A Polymorphism in the Cyclooxygenase 2 Gene as an Inherited Protective Factor Against Myocardial Infarction and Stroke

ContextMyocardial infarction (MI) and ischemic stroke are thought to be caused by matrix digestion by metalloproteinases (MMPs) leading to rupture of atherosclerotic plaques. Production of macrophage MMP-2 and MMP-9 is induced by cyclooxygenase 2 (COX-2) and prostaglandin E2 synthesis. Although COX-2 expression may be genetically determined, the relation between COX-2 polymorphisms and the risk of MI and stroke is unclear.ObjectiveTo investigate the relationship between the −765G→C polymorphism of the COX-2 gene and clinically evident plaque rupture.Design, Setting, and ParticipantsProspective, matched case-control study conducted between March 2002 and October 2003 among 864 patients with first MI or atherothrombotic ischemic stroke and 864 hospitalized controls. The groups were matched for age, sex, body mass index, smoking, hypertension, hypercholesterolemia, and diabetes. The −765G→C variant of the COX-2 gene was genotyped by restriction endonuclease digestion of polymerase chain reaction products.Main Outcome MeasuresPresence of the −765G→C polymorphism of the COX-2 gene; COX-2, MMP-2, and MMP-9 expression and activity in plaques and in peripheral monocytes; urinary 6-keto PGF1α (marker of endothelial prostacyclin); and endothelium-dependent and -independent forearm blood flow vasodilation.ResultsThe prevalence of −765GC was 2.41 times higher among controls than among cases (43.3% vs 17.9%; P<.001). The prevalence of −765CC homozygosity was 5.81 times higher (6.4% vs 1.1%; P = .04). Among participants carrying the −765GC and −765CC genotypes, the prevalence ratios for MI or stroke were 0.48 (95% CI, 0.36-0.68) and 0.33 (95% CI, 0.24-0.55), respectively. Expression of COX-2 and MMPs was significantly lower in atherosclerotic plaques from participants carrying the −765C allele, while the −765G→C polymorphism did not affect endothelial prostacyclin biosynthesis or endothelium-dependent vasodilation in vivo. In subgroup analyses (n = 224 cases), serum high-sensitivity C-reactive protein was significantly lower in patients carrying the −765C allele (mean [SD], 0.78 [0.1] vs 2.56 [0.4] mg/L; P = .04).ConclusionsWe found that the −765G→C polymorphism of the COX-2 gene is associated with a decreased risk of MI and stroke. Detection of this genotype may be useful for predicting genetic risk of MI and stroke

Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes

Receptor for advanced glycation end products (AGEs) (RAGE) plays a central role in the process of plaque rupture in diabetic patients. Recently, it has been reported that RAGE may be downregulated by improving glycemic control. In contrast, despite being well known that RAGE may be induced in human vessels in a glucose-independent fashion, also by myeloperoxidase (MPO)-dependent AGE generation, no data exist regarding the possibility of a pharmacological modulation of glucose-independent RAGE generation. Thus, the aim of this study was to characterize the effect of simvastatin on the expression of RAGE and RAGE-dependent plaque-destabilizing genes in human atherosclerotic plaques

Supervised Component Generalized Linear Regression using a PLS-extension of the Fisher scoring algorithm

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