Identification of TUB as a Novel Candidate Gene Influencing Body Weight in Humans

  1. Ronit Shiri-Sverdlov1,
  2. Anne Custers1,
  3. Jana V. van Vliet-Ostaptchouk1,
  4. Patrick J.J. van Gorp1,
  5. Patrick J. Lindsey2,
  6. Jonathan H.O. van Tilburg3,
  7. Sasha Zhernakova3,
  8. Edith J.M. Feskens4,
  9. Daphne L. van der A4,
  10. Martijn E.T. Dollé5,
  11. Timon W. van Haeften3,
  12. Bobby P.C. Koeleman3,
  13. Marten H. Hofker1 and
  14. Cisca Wijmenga3
  1. 1Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands
  2. 2Department of Population Genetics, Maastricht University, Maastricht, the Netherlands
  3. 3DBG-Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands
  4. 4Centre for Nutrition and Health, National Institute of Public Health and the Environment (RIVM), Bilthoven, the Netherlands
  5. 5Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, Bilthoven, the Netherlands
  1. Address correspondence and reprint requests to Marten H. Hofker, Moleculaire Genetica (UNS50/11), Universiteit Maastricht, Universiteitssingel 50, Postbus 616, Maastricht 6200 MD, Netherlands. E-mail: m.hofker{at}gen.unimaas.nl

Abstract

Previously, we identified a locus on 11p influencing obesity in families with type 2 diabetes. Based on mouse studies, we selected TUB as a functional candidate gene and performed association studies to determine whether this controls obesity. We analyzed the genotypes of 13 single nucleotide polymorphisms (SNPs) around TUB in 492 unrelated type 2 diabetic patients with known BMI values. One SNP (rs1528133) was found to have a significant effect on BMI (1.54 kg/m2, P = 0.006). This association was confirmed in a population enriched for type 2 diabetes, using 750 individuals who were not selected for type 2 diabetes. Two SNPs in linkage disequilibrium with rs1528133 and mapping to the 3′ end of TUB, rs2272382, and rs2272383 also affected BMI by 1.3 kg/m2 (P = 0.016 and P = 0.010, respectively). Combined analysis confirmed this association (P = 0.005 and P = 0.002, respectively). Moreover, comparing 349 obese subjects (BMI >30 kg/m2) from the combined cohort with 289 normal subjects (BMI <25 kg/m2) revealed that the protective alleles have a lower frequency in obese subjects (odds ratio 1.32 [95% CI 1.04–1.67], P = 0.022). Altogether, data from the tubby mouse as well as these data suggest that TUB could be an important factor in controlling the central regulation of body weight in humans.

Footnotes

  • J.H.O.V.T. is currently affiliated with the Department of Human Biology, Maastricht University, Maastricht, the Netherlands.

    Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.

    • Accepted November 8, 2005.
    • Received August 4, 2005.
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This Article

  1. doi: 10.2337/diabetes.55.02.06.db05-0997 Diabetes February 2006 vol. 55 no. 2 385-389
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