Browsing by Subject "Obesity--Genetic aspects"
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Item Liver function markers and obesity-associated phenotypes: genetic and association studies(2007) Bose, Tanushree, 1979-; Freeland-Graves, Jeanne H.The primary goal was to study the influence of adipocyte number and volume, inflammation, insulin resistance, and genetic factors on indicators of liver injury, surrogate marker of non alcoholic fatty liver disease (NAFLD). The secondary goal was to explore the occurrence of NAFLD and its relationship with variations in liver function biomarkers. The first objective was to determine the association of plasma levels of monocyte chemoattractant protein-1 (MCP-1) with omental adipocyte number, insulin resistance and circulating concentrations of liver injury markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in unrelated baboons. Significant associations of MCP-1 with other measured traits were established. The second objective was to examine if adiposity-related parameters are under genetic influence and to evaluate their genetic correlations with AST in pedigreed baboons. Adipocyte volume and number, body weight and plasma AST were heritable. Genetic correlations between adiposity-related phenotypes and AST were significant. A genome wide scan yielded a strong signal for adipocyte volume on chromosome 6. The third aim was to explore the genetic factors that influence variations in plasma levels of [gamma] glutamyl transferase (GGT) and albumin (ALB), and to evaluate their genetic correlations with cardiovascular risk factors in pedigreed baboons. Significant linkages for GGT and albumin were identified on chromosome 20_22 and chromosome 10, respectively. Genetic correlations between ALB and cardiovascular risk factors were significant. No statistically significant associations were found between GGT and cardiovascular-related phenotypes. The fourth objective was to investigate the prevalence of NAFLD and its association with altered liver protein levels in unrelated baboons. The influence of weight and insulin resistance on the occurrence of NAFLD was inconclusive. Significant relationships between the variations in plasma levels of liver injury biomarkers and severity of the disease could not be established. In conclusion, the first three studies provided observational and genetic evidence of a relationship between liver function markers and adiposity-related factors in baboons. However, the results of the fourth study do not provide conclusive evidence to suggest that body weight and insulin resistance play a significant role in the development of NAFLD in these baboons.Item Localization of chromosomal regions influencing the phenotypes of the metabolic syndrome(2004) Cai, Guowen; Freeland-Graves, Jeanne H.The goal of this project was to study the genetic structure of the metabolic syndrome. The first objective was to locate chromosomal regions influencing insulin resistance in Mexican Americans of the San Antonio Family Heart Study (SAFHS). Two studies were performed to achieve this objective using a genomewide scan. In the first study using data from the first visit of the SAFHS, we detected significant linkage evidence on chromosome 8p between marker D8S1130 and D8S1106 and on chromosome 13q between marker D13S787 and D13S252. In the second study that used data from the second visit of the SAFHS, markers D1S1663 on chromosome 1 and D2S436 on chromosome 2 were found to be linked to insulin sensitivity indices. Candidate genes on detected locations were proposed. The significant findings in both studies duplicate those of previous investigations. The second objective of this project was to identify the genetic locations related to the quantitative traits that constitute the metabolic syndrome in the same population of Mexican Americans. Principal component factor analysis (PCFA) was conducted, and significant and suggestive evidence for linkage of lipid (factor 4) and body size/adiposity (factor 1) were found on chromosome 4 near marker D4S403 and chromosome 1 near marker D1S1597, respectively. The third objective of this project was to explore the genetic pleiotropy between insulin resistance and adiposity, especially visceral obesity using the baboon as a model. The present study is the first to use omental tissue to investigate gene pleiotropy between visceral fat and insulin resistance. The results from the baboon study in this thesis, coupled with research in humans, suggest that a common set of genes contribute to insulin resistance and obesity in both species. It is also plausible that those two groups of genes completely overlap each other. At present, the variance decomposition based, multipoint linkage analysis is a mathematical model that can provide useful information for susceptible gene mapping. Future finemapping and the positional candidate gene approach will be helpful to further our understanding of the genetic structure of this complex disease.Item Obesity-associated phenotypes and circulating levels of ghrelin, cholecystokinin, low-density lipoprotein and zinc: genetic and observational studies(2005) Voruganti, Venkata Saroja; Freeland-Graves, Jeanne H.Obesity is a complex problem that is believed to result from both genetic and environmental factors. This condition greatly increases the risk of developing serious health consequences, such as metabolic syndrome and cardiovascular disease. The primary goal of this research was to study the genetic influence on plasma ghrelin, cholecystokinin (CCK), and low-density lipoprotein (LDL), and their relationship with obesity. A secondary goal was to investigate the effect of weight loss on plasma zinc and other risk factors for metabolic syndrome. Aims 1 and 2 were to estimate the additive heritabilities and to localize the responsible chromosomal quantitative trait loci associated with circulating levels of the appetite regulating hormones, ghrelin and CCK, in baboons. Plasma ghrelin and CCK were higher in baboons than humans, with males exhibiting greater levels. Ghrelin was inversely linked to body weight (r = 0.23, p < 0.001), insulin (r = - 0.19, p < 0.05), and leptin (r = - 0.14, p < 0.05). Significant heritabilities were observed for ghrelin and CCK. A strong signal was detected for plasma CCK on chromosome 17p12 (LOD = 3.1, p < 0.01). Aim 3 was to detect heritability and pleiotropy between the obesity-related anthropometric phenotypes and low- density lipoproteins (LDL) in humans. Effect of genes on LDL size was evident, with substantial heritability and strong genetic correlations between LDL and obesity-related traits; small LDL and weight (rhoG = 0.65, p < 0.001), waist (rhoG = 0.80, p < 0.001), and BMI (rhoG = 0.67, p < 0.001), respectively. Aim 4 was to study the impact of weight loss on plasma zinc and risk factors for metabolic syndrome in humans. Weight reduction significantly increased the low plasma zinc observed in obese women, and improved risk factors for metabolic syndrome (HDL, BMI, waist and body fat). A negative correlation was observed between changes in zinc and body fat (r = -0.28, p < 0.05). Collectively, these results demonstrate significant influence of genetic factors on plasma ghrelin, CCK, LDL and obesity phenotypes. In addition, weight loss produced beneficial effects of weight loss on plasma zinc and risk factors for metabolic syndrome.