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

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 <25 kg/m 2 ) 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. Diabetes 55:385-389, 2006

TUB is a candidate gene for late-onset obesity in women

“…Thus, the current study of 892 DZ pairs and an additional 418 MZ pairs and 94 DZ singletons provided even greater power. Table 2 shows genotype and allele frequencies of the three SNPs in our cohort, which are compatible with the study by Shiri-Sverdlov et al [5]. Pairwise LD, quantified by r 2 , was modest for all pairwise combinations of the three SNPs: rs2272382 vs rs2272383: 0.17; rs2272382 vs rs1528133: 0.02; rs2272383 vs rs1528133: 0.09.…”

“…The aim of our study was to replicate the previously observed associations with the three TUB SNPs in diabetic patients and individuals enriched for type 2 diabetes [5] in a large sample of Europid female twins from the general population. We report confirmation of association of rs2272382 with measures of general and central obesity, but only in postmenopausal women, which accords with the association of the mouse homologue Tub with late-onset obesity.…”

“…Age and menopausal status were included as covariates in the models. In consideration of the tubby mouse syndrome characterised by late-onset obesity and both cohorts studied by Shiri-Sverdlov et al [5] involving only older individuals (mean ages of 70.3 years for their Breda cohort and 56.1 years for their RIVM cohort), we explored the hypothesis that TUB is a candidate gene for late-onset obesity in humans through testing the interaction of the SNPs by menopausal status.…”

“…Association analyses were performed using generalised estimating equations (GEEs), which allow for the relatedness between twins and yield unbiased standard errors and p values [9]. More specifically, a recessive model (homozygotes of a minor allele vs carriers of the common allele) was tested for SNPs rs2272382 and rs2272383, and a dominant model (carriers of a minor allele vs homozygotes of the common allele) was tested for SNP rs1528133, following the procedure and significant findings of Shiri-Sverdlov et al [5]. Age and menopausal status were included as covariates in the models.…”

“…Recently, Shiri-Sverdlov et al [5] reported a significant association between single nucleotide polymorphism (SNP) rs1528133 and BMI in 492 individuals with type 2 diabetes, which was replicated in a population of 750 individuals enriched for the disease. SNP rs1528133 is located 22 kb distal to TUB in the flanking gene RIC3 and is in strong linkage disequilibrium (LD) with SNPs in the 3′ end of TUB.…”