Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Kaixin Zhou, Celine Bellenguez, Chris C. A. Spencer, Amanda J. Bennett, Ruth L. Coleman, Roger Tavendale, Simon A. Hawley, Louise A. Donnelly, Chris Schofield, Christopher J. Groves, Lindsay Burch, Fiona Carr, Amy Strange, Colin Freeman, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Aiden Corvin, Nicholas CraddockPanos Deloukas, Serge Dronov, Audrey Duncanson, Sarah Edkins, Emma Gray, Sarah Hunt, Janusz Jankowski, Cordelia Langford, Hugh S. Markus, Christopher G. Mathew, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Nilesh J. Samani, Richard Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Lorna W. Harries, Andrew T. Hattersley, Alex S.F. Doney, Helen Colhoun, Andrew D. Morris, Calum Sutherland, D. Grahame Hardie, Leena Peltonen, Mark I. McCarthy, Rury R. Holman, Colin N. A. Palmer, Peter Donnelly, Ewan R. Pearson, Wellcome Trust Case Control Consor, GoDARTS UKPDS Diabet Pharmacogenet, MAGIC Investigators

    Research output: Contribution to journalLetter

    284 Citations (Scopus)

    Abstract

    Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 x 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

    Original languageEnglish
    Pages (from-to)117-120
    Number of pages4
    JournalNature Genetics
    Volume43
    Issue number2
    DOIs
    Publication statusPublished - Feb 2011

    Keywords

    • ACTIVATED PROTEIN-KINASE
    • GENOME-WIDE ASSOCIATION
    • ATAXIA-TELANGIECTASIA
    • CANCER
    • CELLS
    • RISK
    • AMPK
    • IDENTIFICATION
    • HOMEOSTASIS
    • REDUCTASE

    Cite this

    Zhou, K., Bellenguez, C., Spencer, C. C. A., Bennett, A. J., Coleman, R. L., Tavendale, R., ... Wellcome Trust Case Control Consor, GoDARTS UKPDS Diabet Pharmacogenet, MAGIC Investigators (2011). Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature Genetics, 43(2), 117-120. https://doi.org/10.1038/ng.735
    Zhou, Kaixin ; Bellenguez, Celine ; Spencer, Chris C. A. ; Bennett, Amanda J. ; Coleman, Ruth L. ; Tavendale, Roger ; Hawley, Simon A. ; Donnelly, Louise A. ; Schofield, Chris ; Groves, Christopher J. ; Burch, Lindsay ; Carr, Fiona ; Strange, Amy ; Freeman, Colin ; Blackwell, Jenefer M. ; Bramon, Elvira ; Brown, Matthew A. ; Casas, Juan P. ; Corvin, Aiden ; Craddock, Nicholas ; Deloukas, Panos ; Dronov, Serge ; Duncanson, Audrey ; Edkins, Sarah ; Gray, Emma ; Hunt, Sarah ; Jankowski, Janusz ; Langford, Cordelia ; Markus, Hugh S. ; Mathew, Christopher G. ; Plomin, Robert ; Rautanen, Anna ; Sawcer, Stephen J. ; Samani, Nilesh J. ; Trembath, Richard ; Viswanathan, Ananth C. ; Wood, Nicholas W. ; Harries, Lorna W. ; Hattersley, Andrew T. ; Doney, Alex S.F. ; Colhoun, Helen ; Morris, Andrew D. ; Sutherland, Calum ; Hardie, D. Grahame ; Peltonen, Leena ; McCarthy, Mark I. ; Holman, Rury R. ; Palmer, Colin N. A. ; Donnelly, Peter ; Pearson, Ewan R. ; Wellcome Trust Case Control Consor, GoDARTS UKPDS Diabet Pharmacogenet, MAGIC Investigators. / Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. In: Nature Genetics. 2011 ; Vol. 43, No. 2. pp. 117-120.
    @article{8789ae1c827b4da69c722c0d06634d2f,
    title = "Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes",
    abstract = "Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 x 10(-9), odds ratio = 1.35, 95{\%} CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.",
    keywords = "ACTIVATED PROTEIN-KINASE, GENOME-WIDE ASSOCIATION, ATAXIA-TELANGIECTASIA, CANCER, CELLS, RISK, AMPK, IDENTIFICATION, HOMEOSTASIS, REDUCTASE",
    author = "Kaixin Zhou and Celine Bellenguez and Spencer, {Chris C. A.} and Bennett, {Amanda J.} and Coleman, {Ruth L.} and Roger Tavendale and Hawley, {Simon A.} and Donnelly, {Louise A.} and Chris Schofield and Groves, {Christopher J.} and Lindsay Burch and Fiona Carr and Amy Strange and Colin Freeman and Blackwell, {Jenefer M.} and Elvira Bramon and Brown, {Matthew A.} and Casas, {Juan P.} and Aiden Corvin and Nicholas Craddock and Panos Deloukas and Serge Dronov and Audrey Duncanson and Sarah Edkins and Emma Gray and Sarah Hunt and Janusz Jankowski and Cordelia Langford and Markus, {Hugh S.} and Mathew, {Christopher G.} and Robert Plomin and Anna Rautanen and Sawcer, {Stephen J.} and Samani, {Nilesh J.} and Richard Trembath and Viswanathan, {Ananth C.} and Wood, {Nicholas W.} and Harries, {Lorna W.} and Hattersley, {Andrew T.} and Doney, {Alex S.F.} and Helen Colhoun and Morris, {Andrew D.} and Calum Sutherland and Hardie, {D. Grahame} and Leena Peltonen and McCarthy, {Mark I.} and Holman, {Rury R.} and Palmer, {Colin N. A.} and Peter Donnelly and Pearson, {Ewan R.} and {Wellcome Trust Case Control Consor, GoDARTS UKPDS Diabet Pharmacogenet, MAGIC Investigators}",
    year = "2011",
    month = "2",
    doi = "10.1038/ng.735",
    language = "English",
    volume = "43",
    pages = "117--120",
    journal = "Nature Genetics",
    issn = "1061-4036",
    publisher = "Nature Publishing Group",
    number = "2",

