Abstract
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.
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Acknowledgements
This work was supported by the Wellcome Trust (ISF, NJW, SOR) and the MRC (SOR, NJW). The Ely Study was funded by the Diabetes UK and the Anglia and Oxford Research Development Directorate. We thank the subjects, referring Physicians and the staff of the Ely Study research clinics.
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Hung, CC., Luan, J., Sims, M. et al. Studies of the SIM1 gene in relation to human obesity and obesity-related traits. Int J Obes 31, 429–434 (2007). https://doi.org/10.1038/sj.ijo.0803443
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DOI: https://doi.org/10.1038/sj.ijo.0803443
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