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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:604.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Associations of the UCP2 Gene Locus With Asymptomatic Carotid Atherosclerosis in Middle-Aged Women

H. Oberkofler; B. Iglseder; K. Klein; J. Unger; M. Haltmayer; F. Krempler; B. Paulweber; W. Patsch

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.

Correspondence to Wolfgang Patsch, MD, Paracelsus Private Medical University, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria. E-mail w.patsch{at}salk.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 ß-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.

Uncoupling protein 2 (UCP2) reduces mitochondrial reactive oxygen species production and protects against atherosclerosis in animal models. We report that the UCP2 gene locus is associated with asymptomatic carotid atherosclerosis in females of a cross-sectional study and that a common promoter polymorphism affects UCP2 gene expression in endothelial cells and macrophages.

Key Words: reactive oxygen species • uncoupling protein • single nucleotide polymorphism • gene expression • haplotype

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