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

Identification of TUB as a Novel Candidate Gene Influencing Body Weight in Humans Ronit Shiri-Sverdlov 1 , Anne Custers 1 , Jana V. van Vliet-Ostaptchouk 1 , Patrick J.J. van Gorp 1 , Patrick J. Lindsey 2 , Jonathan H.O. van Tilburg 3 , Sasha Zhernakova 3 , Edith J.M. Feskens 4 , Daphne L. van der A 4 , Martijn E.T. Dollé 5 , Timon W. van Haeften 3 , Bobby P.C. Koeleman 3 , Marten H. Hofker 1 and Cisca Wijmenga 3 1 Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands 2 Department of Population Genetics, Maastricht University, Maastricht, the Netherlands 3 DBG-Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands 4 Centre for Nutrition and Health, National Institute of Public Health and the Environment (RIVM), Bilthoven, the Netherlands 5 Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, Bilthoven, the Netherlands 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/m 2 , 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/m 2 ) from the combined cohort with 289 normal subjects (BMI