Structure and Sequence Variation at the Human Leptin Receptor Gene in Lean and Obese Pima Indians

Abstract

The cloning of human and mouse cDNAs from brain that encode high affinity leptin receptors was recently reported. We have physically localized the human leptin receptor gene (LEPR) to a region at 1p31, between the anonymous microsatellite markers D1S515 and D1S198. The genomic structure of the human leptin receptor gene, corresponding to the published human brain cDNA sequence, spans over 70 kb and includes 20 exons. Since the leptin receptor gene is a candidate gene for obesity, and because of its proximity to D1S198, a marker previously linked to insulin secretion, the LEPR gene was sequenced in 20 non-diabetic Pima Indians chosen for extremes in percent body fat and in their acute insulin response to intravenous glucose. Seven polymorphic sites were identified. Two of these polymorphisms, Lys109Arg and Gln223Arg, are amino acid substitutions in the extracellular domain of the leptin receptor, one polymorphism is a silent substitution, and four occur in non-coding regions of the leptin receptor. Four of these sites are in linkage disequilibrium with one another. Nucleotides at three noncoding polymorphic sites were found exclusively in obese Pima Indians. This demonstrates an association between variation at the leptin receptor gene and obesity in humans.

Association of Trp64Arg polymorphism of the β3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity

“…The Gln223Arg polymorphism of the Ob-R gene was found exclusively in nine obese Pima Indians among 20 samples, 29 and this polymorphism lies 46 amino acids upstream from the missense mutation found in the fatty Zucker rat. 27 Thereafter, several investigations in ethnic populations, including Japanese subjects, on whether this polymorphism is associated with obesity, have been published.…”

“…Previous reports have suggested that allele frequency of the Arg223 of the Ob-R gene was higher in Japanese (0.838 ± 0.872) than in Caucasians (0.421 ± 0.440) and in Pima Indians (0.750). 29,30,33,51,52 These studies showed that allele frequency varies among ethnic groups and that the polymorphism is not associated with obesity. In this study, we observed an allele frequency similar to that reported by Matsuoka et al 30 Our data suggest that the Gln223Arg polymorphism of the Ob-R gene is not associated with obesity.…”

“…Therefore, many studies of the Ob-R gene in humans were performed, and some revealed several sequence polymorphisms in African-Americans, Caucasians and Pima Indians. 28,29 A substitution of glutamine for arginine at position 223 in the extracellular domain of the human Ob-R gene (Gln223Arg polymorphism of the Ob-R gene) was found exclusively in 20 obese Pima Indians, except for a single individual. 29 This amino acid substitution lies 46 amino acids upstream from the missense mutation found in the fatty Zucker rat.…”

Genetics of human obesity: lessons from mouse models and candidate genes

“…In our study we did not identify gene variants that were associated with obesity when comparing obese to a random control sample. However, other studies have reported association of some alleles at the leptin receptor with some measures of obesity [78,80]. No strong evidence for the involvement of leptin receptor gene variants in obesity has so far been demonstrated.…”

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

“…29 On the other hand, allele frequencies were shown to be different between 10 lean and 10 obese Pima Indians for two intronic IVS16-36AaT and IVS19 37CaA, and an exonic 3057GaA (P1019P) nucleotide change (P 0.003), and for haplotypes of the same three allelic variants and the Q223R substitution (P 0.001). 32 In a British male population, the K109R, Q223R, S343S, K656N and P1019P exonic polymorphisms were studied, and no signi®cant differences in allele or genotype frequency distributions were observed between normal weight and obese (body mass index, BMI b 28 kgam 2 ) subjects, whereas a weak association with BMI (P 0.02) was observed with the K656N allelic variant, but only in normal weight subjects. 33 On the other hand, no signi®cant differences between genotypes of the Q223R and K656N variants were observed for BMI or the waist-to-hip ratio (WHR) among lean (mean BMI 21.0AE 1.4 kgam 2 ) and obese (mean BMI 30.5AE 2.9 kgam 2 ) subjects in an American population 37 or with BMI over time (7 ± 47 y) for the same two polymorphisms and the K109R substitution in a group of Danish men with or without a history of juvenile onset obesity.…”