A common pentanucleotide polymorphism of the 3'-untranslated part of the leptin receptor gene generates a putative stem-loop motif in the mRNA and is associated with serum insulin levels in obese individuals.

OBJECTIVE

To find out whether genetic alterations of the leptin receptor gene underlie human forms of obesity.

DESIGN

Among 249 morbidly obese adults (body mass index, BMI > or = 40 kg/m2), we screened 30 patients with the highest serum leptin levels for alterations of their leptin receptor gene by single-strand conformation polymorphism (SSCP) technique.

SUBJECTS

249 severely obese subjects (present or past BMI > or = 40 kg/m2) and 138 lean controls (BMI < or = 25 kg/m2).

MEASUREMENTS

DNA analysis was carried out using SSCP technique, sequencing and polymerase chain reaction (PCR) followed by digestion with the restriction enzyme Rsal. Serum leptin, glucose, insulin and lipid concentrations were determined in obese subjects.

RESULTS

We were able to detect a pentanucleotide insertion (CTTTA) in the 3'-untranslated region of the leptin receptor gene. The presence of this pentanucleotide insert generates a putative stem-loop structure in the mRNA. Association studies were carried out on this variant. The frequency of the insertion allele did not differ between 249 obese (12.4%) and 138 lean (12.0%) subjects. There was no association of serum leptin, glucose or lipid levels with the pentanucleotide genotype in the obese individuals. However, when subjects without medication affecting insulin or glucose levels were considered, serum insulin levels were found to be lower in the heterozygous carriers of the insertion allele (15.1 +/- 9.2 mU/l) than in the subjects homozygous for the deletion allele (21.8 +/- 13.7 mU/l, P = 0.0035).

CONCLUSIONS

We were able to confirm the presence of a frequent insertion/deletion polymorphism close to the 3'-end of the leptin receptor gene. We also showed that serum insulin levels in morbidly obese subjects are associated with 3'-UTR variant genotype.