3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Exploring the role of genetic variation at the leptin and leptin receptor genes (LEP and LEPR) in obesity and hypertension in a black South African cohort(2014-04-04) Ngcungcu, ThandiswaObesity and hypertension often occur together and are risk factors for cardio-metabolic disorders. Single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes have been shown to be associated with obesity and hypertension, but have not been well explored in African populations. The aims of this study were to determine the heritability estimates of anthropometric and blood pressure (BP) measures and leptin levels; to identify additional informative SNPs in and around the LEP and LEPR genes; and to examine the potential relationships between these SNPs and measures of obesity, hypertension and leptin levels in a black South African cohort. Participants from the African Programme on Genes in Hypertension (APOGH) with various anthropometric and BP measurements were genotyped for LEP and LEPR SNPs using the BeadXpress platform. Heritability estimates were determined using Statistical Analysis for Genetic Epidemiology (S.A.G.E.) software and relationships between LEP or LEPR SNPs and obesity, leptin levels and hypertension were assessed using SAS 9.3 and gPLINK vs2.050, taking into account family relationships, various confounders and correcting for multiple testing. The Bonferroni method was used to correct for multiple testing and P≤0.00076 was considered as statistically significant for SNP association tests. Seven-hundred-and-thirteen individuals were successfully genotyped and there were more women (66%) than men. The prevalence of obesity (42%) and hypertension (46%) were high in the sample. Significant heritability (h2 %, P<0.05) was noted for body weight (38%), body mass index (26%), waist (35%) and hip circumference (42%), waist-to-hip ratio (46%), skinfold thickness (44%), systolic (34%), diastolic (27%) and central systolic (33%) BP; but leptin levels were not significantly heritable (h2 %=15%, P=0.228). LEP rs17151914 (P=0.0002) and LEPR rs6690661 (P=0.0007) were significantly associated with leptin levels and diastolic BP, respectively, in women. The LEP rs17151913T-rs6956510G haplotype was associated with an increase in central systolic BP in women (P=0.012 with Bonferroni correction) whereas the LEPR rs2154381C-rs1171261T haplotype was associated with lower systolic BP in men (P=0.0359 with Bonferroni correction). LEP gene variants were significantly correlated with effects on leptin levels in women and the LEPR gene variants were significantly correlated with effects on diastolic BP also in women. These results indicate that further exploration of the role of genetic variation in the LEP and LEPR genes in obesity and hypertension in individuals of African ancestry is warranted.Item The effects of chronic intermittent hypoxia on insulin and leptin homeostasis in the rat(2006-11-16T08:37:37Z) Romain, Heidi ShiraThere is a high prevalence of insulin and leptin resistance and increased cortisol concentrations in sleep apnoea patients, independent of obesity. Chronic intermittent hypoxia is used an experimental animal model to simulate the hypoxia occurring in sleep apnoea patients. The aim of this study was to measure plasma insulin and leptin concentrations and hypothalamic-pituitary-axis activity in rats exposed to either intermittent hypoxia (CIH) or sham hypoxia (SH) for fourteen days. To induce CIH plexiglass cylinders were flushed with 100% nitrogen for nine seconds every 90 seconds, seven hours/day. The rats were weighed each day during the exposure period. Venous blood samples for insulin and leptin were collected on days one, three, five, eight and fifteen. Faecal samples were collected to measure glucocorticoid metabolites. There was no significant difference in the daily change in body weight between the rats exposed to CIH compared to the rats exposed to SH (unpaired t-test). Plasma insulin concentrations were not affected by CIH. In both groups of rats plasma leptin concentrations were significantly higher on day fifteen compared to day five (p=0.03, unpaired t-test). Glucocorticoid metabolites were significantly increased in the intermittent hypoxia group on day two (p=0.003 one-way ANOVA). In conclusion, exposing normal weight rats to CIH for fourteen days resulted in a transient iv increase in HPA axis activity on day two and an elevation in plasma leptin levels, in both groups of rats, at day fifteen.