Many common diseases such as obesity and type-2 diabetes have a significant genetic component that contributes to susceptibility. Peroxisome proliferator activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptors (RXRs) to influence the expression of many genes involved in adipocyte differentiation and lipid metabolism such as the fatty acid binding proteins (FABPs) and the uncoupling proteins (UCPs). Genetic variation in any of these gene families could potentially alter metabolic traits related to obesity and type-2 diabetes. The goal of this project is to identify genetic variation in the PPARs and RXRs and then to determine if this variation is associated to quantitative traits related to obesity and type-2 diabetes using a multi-locus analysis approach. In this study, three sets of regression models were constructed: the first containing polymorphisms in just the PPARs or RXRs; the second with variants from all four gene families; and the third using polymorphisms from the gene isoforms showing the highest level of expression in each of three tissues. Some of the models were only able to account for small portions of the particular trait variation; however, many of the models accounted for a large amount of variation in the trait, up to 23.4% in the Hispanic female model for fasting free fatty acids. Multi-locus genotypes, as opposed to single locus effects, were found to be the best predictors of variation in almost all of the final models. These analyses confirmed the importance of gene-gene interactions on traits related to obesity and type-2 diabetes such as fasting free fatty acids and cholesterol; therefore, multiple polymorphisms should be considered together to fully understand their influence on a quantitative trait.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-03282002-161902 |
| Date | 12 April 2002 |
| Creators | Moffett, Susan Patricia |
| Contributors | Robert E. Ferrell, PhD, Eleanor Feingold, PhD, David N. Finegold, MD, M. Michael Barmada, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu:80/ETD/available/etd-03282002-161902/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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