GENETIC-STUDIES OF THE LEPTIN RECEPTOR GENE IN MORBIDLY OBESE FRENCH CAUCASIAN FAMILIES

Family studies have shown that in some populations up to 75% of the va riation of body mass index can be explained by genetic factors. Howeve r, in humans, no major obesity gene has been identified to date. In co ntrast, there are a number of genetically well defined animal models f or obesity. In two of those models (ob/ob and db/db), defects in the s ame pathway are responsible for obesity. Recently, some evidence has b een found for the OB gene also being involved in human obesity. In thi s study we investigated the potential role of the OB receptor (OBR) in the etiology of massive obesity in humans using familial linkage anal yses and case-control association studies. The typing of two microsate llite markers (D1S198 and D1S209), flanking the OBR gene, in 256 sib p airs showed no evidence for linkage with obesity. In order to be able to detect small gene effects, association studies with a 3'-UTR insert ion/deletion polymorphism were carried out. The results of these analy ses remained non-significant (chi(2) = 3.442, P = 0.18). However, subj ects heterozygous for the insertion/deletion polymorphism showed a sli ght trend towards lower insulin values 30 min after an oral glucose lo ad compared to homozygous individuals (P = 0.02). In summary, our resu lts do not support a major role of the human OBR gene in the developme nt of morbid obesity in our population.