Obesity is an important risk factor for atherosclerosis. However, the reasons for the relationship between these disorder are still poorly understood. Evidence from body composition studies suggest that adiposity is highly correlated with several important endocrine measures including phenotypes related to glucoregulatory hormones, growth hormones, and thyroid hormones. These endocrine traits may also directly influence lipoprotein metabolism. Little is known regarding the genes that influence adiposity and their pleiotropic effects on these endocrine parameters and on correlated risk factors for atherosclerosis such as lipoprotein phenotypes. In Project 3, we will measure several adiposity-related phenotypes including total body fat (estimated using bioimpedance), serum concentrations of leptin, insulin-like growth factor I, insulin, triiodothyronine, and thyroxine in pedigreed baboons on three different dietary regimens (chow, a low cholesterol/high fat diet, and a high cholesterol/high fat diet). To better examine the underlying genetic determinants of variable gene expression, we will also measure quantitative mRNA levels of three candidate genes (the leptin structural gene, the lipoprotein lipase gene, and the glucose transporter 4 gene) in biopsied omental fat tissue. We will detect and localize loci influencing these adiposity-related phenotypes and test hypothesis regarding their pleiotropic effects on lipoprotein traits and genotype x diet interaction. Localization of quantitative trait loci will be accomplished via a genomic screen using candidate gene and STR polymorphisms in a single pedigree of 750 non-inbred baboons and in a second sample of 541 purposely inbred pedigreed baboons and their parents. Statistical linkage analyses will be performed using the multipoint variance component method which makes efficient use of all available information and which we have extended to accommodate the complications of inbred pedigrees. The resulting incorporation of inbred animals into our study design will significantly improve our power to detect quantitative trait loci influencing adiposity related phenotypes. Once a quantitative trait locus is found, we will utilize multivariate linkage analysis to determine if adiposity-related genes have pleiotropic effects on lipoprotein phenotypes.
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