Genetic Variants of PPARgamma2: Function Studies (pilot)

$0S06FY2002GMNIH

Morehouse School Of Medicine, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Although the epidemiological research has been successful in describing genetic components for complex traits, very little is known about the effects of the genetic variations on the gene function/ expression. PPAR-gamma is the molecular target for anti-diabetic thiazolidinedione drugs. It may provide a critical link for insulin resistance diabetes, obesity, and hypertension. The PPAR-gamma-2-specific polymorphism P12A has been confirmed to associate with the type II diabetes in the Caucasian population. However, it is unclear whether this variant has a functional role in the pathogenesis of type II diabetes, or it is in linkage disequilibrium with the causative variant nearby. We are intrigued that the PPAR-gamma expression level is closely related to insulin sensitivity, placental vascularization and atherosclerosis. Recently, we have found 12 genetic variants in regulatory region for the PPAR-gamma-2 gene expression. Seven of them altered the core sequences of the putative binding sites for transcription factors, such as GATA proteins, c-MyB, MyoD, and HNF3B, which have been implicated in insulin resistance, diabetes and atherosclerosis by previous studies. Among these transcription factors, the GATA proteins have been found to regulate the PPAR- gamma-2 expression and adipocyte differentiation in the mouse. We postulate that these genetic variants modify the transcriptional control of the PPAR-gamma-2 expression. The variants at the GATA binding site (nucleotide-726) in the human PPAR-gamma-2 proximal promoter will become the focus of this pilot study. Specifically, we will seek to (1) determine the functional role of the polymorphism at 726 GATA motif in the transcriptional regulation of the PPAR-gamma-2 gene expression in pre-adipocytes and adipocytes; (2) determine the functional role of this polymorphism in the transcriptional regulation of the PPAR-gamma-2 gene expression in vascular smooth muscle cells. This work will provide new insights into the role of genetic variants in the PPAR-gamma-2 gene in diabetes and cardiovascular complications.

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