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. 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/m(2)). Association study: 395 unrelated morbidly obese subjects (BMI > 40 kg/m(2)), 121 lean, non-diabetic control individuals, 72 women of a random sample with an average BMI 32.5 kg/m(2). 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.