externally published	Yes

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

SDG 3 Good Health and Well-being

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10.1038/ng.3632

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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., Zidzik, J., Levin, A. M., ... Pearson, E. R. (2016). Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nature Genetics, 48(9), 1055-1059. https://doi.org/10.1038/ng.3632

@article{16a7e3512b0d41f98e69c143c6f4bd27,

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.",

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 Zidzik and Levin, \{Albert M.\} and \{Keoki Williams\}, L. and Tanja Dujic and Sabina Semiz and Michiaki Kubo and Chien, \{Huan Chieh\} and Shiro Maeda and Witte, \{John S.\} and Longyang Wu and Ivan Tk{\'a} 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.\} 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.\}",

year = "2016",

month = sep,

day = "1",

doi = "10.1038/ng.3632",

language = "English",

volume = "48",

pages = "1055--1059",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

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, Zidzik, J, Levin, AM, Keoki Williams, L, Dujic, T, Semiz, S, Kubo, M, Chien, HC, Maeda, S, Witte, JS, Wu, L, Tká, 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 2016, 'Variation in the glucose transporter gene SLC2A2 is associated with glycemic 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 glycemic 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 - Zidzik, Jozef

AU - Levin, Albert M.

AU - Keoki Williams, L.

AU - Dujic, Tanja

AU - Semiz, Sabina

AU - Kubo, Michiaki

AU - Chien, Huan Chieh

AU - Maeda, Shiro

AU - Witte, John S.

AU - Wu, Longyang

AU - Tká, 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.

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.

PY - 2016/9/1

Y1 - 2016/9/1

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.

UR - https://www.scopus.com/pages/publications/84981287483

U2 - 10.1038/ng.3632

DO - 10.1038/ng.3632

M3 - Article

C2 - 27500523

AN - SCOPUS:84981287483

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 glycemic response to metformin

Abstract

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