title: Studies of the SIM1 gene in relation to human obesity and obesity-related traits.
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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: University Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: C-C C
authors.initials: CC
authors.lastname: Hung
authors.forename: J
authors.initials: J
authors.lastname: Luan
authors.forename: M
authors.initials: M
authors.lastname: Sims
authors.forename: J M
authors.initials: JM
authors.lastname: Keogh
authors.forename: C
authors.initials: C
authors.lastname: Hall
authors.forename: N J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: S
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: I S
authors.initials: IS
authors.lastname: Farooqi
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006963:Hyperphagia / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C491094:SIM1 protein, human