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A Method to Study the C924T Polymorphism of the Thromboxane A2 Receptor Gene
Published on: April 1, 2019
A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and
Francesco Cipollone1, Elena Toniato, Stefano Martinotti
1G. d'Annunzio University of Chieti and G. d'Annunzio University Foundation, Chieti, Italy.
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.
Insights
The -765G-->C polymorphism in the cyclooxygenase-2 (COX-2) gene is linked to a reduced risk of myocardial infarction (MI) and stroke. Identifying this genetic variant may help predict an individual's susceptibility to these cardiovascular events.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Epidemiology
Background:
- Myocardial infarction (MI) and ischemic stroke are linked to atherosclerotic plaque rupture, potentially mediated by matrix metalloproteinases (MMPs).
- Macrophage production of MMP-2 and MMP-9 is upregulated by cyclooxygenase-2 (COX-2) and prostaglandin E2.
- The genetic basis of COX-2 expression and its association with MI and stroke risk remain unclear.
Purpose of the Study:
- To investigate the association between the -765G-->C polymorphism of the COX-2 gene and the occurrence of clinically evident plaque rupture.
- To determine if this COX-2 gene variant influences the risk of myocardial infarction (MI) or atherothrombotic ischemic stroke.
Main Methods:
- A prospective, matched case-control study involving 864 patients with first MI or ischemic stroke and 864 controls.
- Genotyping of the -765G-->C variant of the COX-2 gene using polymerase chain reaction and restriction endonuclease digestion.
- Assessment of COX-2, MMP-2, MMP-9 expression, urinary 6-keto PGF1alpha, and forearm blood flow vasodilation.
Main Results:
- The -765G-->C polymorphism (both heterozygous -765GC and homozygous -765CC) was significantly less prevalent in patients with MI or stroke compared to controls.
- Carriers of the -765C allele had a reduced risk of MI or stroke (odds ratios 0.48 and 0.33, respectively).
- Lower expression of COX-2 and MMPs was observed in plaques from -765C allele carriers; no significant impact on prostacyclin biosynthesis or vasodilation was found.
Conclusions:
- The -765G-->C polymorphism of the COX-2 gene is associated with a decreased risk of myocardial infarction and stroke.
- This genotype may serve as a useful marker for predicting genetic predisposition to MI and stroke.
- The findings suggest a protective role of the -765C allele against cardiovascular events.
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