A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke

Maurizio Averna, Andrea Mezzetti, Chiara Cuccurullo, Sebastiano Ursi, Maria Fazia, Gianfranco Vitullo, Sante Ucchino, Elena Toniato, Barbara Pini, Francesco Spigonardo, Annalisa Iezzi, Francesco Cipollone, Anna Montali, Stefano Martinotti, Filomena Campagna, Franco Cuccurullo, Agostino Virdis, Giovanni Ciabattoni, Marcello Arca, Stefano Taddei

Risultato della ricerca: Article

229 Citazioni (Scopus)

Abstract

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 E(2) 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 PGF1alpha (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 =.04).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.
Lingua originaleEnglish
pagine (da-a)2221-2228
Numero di pagine8
RivistaJAMA
Volume291
Stato di pubblicazionePublished - 2004

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Cyclooxygenase 2
Stroke
Myocardial Infarction
Digestion
Genes
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Epoprostenol
Vasodilation
Endothelium
Rupture
Protective Factors
DNA Restriction Enzymes
Atherosclerotic Plaques
Prostaglandins E
Hypercholesterolemia
Matrix Metalloproteinases
Forearm
C-Reactive Protein
Case-Control Studies

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Averna, M., Mezzetti, A., Cuccurullo, C., Ursi, S., Fazia, M., Vitullo, G., ... Taddei, S. (2004). A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA, 291, 2221-2228.

A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. / Averna, Maurizio; Mezzetti, Andrea; Cuccurullo, Chiara; Ursi, Sebastiano; Fazia, Maria; Vitullo, Gianfranco; Ucchino, Sante; Toniato, Elena; Pini, Barbara; Spigonardo, Francesco; Iezzi, Annalisa; Cipollone, Francesco; Montali, Anna; Martinotti, Stefano; Campagna, Filomena; Cuccurullo, Franco; Virdis, Agostino; Ciabattoni, Giovanni; Arca, Marcello; Taddei, Stefano.

In: JAMA, Vol. 291, 2004, pag. 2221-2228.

Risultato della ricerca: Article

Averna, M, Mezzetti, A, Cuccurullo, C, Ursi, S, Fazia, M, Vitullo, G, Ucchino, S, Toniato, E, Pini, B, Spigonardo, F, Iezzi, A, Cipollone, F, Montali, A, Martinotti, S, Campagna, F, Cuccurullo, F, Virdis, A, Ciabattoni, G, Arca, M & Taddei, S 2004, 'A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke', JAMA, vol. 291, pagg. 2221-2228.
Averna M, Mezzetti A, Cuccurullo C, Ursi S, Fazia M, Vitullo G e altri. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA. 2004;291:2221-2228.
Averna, Maurizio ; Mezzetti, Andrea ; Cuccurullo, Chiara ; Ursi, Sebastiano ; Fazia, Maria ; Vitullo, Gianfranco ; Ucchino, Sante ; Toniato, Elena ; Pini, Barbara ; Spigonardo, Francesco ; Iezzi, Annalisa ; Cipollone, Francesco ; Montali, Anna ; Martinotti, Stefano ; Campagna, Filomena ; Cuccurullo, Franco ; Virdis, Agostino ; Ciabattoni, Giovanni ; Arca, Marcello ; Taddei, Stefano. / A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. In: JAMA. 2004 ; Vol. 291. pagg. 2221-2228.
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title = "A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke",
abstract = "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 E(2) 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 PGF1alpha (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 =.04).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.",
keywords = "Genetic; Prospective Studies; Prostaglandin-Endoperoxide Synthases; Risk Factors, rteriosclerosis; Carotid Stenosis; Cerebrovascular Accident; Cohort Studies; Cyclooxygenase 2; Epoprostenol; Female; Genotype; Humans; Isoenzymes; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Membrane Proteins; Middle Aged; Myocardial Infarction; Phenotype; Polymorphism",
author = "Maurizio Averna and Andrea Mezzetti and Chiara Cuccurullo and Sebastiano Ursi and Maria Fazia and Gianfranco Vitullo and Sante Ucchino and Elena Toniato and Barbara Pini and Francesco Spigonardo and Annalisa Iezzi and Francesco Cipollone and Anna Montali and Stefano Martinotti and Filomena Campagna and Franco Cuccurullo and Agostino Virdis and Giovanni Ciabattoni and Marcello Arca and Stefano Taddei",
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language = "English",
volume = "291",
pages = "2221--2228",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
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TY - JOUR

T1 - A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke

AU - Averna, Maurizio

AU - Mezzetti, Andrea

AU - Cuccurullo, Chiara

AU - Ursi, Sebastiano

AU - Fazia, Maria

AU - Vitullo, Gianfranco

AU - Ucchino, Sante

AU - Toniato, Elena

AU - Pini, Barbara

AU - Spigonardo, Francesco

AU - Iezzi, Annalisa

AU - Cipollone, Francesco

AU - Montali, Anna

AU - Martinotti, Stefano

AU - Campagna, Filomena

AU - Cuccurullo, Franco

AU - Virdis, Agostino

AU - Ciabattoni, Giovanni

AU - Arca, Marcello

AU - Taddei, Stefano

PY - 2004

Y1 - 2004

N2 - 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 E(2) 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 PGF1alpha (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 =.04).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.

AB - 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 E(2) 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 PGF1alpha (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 =.04).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.

KW - Genetic; Prospective Studies; Prostaglandin-Endoperoxide Synthases; Risk Factors

KW - rteriosclerosis; Carotid Stenosis; Cerebrovascular Accident; Cohort Studies; Cyclooxygenase 2; Epoprostenol; Female; Genotype; Humans; Isoenzymes; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Membrane Proteins; Middle Aged; Myocardial Inf

UR - http://hdl.handle.net/10447/19807

M3 - Article

VL - 291

SP - 2221

EP - 2228

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

ER -