Complementary genetic and functional analyses of genes involved in adiposity.

MEECHAN, Daniel W. (2003). Complementary genetic and functional analyses of genes involved in adiposity. Doctoral, Sheffield Hallam University (United Kingdom)..

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Abstract

Leptin is a 16-kDa protein that is primarily secreted by adipose tissue. It affects body mass regulation by constituting part of the adipostat, that acts to alert the brain of the body's stored energy levels. Additional roles in immune function, reproduction and inflammation are known.Genetic studies of single nucleotide polymorphisms (SNPs), that exist in the extracellular domain of the leptin receptor gene, were undertaken in a population of European Caucasian postmenopausal women to investigate associations with indicators of adiposity. Homozygosity of the G allele of the LYS109ARG SNP was associated with lower mean fat mass levels and BMI. Furthermore, linkage disequilibrium was detected between this SNP and GLN223ARG, which in previous studies was also associated with indicators of adiposity. No associations were found between the LYS656ASN SNP and the tested phenotypes.To complement genetic studies of the leptin receptor, cDNA constructs representing different combinations of the alleles for SNPs in the leptin receptor were generated and subsequent expression of protein variants was conducted in COS-7 cells. Using a radioactive ligand-binding assay, labelled leptin was shown to specifically bind to the LYS109ARG223 and GLN223ARG protein variants, thereby testing the effect of the GLN223ARG mutation on LBA Preliminary data, suggest that the ARG allele appeared to bind less leptin than the GLN.Genetic studies were carried out on polymorphisms in related candidate genes. A promoter polymorphism (G-2548 A) in the leptin gene was associated with lower mean BMI and leptin levels in a cohort of European Caucasian postmenopausal womenIndividuals who lacked the 2 repeat allele of the variable number tandem repeat (VNTR) polymorphism present in intron two of the interleukin 1 receptor antagonist gene had an association with lower leptin levels but not BMI or fat mass. This suggests a potential feedback and / or cross-talk mechanism between leptin and members of the IL-1 family of cytokines in processes other than adiposity. Immunity and inflammation are processes where the interleukin one receptor antagonist protein has a prominent role and in which the function of leptin is increasingly being investigated, therefore an interaction between the two cytokines may be specific for these conditions.The TNF alpha (G-308 A) SNP was also investigated but no associations were observed between this SNP and the phenotypes in the postmenopausal cohort. To investigate the influence of the leptin receptor gene in conditions at the opposite end of the body weight spectrum to obesity, a case-control association study was undertaken to compare allele frequencies of the LYS109 ARG, GLN223ARG and LYS656ASN leptin receptor SNPs between anorexic women and controls. No significant differences were observed in allele or haplotype frequencies.

Item Type: Thesis (Doctoral)
Additional Information: Thesis (Ph.D.)--Sheffield Hallam University (United Kingdom), 2003.
Research Institute, Centre or Group: Sheffield Hallam Doctoral Theses
Depositing User: EPrints Services
Date Deposited: 10 Apr 2018 17:21
Last Modified: 10 Apr 2018 17:21
URI: http://shura.shu.ac.uk/id/eprint/20051

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