EXTREME OBESITY MAY BE LINKED TO MARKERS FLANKING THE HUMAN OB GENE

Mice with mutations of the ob gene are extremely obese, and the human homologue (OB) has been cloned and physically mapped, The protein prod uct of the ob gene (leptin) reduces body fat in mice when given exogen ously, and leptin has been proposed to provide a lipostatic signal tha t regulates adiposity, Variation in the OB gene may be one genetically determined cause of obesity in human populations, To test this hypoth esis, we genotyped siblings from 78 families at markers flanking the h uman OB gene, Pairs of siblings with extreme obesity (BMI greater than or equal to 40; n = 59) shared haplotypes identical-by-descent for th e region containing the OB gene at greater than chance levels (correct ed P = 0.04), Furthermore, one haplotype containing the OB gene was tr ansmitted by heterozygous parents to extremely obese (BMI greater than or equal to 40) offspring more frequently than expected by chance, in dicting significant allelic disequilibrium (corrected P = 0.027), One explanation for these linkage findings is that some individuals with e xtreme obesity have an allelic variant of the OB gene, although other nearby genes could contribute to obesity in these families.