Context Myocardial 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.
Objective To investigate the relationship between the −765G→C polymorphism
of the COX-2 gene and clinically evident plaque rupture.
Design, Setting, and Participants Prospective, 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 Measures Presence 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.
Results The 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 =
Conclusions We 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.