    }

    Zhou, K, Bellenguez, C, Spencer, CCA, Bennett, AJ, Coleman, RL, Tavendale, R, Hawley, SA, Donnelly, LA, Schofield, C, Groves, CJ, Burch, L, Carr, F, Strange, A, Freeman, C, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Craddock, N, Deloukas, P, Dronov, S, Duncanson, A, Edkins, S, Gray, E, Hunt, S, Jankowski, J, Langford, C, Markus, HS, Mathew, CG, Plomin, R, Rautanen, A, Sawcer, SJ, Samani, NJ, Trembath, R, Viswanathan, AC, Wood, NW, Harries, LW, Hattersley, AT, Doney, ASF, Colhoun, H, Morris, AD, Sutherland, C, Hardie, DG, Peltonen, L, McCarthy, MI, Holman, RR, Palmer, CNA, Donnelly, P, Pearson, ER & Wellcome Trust Case Control Consor, GoDARTS UKPDS Diabet Pharmacogenet, MAGIC Investigators 2011, 'Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes', Nature Genetics, vol. 43, no. 2, pp. 117-120. https://doi.org/10.1038/ng.735

    Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. / Zhou, Kaixin; Bellenguez, Celine; Spencer, Chris C. A.; Bennett, Amanda J.; Coleman, Ruth L.; Tavendale, Roger; Hawley, Simon A.; Donnelly, Louise A.; Schofield, Chris; Groves, Christopher J.; Burch, Lindsay; Carr, Fiona; Strange, Amy; Freeman, Colin; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Craddock, Nicholas; Deloukas, Panos; Dronov, Serge; Duncanson, Audrey; Edkins, Sarah; Gray, Emma; Hunt, Sarah; Jankowski, Janusz; Langford, Cordelia; Markus, Hugh S.; Mathew, Christopher G.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Samani, Nilesh J.; Trembath, Richard; Viswanathan, Ananth C.; Wood, Nicholas W.; Harries, Lorna W.; Hattersley, Andrew T.; Doney, Alex S.F.; Colhoun, Helen; Morris, Andrew D.; Sutherland, Calum; Hardie, D. Grahame; Peltonen, Leena; McCarthy, Mark I.; Holman, Rury R.; Palmer, Colin N. A.; Donnelly, Peter; Pearson, Ewan R. (Lead / Corresponding author); Wellcome Trust Case Control Consor, GoDARTS UKPDS Diabet Pharmacogenet, MAGIC Investigators.

    In: Nature Genetics, Vol. 43, No. 2, 02.2011, p. 117-120.

    Research output: Contribution to journalLetter

    TY - JOUR

    T1 - Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

    AU - Zhou, Kaixin

    AU - Bellenguez, Celine

    AU - Spencer, Chris C. A.

    AU - Bennett, Amanda J.

    AU - Coleman, Ruth L.

    AU - Tavendale, Roger

    AU - Hawley, Simon A.

    AU - Donnelly, Louise A.

    AU - Schofield, Chris

    AU - Groves, Christopher J.

    AU - Burch, Lindsay

    AU - Carr, Fiona

    AU - Strange, Amy

    AU - Freeman, Colin

    AU - Blackwell, Jenefer M.

    AU - Bramon, Elvira

    AU - Brown, Matthew A.

    AU - Casas, Juan P.

    AU - Corvin, Aiden

    AU - Craddock, Nicholas

    AU - Deloukas, Panos

    AU - Dronov, Serge

    AU - Duncanson, Audrey

    AU - Edkins, Sarah

    AU - Gray, Emma

    AU - Hunt, Sarah

    AU - Jankowski, Janusz

    AU - Langford, Cordelia

    AU - Markus, Hugh S.

    AU - Mathew, Christopher G.

    AU - Plomin, Robert

    AU - Rautanen, Anna

    AU - Sawcer, Stephen J.

    AU - Samani, Nilesh J.

    AU - Trembath, Richard

    AU - Viswanathan, Ananth C.

    AU - Wood, Nicholas W.

    AU - Harries, Lorna W.

    AU - Hattersley, Andrew T.

    AU - Doney, Alex S.F.

    AU - Colhoun, Helen

    AU - Morris, Andrew D.

    AU - Sutherland, Calum

    AU - Hardie, D. Grahame

    AU - Peltonen, Leena

    AU - McCarthy, Mark I.

    AU - Holman, Rury R.

    AU - Palmer, Colin N. A.

    AU - Donnelly, Peter

    AU - Pearson, Ewan R.

    AU - Wellcome Trust Case Control Consor, GoDARTS UKPDS Diabet Pharmacogenet, MAGIC Investigators

    PY - 2011/2

    Y1 - 2011/2

    N2 - Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 x 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

    AB - Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 x 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

    KW - ACTIVATED PROTEIN-KINASE

    KW - GENOME-WIDE ASSOCIATION

    KW - ATAXIA-TELANGIECTASIA

    KW - CANCER

    KW - CELLS

    KW - RISK

    KW - AMPK

    KW - IDENTIFICATION

    KW - HOMEOSTASIS

    KW - REDUCTASE

    U2 - 10.1038/ng.735

    DO - 10.1038/ng.735

    M3 - Letter

    C2 - 21186350

    VL - 43

    SP - 117

    EP - 120

    JO - Nature Genetics

    JF - Nature Genetics

    SN - 1061-4036

    IS - 2

    ER -