LEPR gene polymorphisms: associations with overweight, fat mass and response to diet in women

Background In humans, a mutation of the leptin receptor gene (LEPR) leads t o a rare obese syndrome of mendelian inheritance. However, obesity in human s results from interactions between genes and environment, mainly nutrition al factors. Variations at the LEPR locus could be involved in the regulatio n of body weight. Design Genetic variations at the LEPR locus were screened in a selection of 30 French overweight subjects by Single Strand Conformation Polymorphism ( SSCP) analysis, then an association study between genotypes and obesity phe notypes was performed in 179 French overweight patients recruited from the Nutrition Department of Bichat Hospital in Paris who were prescribed a low calorie diet and in 387 unrelated volunteers (98 overweight, 289 normal wei ght) drawn from the Stanislas Family Study in Nancy. Results Two new genetic variants were found: T + 70 --> C (exon 1) and Asp (A) 96 Asp (G) (exon 4). In Nancy, the T + 70 --> C polymorphism was associ ated with fat mass adjusted for BMI in women (P = 0.025). The genotype and allele frequencies of the Ser (T) 343 Ser (C) polymorphism (exon 9) were si gnificantly different between normal and overweight women, with the T allel e being more frequent in the overweight group (T frequency in Nancy, 0.82; in Nancy + Paris, 0.79) than in the normal weight group (0.69; P = 0.017 vs . Nancy overweight, P = 0.003 vs. Nancy + Paris overweight). In women from Nancy, fat mass adjusted for BMI was significantly associated with this pol ymorphism (P = 0.01). The overweight women carrying the C allele of this po lymorphism lost more weight in response to low calorie diet than the non ca rriers (P = 0.006). Conclusions In women, genetic variations at the LEPR gene level are associa ted with overweight and fat mass in a cross sectional study and with respon se to low calorie diet in an intervention study. These results indicate tha t variations at the leptin receptor locus are associated with common obesit y phenotypes and are a part of the polygenic influences on the response to nutritional environment.