on December 16, 2004
Published online before print December 16, 2004, doi: 10.1161/01.ATV.0000153141.42033.22
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Submitted on July 19, 2004
Accepted on December 1, 2004
Associations of the UCP2 Gene Locus With Asymptomatic Carotid Atherosclerosis in Middle-Aged Women
H. Oberkofler ;
From the Paracelsus Private Medical University and Salzburger Landeskliniken (H.O., B.I., K.K., J.U., B.P., W.P.), Salzburg; Konventhospital Barmherzige Brueder (M.H.), Linz; and Krankenhaus Hallein (F.K.), Hallein, Austria.
* To whom correspondence should be addressed. E-mail: w.patsch{at}lks.at.
Objective--Reactive oxygen species (ROS) contribute to atherogenesis. Uncoupling protein 2 (UCP2) reduces mitochondrial ROS generation and protects against the disease in animal models. A common -866G/A promoter polymorphism that has been associated with obesity and 
-cell function may also affect UCP2 gene expression in cells of the arterial wall.
Methods and Results--Genotype distributions of the -866G/A and of a 45nt-del/ins polymorphism in the 3'-untranslated region of the UCP2 gene were determined in 1334 participants of the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR). We observed a modest association of the -866G/A promoter polymorphism and 2-loci haplotypes with asymptomatic carotid atherosclerosis in female study participants. Functional studies revealed increased expression of the -866G wild-type allele in human umbilical vein endothelial cells and differentiated THP-1 cells. Electrophoretic mobility shift assay studies and antibody-interference assays performed with nuclear extracts of various cell lines showed binding of cell-type specific protein complexes to the region encompassing the -866 site and suggested involvement of hypoxia inducible factor 1
in the regulation of UCP2 gene expression in endothelial cells and macrophages.
Conclusions--Our results suggest a role of UCP2 in atherogenesis as originally proposed from studies in animal and cell culture models.
Key words: reactive oxygen species • uncoupling protein • single nucleotide polymorphism • gene expression • haplotype
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