A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes

a replication and meta-analysis of five cohorts

N van Leeuwen, G Nijpels, M L Becker, H Deshmukh, K Zhou, B H C Stricker, A G Uitterlinden, A Hofman, E van 't Riet, C N A Palmer, B Guigas, P E Slagboom, P Durrington, R A Calle, A Neil, G Hitman, S J Livingstone, H Colhoun, R R Holman, M I McCarthy & 3 others J M Dekker, L M 't Hart, Ewan Pearson

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    Abstract

    AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n?=?929) and the Rotterdam Study (n?=?182) from the Netherlands, and the CARDS Trial (n?=?254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) =7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p?=?0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p?=?0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p?=?0.016 and OR 1.25, 95% CI 1.33, 1.38, p?=?7.8?×?10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.
    Original languageEnglish
    Pages (from-to)1971-1977
    Number of pages7
    JournalDiabetologia
    Volume55
    Issue number7
    DOIs
    Publication statusPublished - 2012

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    Metformin
    Type 2 Diabetes Mellitus
    Meta-Analysis
    Genes
    Netherlands
    Therapeutics
    Genotype
    Ataxia Telangiectasia
    Single Nucleotide Polymorphism
    Ataxia-Telangiectasia Variant
    Cohort Studies
    Population

    Cite this

    van Leeuwen, N ; Nijpels, G ; Becker, M L ; Deshmukh, H ; Zhou, K ; Stricker, B H C ; Uitterlinden, A G ; Hofman, A ; van 't Riet, E ; Palmer, C N A ; Guigas, B ; Slagboom, P E ; Durrington, P ; Calle, R A ; Neil, A ; Hitman, G ; Livingstone, S J ; Colhoun, H ; Holman, R R ; McCarthy, M I ; Dekker, J M ; 't Hart, L M ; Pearson, Ewan. / A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes : a replication and meta-analysis of five cohorts. In: Diabetologia. 2012 ; Vol. 55, No. 7. pp. 1971-1977.
    @article{8b6be18bc15e4551ae979d397738715a,
    title = "A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts",
    abstract = "AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n?=?929) and the Rotterdam Study (n?=?182) from the Netherlands, and the CARDS Trial (n?=?254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) =7 {\%} (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95{\%} CI 1.03, 1.58, p?=?0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95{\%} CI 0.87, 2.39, p?=?0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95{\%} CI 1.04, 1.49, p?=?0.016 and OR 1.25, 95{\%} CI 1.33, 1.38, p?=?7.8?×?10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.",
    author = "{van Leeuwen}, N and G Nijpels and Becker, {M L} and H Deshmukh and K Zhou and Stricker, {B H C} and Uitterlinden, {A G} and A Hofman and {van 't Riet}, E and Palmer, {C N A} and B Guigas and Slagboom, {P E} and P Durrington and Calle, {R A} and A Neil and G Hitman and Livingstone, {S J} and H Colhoun and Holman, {R R} and McCarthy, {M I} and Dekker, {J M} and {'t Hart}, {L M} and Ewan Pearson",
    year = "2012",
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    }

    van Leeuwen, N, Nijpels, G, Becker, ML, Deshmukh, H, Zhou, K, Stricker, BHC, Uitterlinden, AG, Hofman, A, van 't Riet, E, Palmer, CNA, Guigas, B, Slagboom, PE, Durrington, P, Calle, RA, Neil, A, Hitman, G, Livingstone, SJ, Colhoun, H, Holman, RR, McCarthy, MI, Dekker, JM, 't Hart, LM & Pearson, E 2012, 'A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts', Diabetologia, vol. 55, no. 7, pp. 1971-1977. https://doi.org/10.1007/s00125-012-2537-x

    A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes : a replication and meta-analysis of five cohorts. / van Leeuwen, N; Nijpels, G; Becker, M L; Deshmukh, H; Zhou, K; Stricker, B H C; Uitterlinden, A G; Hofman, A; van 't Riet, E; Palmer, C N A; Guigas, B; Slagboom, P E; Durrington, P; Calle, R A; Neil, A; Hitman, G; Livingstone, S J; Colhoun, H; Holman, R R; McCarthy, M I; Dekker, J M; 't Hart, L M (Lead / Corresponding author); Pearson, Ewan (Lead / Corresponding author).

    In: Diabetologia, Vol. 55, No. 7, 2012, p. 1971-1977.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes

    T2 - a replication and meta-analysis of five cohorts

    AU - van Leeuwen, N

    AU - Nijpels, G

    AU - Becker, M L

    AU - Deshmukh, H

    AU - Zhou, K

    AU - Stricker, B H C

    AU - Uitterlinden, A G

    AU - Hofman, A

    AU - van 't Riet, E

    AU - Palmer, C N A

    AU - Guigas, B

    AU - Slagboom, P E

    AU - Durrington, P

    AU - Calle, R A

    AU - Neil, A

    AU - Hitman, G

    AU - Livingstone, S J

    AU - Colhoun, H

    AU - Holman, R R

    AU - McCarthy, M I

    AU - Dekker, J M

    AU - 't Hart, L M

    AU - Pearson, Ewan

    PY - 2012

    Y1 - 2012

    N2 - AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n?=?929) and the Rotterdam Study (n?=?182) from the Netherlands, and the CARDS Trial (n?=?254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) =7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p?=?0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p?=?0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p?=?0.016 and OR 1.25, 95% CI 1.33, 1.38, p?=?7.8?×?10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.

    AB - AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n?=?929) and the Rotterdam Study (n?=?182) from the Netherlands, and the CARDS Trial (n?=?254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) =7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p?=?0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p?=?0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p?=?0.016 and OR 1.25, 95% CI 1.33, 1.38, p?=?7.8?×?10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.

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    U2 - 10.1007/s00125-012-2537-x

    DO - 10.1007/s00125-012-2537-x

    M3 - Article

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    SP - 1971

    EP - 1977

    JO - Diabetologia

    JF - Diabetologia

    SN - 0012-186X

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