Leptin Receptor Gene Variation and Obesity: Lack of Association in a White British Male Population

Abstract

Leptin, a hormone secreted by adipocytes, plays a pivotal role in the control of body weight. Rodents with mutations in the leptin receptor gene develop morbid obesity. It is possible, therefore, that leptin receptor gene mutations contribute to human obesity. To test this possibility, we determined the entire coding sequence of the human leptin receptor cDNA from peripheral blood lymphocytes of 22 morbidly obese patients with body-mass index (BMI) between 35.1 and 60.9 kg/m2. We identified five common DNA sequence variants distributed throughout the coding sequence at codons 109, 223, 343, 656 and 1019, one rare silent mutation at codon 986 and one novel alternatively spliced form of transcript. None of the five common variants, including the three that predict amino acid changes, are null mutations causing morbid obesity, because homozygotes for the variant sequences were also found in lean subjects. Furthermore, the frequency of each variant allele and the distribution of genotypes and haplotypes were similar in 190 obese (BMI >28 kg/m2) and 132 lean (BMI <22 kg/m2) white British males selected from a population-based epidemiological survey. In these subjects, there was no evidence for a significant effect of the common variants on obesity or obesity-related phenotypes. These results suggest that mutations in the leptin receptor gene are not a common cause of human obesity.

SNP analyses of postprandial responses in (an)orexigenic hormones and feelings of hunger reveal long-term physiological adaptations to facilitate homeostasis

“…These SNPs were in LD, as was observed earlier by others. 35,37,39 This association reduces the risk for overeating in subjects homozygous for the 109Arg-encoding allele, consistent with results from Rosmond et al 38 who showed a lower BMI and abdominal sagittal diameter in subjects with this genotype. This seems to confirm the association between the postprandial response in plasma ghrelin levels and the 326A4G SNP as a long-term physiological adaptation to facilitate homeostasis.…”

“…33,34 However, subjects homozygous for the 223Arg-encoding allele had a higher BMI than subjects homozygous for the common 223Gln-encoding allele in some, 14,35,36 but not all studies. 37,38 Again, long-term physiological adaptations required to facilitate homeostasis may be involved. First of all, subjects homozygous for the 223Arg-encoding allele were shown earlier to have higher plasma leptin levels.…”

Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms

“…Using LEP 19GG as the referent group, the recalculated FL risk estimate for the LEP 19AA genotype is 0.6 (95% CI 0.3 -1.3), similar to the OR of 0.5 (95% CI 0.3 -0.8) presented here. As has been observed elsewhere, the BMIs of our controls were not correlated with LEP 19G4A (r ¼ 0.014, P ¼ 0.70) (Karvonen et al, 1998;Lucantoni et al, 2000), LEP À2548G4A (r ¼ À0.013, P ¼ 0.72) (Mammes et al, 1998;Le Stunff et al, 2000), LEPR 223Q4R (r ¼ À0.008, P ¼ 0.83) (Gotoda et al, 1997;Rosmond et al, 2000;Wauters et al, 2001) or APM1 276G4T (r ¼ À0.024, P ¼ 0.51) (Menzaghi et al, 2002;Fumeron et al, 2004). Moreover, this and the previous report by Skibola et al found little evidence that risks associated with BMI varied by genotype.…”

“…However, while positive associations have been reported between NHL and anthropometric characteristics (Holly et al, 1999;Calle et al, 2003;Bahl et al, 2004;Pan et al, 2004), others have not (Paffenbarger Jr et al, 1978;Whittemore et al, 1985;Franceschi et al, 1989;La Vecchia et al, 1990;Zhang et al, 1999;Cerhan et al, 2002;Chang et al, 2005). Furthermore, polymorphisms in the LEP (an A to G nucleotide (nt) change at position 19 in the 5 0 -untranslated region (Hager et al, 1998), and a G to A substitution at nt À2548 upstream of the ATG start site (Mammes et al, 1998)) and LEPR (an A to G transition at nt 668 from the start codon that converts glutamine to arginine at codon 223 (223Q4R) (Gotoda et al, 1997)) genes were recently shown to modulate NHL risk (Skibola et al, 2004).…”

The Gln223Arg polymorphism in the leptin receptor is associated with familial combined hyperlipidemia

“…31 The Gln223Arg polymorphism has been associated with body mass index (BMI), fat mass, leptin levels, and systolic and diastolic blood pressure in some studies; 27,30,32 however, other studies did not find these associations. [33][34][35] The aim of this study was to investigate whether there is an association between the presence of the Arg allele defined by the Gln223Arg polymorphism in the LEPR gene and FCH and its associated phenotypes.…”