Studies of the SIM1 gene in relation to human obesity and obesity-related traits

Objective: The single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor, which plays a critical role in the development of the paraventricular nucleus (PVN) of the hypothalamus. SIM1-deficient mice have a hypocellular PVN and are severely obese with increased food intake. Design: We examined whether variants in the SIM1 gene might be associated with severe early-onset obesity in humans. Two hundred and seventy-seven subjects with hyperphagia and severe, early-onset obesity were screened. Association studies with common single-nucleotide polymorphisms (SNPs) in the SIM1 gene were performed in two population-based cohorts. Results: One novel missense mutation, I128T, was found in one obese subject and not in 192 controls. However, the variant did not co-segregate with obesity in the family. Four SNPs, IVS4+83GA, P352T, A371V and T653T, were also identified. The two common SNPs, P352T and A371V, which are in complete linkage disequilibrium, were genotyped in 981 subjects from a population-based cohort, the Ely Study. An allele frequency of 0.13 was observed. Male subjects carrying the P352T/A371V haplotype were found to have a slightly higher body mass index (BMI; P=0.038). Female subjects homozygous for the haplotype gained more weight over a period of 4.5 and 10 years (P=0.003 and P=0.02, respectively). The association studies were repeated in another population-based cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC) - Norfolk Study with 4869 subjects successfully genotyped. Male subjects homozygous for the P352T/A371V haplotype had slightly higher BMI (P=0.04). Conclusion: Mutations in SIM1 are not commonly found in humans with severe early-onset obesity. The relationship between the common variants in SIM1 with BMI and body weight gain deserves further exploration in other populations.