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

  1. Rachel M Freathy, PhD1,
  2. Nicholas J Timpson, PhD2,,3,
  3. Debbie A Lawlor, PhD3,,4,
  4. Anneli Pouta, PhD5,
  5. Yoav Ben-Shlomo, PhD4,
  6. Aimo Ruokonen, PhD5,
  7. Shah Ebrahim, DM6,
  8. Beverley Shields, PhD1,
  9. Eleftheria Zeggini, PhD2,
  10. Michael N Weedon, PhD1,
  11. Cecilia M Lindgren, PhD2,,7,
  12. Hana Lango, MSc1,
  13. David Melzer, PhD1,
  14. Luigi Ferrucci, PhD8,
  15. Giuseppe Paolisso, MD9,
  16. Matthew J Neville, DPhil7,
  17. Fredrik Karpe, PhD7,
  18. Colin N A Palmer, PhD10,
  19. Andrew D Morris, MD10,
  20. Paul Elliott, PhD11,
  21. Marjo-Riitta Jarvelin, PhD5,,11,
  22. George Davey Smith, DSc3,,4,
  23. Mark I McCarthy, FMedSci2,,7,
  24. Andrew T Hattersley, DM1 and
  25. Timothy M Frayling, PhD (tim.frayling{at}pms.ac.uk)1
  1. 1Peninsula Medical School, Exeter, UK
  2. 2Wellcome Trust Centre for Human Genetics, University of Oxford, UK
  3. 3MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, UK
  4. 4Dept of Social Medicine, Bristol University, UK
  5. 5National Public Health Institute and University of Oulu, Finland
  6. 6London School of Hygiene and Tropical Medicine, London, UK
  7. 7Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK
  8. 8National Institute on Aging, NIH, USA
  9. 9II University of Naples, Naples, Italy
  10. 10Ninewells Hospital and Medical School, University of Dundee, UK
  11. 11Dept of Epidemiology and Public Health, Imperial College - London, London, UK

    Abstract

    Objective: Common variation in the FTO gene is associated with body mass index (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 ten 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 (0.039SD [95%CI:0.013-0.064]; P=0.003), glucose (0.024SD [0.001-0.048]; P=0.044), and triglycerides (0.028SD [0.003-0.052]; P=0.025), and lower HDL-cholesterol (0.032SD [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 and LDL-cholesterol, HbA1c 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 greater than 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

      • Received October 13, 2007.
      • Accepted January 27, 2008.

    This Article

    1. Diabetes
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