A polymorphism in the 5' untranslated region of the human ob gene is associated with low leptin levels.
OBJECTIVE
To search the human ob gene for mutations and evaluate their role in massive obesity.


METHODS
Direct mutation screening of the gene and case-control association study. Multivariate analyses for evaluation of differences in clinical parameters.


METHODS
Primary mutation screening: 24 morbidly obese subjects (body mass index (BMI) > 40 kg/m2). Association study: 395 unrelated morbidly obese subjects (BMI > 40 kg/m2), 121 lean, non-diabetic control individuals, 72 women of a random sample with an average BMI 32.5 kg/m2.


RESULTS
We report the finding of a DNA variant in exon 1 of the human ob gene (A --> G substitution, base + 19). This variant showed a prevalence of 62% in our study population. Association analyses under different genetic models (dominant, co-dominant, recessive) showed no significant evidence for an association of this variant with BMI. However, obese individuals homozygous for the G-allele showed significantly lower leptin concentrations compared to obese patients either heterozygous or homozygous for the A-allele after correction for BMI.


CONCLUSIONS
Recent linkage studies have shown evidence for linkage of the hsob locus with obesity. Our study provides further evidence that a defect in the ob gene in linkage disequilibrium with the G-allele of exon 1 might be involved in obesity by affecting leptin concentrations.
Hager
J
J
CNRS EP10 Institut Pasteur de Lille, France.
Clement
K
K
Francke
S
S
Dina
C
C
Raison
J
J
Lahlou
N
N
Rich
N
N
Pelloux
V
V
Basdevant
A
A
Guy-Grand
B
B
North
M
M
Froguel
P
P
D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D015331:Cohort Studies; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005838:Genotype; D006801:Humans; D020738:Leptin; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics*; D009767:Obesity, Morbid / Q000097:blood / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics; D011506:Proteins / Q000032:analysis / Q000235:genetics*
D017931:DNA Primers; D020738:Leptin; D011506:Proteins