Associations of the UCP2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women.
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 beta-cell function may also affect UCP2 gene expression in cells of the arterial wall.


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 1alpha 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.
Oberkofler
H
H
Paracelsus Private Medical University and Salzburger Landeskliniken, Salzburg, Austria.
Iglseder
B
B
Klein
K
K
Unger
J
J
Haltmayer
M
M
Krempler
F
F
Paulweber
B
B
Patsch
W
W
D000328:Adult; D017677:Age Distribution; D000368:Aged; D002340:Carotid Artery Diseases / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003430:Cross-Sectional Studies; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels; D008264:Macrophages / Q000166:cytology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D017678:Sex Distribution; D000071246:Uncoupling Protein 2
D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2