Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI

Rachel M. Freathy, Nicholas J. Timpson, Debbie A. Lawlor, Anneli Pouta, Yoav Ben-Shlomo, Aimo Ruokonen, Shah Ebrahim, Beverley Shields, Eleftheria Zeggini, Michael N. Weedon, Cecilia M. Lindgren, Hana Lango, David Melzer, Luigi Ferrucci, Giuseppe Paolisso, Matthew J. Neville, Fredrik Karpe, Colin N. A. Palmer, Andrew D. Morris, Paul Elliott & 5 others Marjo-Riitta Jarvelin, George Davey Smith, Mark I. McCarthy, Andrew T. Hattersley, Timothy M. Frayling

    Research output: Contribution to journalArticle

    222 Citations (Scopus)

    Abstract

    OBJECTIVE-Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.

    RESEARCH DESIGN AND METHODS-We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations.

    RESULTS-Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95% Cl 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.0481]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10-1.25]; P = 3 x 10(-6)).

    CONCLUSIONS-FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of > 12,000 individuals were needed to detect associations at P < 0. 05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.

    Original languageEnglish
    Pages (from-to)1419-1426
    Number of pages8
    JournalDiabetes
    Volume57
    Issue number5
    DOIs
    Publication statusPublished - May 2008

    Keywords

    • GENOME-WIDE ASSOCIATION
    • MENDELIAN RANDOMIZATION
    • ADULT OBESITY
    • VARIANTS
    • RISK
    • EPIDEMIOLOGY
    • CHILDHOOD
    • DISEASE
    • POLYMORPHISMS
    • INDIVIDUALS

    Cite this

    Freathy, R. M., Timpson, N. J., Lawlor, D. A., Pouta, A., Ben-Shlomo, Y., Ruokonen, A., ... Frayling, T. M. (2008). Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI. Diabetes, 57(5), 1419-1426. https://doi.org/10.2337/db07-1466
    Freathy, Rachel M. ; Timpson, Nicholas J. ; Lawlor, Debbie A. ; Pouta, Anneli ; Ben-Shlomo, Yoav ; Ruokonen, Aimo ; Ebrahim, Shah ; Shields, Beverley ; Zeggini, Eleftheria ; Weedon, Michael N. ; Lindgren, Cecilia M. ; Lango, Hana ; Melzer, David ; Ferrucci, Luigi ; Paolisso, Giuseppe ; Neville, Matthew J. ; Karpe, Fredrik ; Palmer, Colin N. A. ; Morris, Andrew D. ; Elliott, Paul ; Jarvelin, Marjo-Riitta ; Smith, George Davey ; McCarthy, Mark I. ; Hattersley, Andrew T. ; Frayling, Timothy M. / Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI. In: Diabetes. 2008 ; Vol. 57, No. 5. pp. 1419-1426.
    @article{ed7501cc01df4d12a8bd16c164772d85,
    title = "Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI",
    abstract = "OBJECTIVE-Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.RESEARCH DESIGN AND METHODS-We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations.RESULTS-Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95{\%} Cl 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.0481]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95{\%} CI 1.10-1.25]; P = 3 x 10(-6)).CONCLUSIONS-FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of > 12,000 individuals were needed to detect associations at P < 0. 05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.",
    keywords = "GENOME-WIDE ASSOCIATION, MENDELIAN RANDOMIZATION, ADULT OBESITY, VARIANTS, RISK, EPIDEMIOLOGY, CHILDHOOD, DISEASE, POLYMORPHISMS, INDIVIDUALS",
    author = "Freathy, {Rachel M.} and Timpson, {Nicholas J.} and Lawlor, {Debbie A.} and Anneli Pouta and Yoav Ben-Shlomo and Aimo Ruokonen and Shah Ebrahim and Beverley Shields and Eleftheria Zeggini and Weedon, {Michael N.} and Lindgren, {Cecilia M.} and Hana Lango and David Melzer and Luigi Ferrucci and Giuseppe Paolisso and Neville, {Matthew J.} and Fredrik Karpe and Palmer, {Colin N. A.} and Morris, {Andrew D.} and Paul Elliott and Marjo-Riitta Jarvelin and Smith, {George Davey} and McCarthy, {Mark I.} and Hattersley, {Andrew T.} and Frayling, {Timothy M.}",
    year = "2008",
    month = "5",
    doi = "10.2337/db07-1466",
    language = "English",
    volume = "57",
    pages = "1419--1426",
    journal = "Diabetes",
    issn = "0012-1797",
    publisher = "American Diabetes Association",
    number = "5",

