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 thei r role in massive obesity. DESIGN: Direct mutation screening of the ge ne and case-control association study, Multivariate analyses for evalu ation of differences in clinical parameters. SUBJECTS: Primary mutatio n 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 su bstitution, 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 h omozygous for the G-allele showed significantly lower leptin concentra tions compared to obese patients either heterozygous or homozygous for the A-allele after correction for BMI. CONCLUSION: Recent linkage stu dies have shown evidence for linkage of the hsob locus with obesity. O ur study provides further evidence that a defect in the ob gene in lin kage disequilibrium with the G-allele of exon 1 might be involved in o besity by affecting leptin concentrations.