Genetic studies of the leptin receptor gene in morbidly obese French Caucasian families

Abstract

Family studies have shown that in some populations up to 75% of the variation of body mass index can be explained by genetic factors. However, in humans, no major obesity gene has been identified to date. In contrast, there are a number of genetically well defined animal models for obesity. In two of those models (ob/ob and db/db), defects in the same pathway are responsible for obesity. Recently, some evidence has been found for the OB gene also being involved in human obesity. In this study we investigated the potential role of the OB receptor (OBR) in the etiology of massive obesity in humans using familial linkage analyses and case-control association studies. The typing of two microsatellite markers (D1S198 and D1S209), flanking the OBR gene, in 256 sib pairs showed no evidence for linkage with obesity. In order to be able to detect small gene effects, association studies with a 3'-UTR insertion/deletion polymorphism were carried out. The results of these analyses remained non-significant (chi 2 = 3.442, P = 0.18). However, subjects heterozygous for the insertion/deletion polymorphism showed a slight trend towards lower insulin values 30 min after an oral glucose load compared to homozygous individuals (P = 0.02). In summary, our results do not support a major role of the human OBR gene in the development of morbid obesity in our population.

Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Québec Family Study

“…No signi®cant differences in allele frequencies or genotype distributions were observed between leaner and heavier subjects in QFS as in other studies of British, 33 Danish, 34 French, 27 American, 37 or Japanese 35 populations. To a certain extent, these results are not surprising considering the polygenic nature of most human obesity cases, in which each individual gene is expected to contribute in a minor way to the phenotypic variation.…”

“…The exonic polymorphisms allele frequencies are very similar to those reported in the Centre d'Etude du Polymorphisme. Humain (CEPH) families 27 and in British, 33 Danish, 34 American 37 and Japanese 35 populations, except for the Q223R polymorphism in the Japanese 35 and in another non-Caucasian population of Pima Indians, 32 which showed strong differences (Table 1). Therefore, allelic variations in LEPR show a signi®cant race andaor population component.…”

“…16 The human leptin receptor LEPR gene 22 maps to 1p31-p22. 23 No linkage was observed between markers in the vicinity of LEPR and obesity in Pima Indians, 24 ± 26 as in a French population, 27 whereas suggestive linkages were reported in the Que Âbec Family Study (QFS). 28 Some 18 different polymorphisms in the human LEPR gene have been reported (Figure 1).…”

“…40 kgam 2 ) subjects. 27 Recently, a splice-mutation producing a skipping of exon 18, resulting in a truncated leptin receptor lacking both the transmembrane and the intracellular portion of LEPR, has been reported in a consanguinous family of Kabilian origin. 36 In this family of nine children, three sisters were shown to be homozygotes for the mutation, which produced an early-onset morbid obesity developing in the ®rst months of life, with hyperphagia, hypogonadotropic hypogonadism but, in contrast to db mouse, normal Leptin receptor gene and body composition YC Chagnon et al glycaemia and insulinaemia, and normal triglyceridaemia and cholesterolaemia.…”

Chronic stress aggravates glucose intolerance in leptin receptor-deficient (db/db) mice

“…In contrast to congenital leptin deficiency, the majority of obese individuals have higher leptin concentrations than lean individuals and are leptin resistant (Considine et al 1996a;Moon et al 2011). Hyperleptinemia in humans can be due to mutations at highly conserved positions of the extracellular domain of the leptin receptor gene (Chung et al 1997;Francke et al 1997; Thompson et al 1997;Clément et al 1998). In 1966, Hummel et al described a spontaneous mutation in a C57BL/Ks mouse colony that provoked hyperphagia, decreased energy expenditure and obesity, fasting hyperglycemia increasing with age and increase in plasma insulin and leptin concentration (Hummel et al 1966;Coleman and Hummel 1967;Frederich et al 1995;Chen et al 1996;Chua et al 1996; Lee et al 1996;Madiehe et al 2002).…”