    }

    Freathy, RM, Timpson, NJ, Lawlor, DA, Pouta, A, Ben-Shlomo, Y, Ruokonen, A, Ebrahim, S, Shields, B, Zeggini, E, Weedon, MN, Lindgren, CM, Lango, H, Melzer, D, Ferrucci, L, Paolisso, G, Neville, MJ, Karpe, F, Palmer, CNA, Morris, AD, Elliott, P, Jarvelin, M-R, Smith, GD, McCarthy, MI, Hattersley, AT & Frayling, TM 2008, 'Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI', Diabetes, vol. 57, no. 5, pp. 1419-1426. https://doi.org/10.2337/db07-1466

    Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI. / Freathy, Rachel M.; Timpson, Nicholas J.; Lawlor, Debbie A.; Pouta, Anneli; Ben-Shlomo, Yoav; Ruokonen, Aimo; Ebrahim, Shah; Shields, Beverley; Zeggini, Eleftheria; Weedon, Michael N.; Lindgren, Cecilia M.; Lango, Hana; Melzer, David; Ferrucci, Luigi; Paolisso, Giuseppe; Neville, Matthew J.; Karpe, Fredrik; Palmer, Colin N. A.; Morris, Andrew D.; Elliott, Paul; Jarvelin, Marjo-Riitta; Smith, George Davey; McCarthy, Mark I.; Hattersley, Andrew T.; Frayling, Timothy M.

    In: Diabetes, Vol. 57, No. 5, 05.2008, p. 1419-1426.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI

    AU - Freathy, Rachel M.

    AU - Timpson, Nicholas J.

    AU - Lawlor, Debbie A.

    AU - Pouta, Anneli

    AU - Ben-Shlomo, Yoav

    AU - Ruokonen, Aimo

    AU - Ebrahim, Shah

    AU - Shields, Beverley

    AU - Zeggini, Eleftheria

    AU - Weedon, Michael N.

    AU - Lindgren, Cecilia M.

    AU - Lango, Hana

    AU - Melzer, David

    AU - Ferrucci, Luigi

    AU - Paolisso, Giuseppe

    AU - Neville, Matthew J.

    AU - Karpe, Fredrik

    AU - Palmer, Colin N. A.

    AU - Morris, Andrew D.

    AU - Elliott, Paul

    AU - Jarvelin, Marjo-Riitta

    AU - Smith, George Davey

    AU - McCarthy, Mark I.

    AU - Hattersley, Andrew T.

    AU - Frayling, Timothy M.

    PY - 2008/5

    Y1 - 2008/5

    N2 - OBJECTIVE-Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.RESEARCH DESIGN AND METHODS-We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations.RESULTS-Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95% Cl 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.0481]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10-1.25]; P = 3 x 10(-6)).CONCLUSIONS-FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of > 12,000 individuals were needed to detect associations at P < 0. 05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.

    AB - OBJECTIVE-Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.RESEARCH DESIGN AND METHODS-We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations.RESULTS-Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95% Cl 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.0481]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10-1.25]; P = 3 x 10(-6)).CONCLUSIONS-FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of > 12,000 individuals were needed to detect associations at P < 0. 05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.

    KW - GENOME-WIDE ASSOCIATION

    KW - MENDELIAN RANDOMIZATION

    KW - ADULT OBESITY

    KW - VARIANTS

    KW - RISK

    KW - EPIDEMIOLOGY

    KW - CHILDHOOD

    KW - DISEASE

    KW - POLYMORPHISMS

    KW - INDIVIDUALS

    U2 - 10.2337/db07-1466

    DO - 10.2337/db07-1466

    M3 - Article

    VL - 57

    SP - 1419

    EP - 1426

    JO - Diabetes

    JF - Diabetes

    SN - 0012-1797

    IS - 5

    ER -