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.


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.
Hung
C-C C
CC
University Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
Luan
J
J
Sims
M
M
Keogh
J M
JM
Hall
C
C
Wareham
N J
NJ
O'Rahilly
S
S
Farooqi
I S
IS
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*
D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C491094:SIM1 protein, human