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The PPAR Pathway to Obesity and Type-2 Diabetes: A Multi-Locus Approach to Understanding Complex Disease

Moffett, Susan Patricia (2002) The PPAR Pathway to Obesity and Type-2 Diabetes: A Multi-Locus Approach to Understanding Complex Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Moffett, Susan Patriciasusan.moffett@hgen.pitt.edu
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFerrell, Robert Erferrell@helix.hgen.pitt.eduRFERRELL
Committee MemberFinegold, David Ndnf@mars1.mars.upmc.edu
Committee MemberFeingold, Eleanorefein@helix.hgen.pitt.edu
Committee MemberBarmada, M. Michaelmichael.barmada@hgen.pitt.eduBARMADA
Date: 12 April 2002
Date Type: Completion
Defense Date: 19 February 2002
Approval Date: 12 April 2002
Submission Date: 28 March 2002
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: BMI; fat mass; glucose; insulin; insulin sensitivity; lean mass; PPAR alpha; PPAR beta; PPAR gamma
Other ID: http://etd.library.pitt.edu:80/ETD/available/etd-03282002-161902/, etd-03282002-161902
Date Deposited: 10 Nov 2011 19:33
Last Modified: 19 Dec 2016 14:35
URI: http://d-scholarship.pitt.edu/id/eprint/6612

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