¹CNRS EP10 Institut Pasteur de Lille, Lille, France

²Hotel-Dieu Hospital, Paris, France

³Inst für klin. Biochemie, Universität Bonn, Germany

⁴Inserm U342 Hôpital Saint-Vincent de Paul, Paris, France

⁵Sequana Therapeutics Inc, San Diego, CA, USA

^aCorrespondence: Dr Jörg Hager, Institut Pasteur de Lille CNRS EP10, 1, rue du Prof. Calmette, 59019 Lille CEDEX, France.

OBJECTIVE: To search the human ob gene for mutations and evaluate their role in massive obesity.

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

SUBJECTS: 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.

CONCLUSION: 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.

ob-gene; leptin levels; mutation screening; association study; massive obesity