Common Variation in the FTO Gene Alters Diabetes-Related Metabolic Traits to the Extent Expected Given Its Effect on BMI

  1. Rachel M. Freathy1,
  2. Nicholas J. Timpson23,
  3. Debbie A. Lawlor34,
  4. Anneli Pouta5,
  5. Yoav Ben-Shlomo4,
  6. Aimo Ruokonen5,
  7. Shah Ebrahim6,
  8. Beverley Shields1,
  9. Eleftheria Zeggini2,
  10. Michael N. Weedon1,
  11. Cecilia M. Lindgren27,
  12. Hana Lango1,
  13. David Melzer1,
  14. Luigi Ferrucci8,
  15. Giuseppe Paolisso9,
  16. Matthew J. Neville7,
  17. Fredrik Karpe7,
  18. Colin N.A. Palmer10,
  19. Andrew D. Morris10,
  20. Paul Elliott11,
  21. Marjo-Riitta Jarvelin511,
  22. George Davey Smith34,
  23. Mark I. McCarthy27,
  24. Andrew T. Hattersley1 and
  25. Timothy M. Frayling1
  1. 1Peninsula Medical School, Exeter, U.K
  2. 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
  3. 3MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Bristol, U.K
  4. 4Department of Social Medicine, Bristol University, Bristol, U.K
  5. 5National Public Health Institute and University of Oulu, Oulu, Finland
  6. 6London School of Hygiene and Tropical Medicine, London, U.K
  7. 7Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
  8. 8National Institute on Aging, National Institutes of Health, Bethesda, Maryland
  9. 9II University of Naples, Naples, Italy
  10. 10Ninewells Hospital and Medical School, University of Dundee, Nethergate, Dundee, Scotland, U.K
  11. 11Department of Epidemiology and Public Health, Imperial College, London, U.K
  1. Corresponding author: Prof. Timothy M. Frayling, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Rd., Exeter, EX1 2LU, U.K. E-mail: tim.frayling{at}pms.ac.uk

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% CI 0.013–0.064]; P = 0.003), glucose (0.024 [0.001–0.048]; 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, γ-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 × 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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 17 March 2008. DOI: 10.2337/db07-1466.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1466.

    R.M.F. and N.J.T. contributed equally to this work.

    M.-R.J., G.D.S., M.I.M., A.T.H., and T.M.F. contributed equally to this work.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted January 27, 2008.
    • Received October 13, 2007.
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  1. Diabetes vol. 57 no. 5 1419-1426
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