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 & 29 others 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

Research output: Contribution to journalLetter

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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 languageEnglish
Pages (from-to)1055-1059
Number of pages5
JournalNature Genetics
Volume48
Issue number9
Early online date8 Aug 2016
DOIs
Publication statusPublished - Sep 2016

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Facilitative Glucose Transport Proteins
Metformin
Genes
Alleles
Homozygote
Hemoglobins
Quantitative Trait Loci
Genome-Wide Association Study
Liver
Hypoglycemic Agents
Introns
Biomarkers
Medicine

Keywords

  • Genetics research
  • Genome-wide association studies
  • Type 2 diabetes

Cite this

Zhou, K., Yee, S. W., Seiser, E. L., van Leeuwen, N., Tavendale, R., Bennett, A. J., ... 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
Zhou, Kaixin ; Yee, Sook Wah ; Seiser, Eric L ; van Leeuwen, Nienke ; Tavendale, Roger ; Bennett, Amanda J ; Groves, Christopher J ; Coleman, Ruth L ; van der Heijden, Amber A ; Beulens, Joline W ; de Keyser, Catherine E ; Zaharenko, Linda ; Rotroff, Daniel M ; Out, Mattijs ; Jablonski, Kathleen A ; Chen, Ling ; Javorský, Martin ; Židzik, Jozef ; Levin, Albert M ; Williams, L Keoki ; Dujic, Tanja ; Semiz, Sabina ; Kubo, Michiaki ; Chien, Huan-Chieh ; Maeda, Shiro ; Witte, John S ; Wu, Longyang ; Tkáč, Ivan ; Kooy, Adriaan ; van Schaik, Ron H N ; Stehouwer, Coen D A ; Logie, Lisa ; Sutherland, Calum ; Klovins, Janis ; Pirags, Valdis ; Hofman, Albert ; Stricker, Bruno H ; Motsinger-Reif, Alison A ; Wagner, Michael J ; Innocenti, Federico ; Hart, Leen M 't ; Holman, Rury R ; McCarthy, Mark I ; Hedderson, Monique M ; Palmer, Colin N A ; Florez, Jose C ; Giacomini, Kathleen M ; Pearson, Ewan R ; MetGen Investigators. / Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin. In: Nature Genetics. 2016 ; Vol. 48, No. 9. pp. 1055-1059.
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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

Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin. / Zhou, Kaixin; Yee, Sook Wah; Seiser, Eric L; van Leeuwen, Nienke; Tavendale, Roger; Bennett, Amanda J; Groves, Christopher J; Coleman, Ruth L; van der Heijden, Amber A; Beulens, Joline W; de Keyser, Catherine E; Zaharenko, Linda; Rotroff, Daniel M; Out, Mattijs; Jablonski, Kathleen A; Chen, Ling; Javorský, Martin; Židzik, Jozef; Levin, Albert M; Williams, L Keoki; Dujic, Tanja; Semiz, Sabina; Kubo, Michiaki; Chien, Huan-Chieh; Maeda, Shiro; Witte, John S; Wu, Longyang; Tkáč, Ivan; Kooy, Adriaan; van Schaik, Ron H N; Stehouwer, Coen D A; Logie, Lisa; Sutherland, Calum; Klovins, Janis; Pirags, Valdis; Hofman, Albert; Stricker, Bruno H; Motsinger-Reif, Alison A; Wagner, Michael J; Innocenti, Federico; Hart, Leen M 't; Holman, Rury R; McCarthy, Mark I; Hedderson, Monique M; Palmer, Colin N A; Florez, Jose C; Giacomini, Kathleen M (Lead / Corresponding author); Pearson, Ewan R (Lead / Corresponding author); MetGen Investigators.

In: Nature Genetics, Vol. 48, No. 9, 09.2016, p. 1055-1059.

Research output: Contribution to journalLetter

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

VL - 48

SP - 1055

EP - 1059

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 9

ER -