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Francesco Cipollone, MD; Elena Toniato, PhD; Stefano Martinotti, MD; Maria Fazia, PhD; Annalisa Iezzi, MD; Chiara Cuccurullo, MD; Barbara Pini, MD; Sebastiano Ursi, PhD; Gianfranco Vitullo, MD; Maurizio Averna, MD; Marcello Arca, MD; Anna Montali, BS; Filomena Campagna, PhD; Sante Ucchino, MD; Francesco Spigonardo, MD; Stefano Taddei, MD; Agostino Virdis, MD; Giovanni Ciabattoni, MD; Alberto Notarbartolo, MD; Franco Cuccurullo, MD; Andrea Mezzetti, MD; for the Identification of New Elements of Plaque Stability (INES) Study Group

JAMA. 2004;291:2221-2228.

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 –765GC 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 –765GC variant of the COX-2 gene was genotyped by restriction endonuclease digestion of polymerase chain reaction products.

Main Outcome Measures  Presence of the –765GC 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 PGF₁ (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 –765GC 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).

Conclusions  We found that the –765GC 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.

Author Affiliations: G. d'Annunzio University of Chieti and G. d'Annunzio University Foundation, Chieti, Italy (Drs Cipollone, Toniato, Martinotti, Fazia, Iezzi, C. Cuccurullo, Pini, Ursi, Vitullo, Ucchino, Spigonardo, Ciabattoni, F. Cuccurullo, and Mezzetti); University of Palermo, Palermo, Italy (Drs Averna and Notarbartolo); University of Rome La Sapienza, Rome, Italy (Drs Arca and Campagna and Ms Montali); and the University of Pisa, Pisa, Italy (Drs Taddei and Virdis).

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