COX-2 Gene Promoter Polymorphism and Coronary Artery Disease in Middle-Aged Men: The Helsinki Sudden Death Study

Department of Medical Biochemistry, Medical School, University of Tampere, 33104 Tampere, Finland.
Mediators of Inflammation (Impact Factor: 3.24). 02/2008; 2008(1):289453. DOI: 10.1155/2008/289453
Source: PubMed


Cyclooxygenase (COX) catalyzes formation of prostaglandins that contribute to the inflammation in atherosclerosis. Our objective was to study whether the functional C variant of the polymorphism in the human COX-2 gene associates with the severity of coronary atherosclerosis measured at the coronary artery level. The Helsinki sudden death study autopsy material (n = 300) comprised of Finnish men who died suddenly. The area of atherosclerotic lesions in the coronary arteries was quantitated, and coronary narrowing was measured. The occurrence of myocardial infarction (MI) was assessed. Genotyping was by restriction endonuclease analysis. Men carrying the minor C allele had larger areas of complicated lesions (P = .024) and a higher number of coronary arteries that had over 50%
stenosis (P = .036) compared to men representing the
common GG genotype. The COX-2 polymorphism was not associated with
MI. Our data suggest that COX-2 may be involved in plaque

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Available from: Pekka Karhunen
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    • "W badaniu Physicians' Health Study, które obejmowało wyłącznie mężczyzn rasy kaukaskiej , wykonujących zawód lekarza nie wykazano związku polimorfizmu G-765C z ryzykiem zawału serca i udaru mózgu[18]. Podobnie, w badaniu Helsinki Sudden Death Study, w grupie 300 mężczyzn, którzy zmarli nagle, nie stwierdzono istotnej zależności między polimorfizmem G-765C a zapadalnością na zawał serca[11]. Wyniki własne potwierdzają postulowany w piśmiennictwie, prawdopodobny związek polimorfizmu G-765C w genie COX-2 z procesami aterogenezy. Istnieje uzasadnienie dla dalszych badań nad rolą polimorfizmu G-765C genu COX-2 w patogenezie wielonaczyniowej choroby wieńcowej. "
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    ABSTRACT: BACKGROUND: Chronic inflammation of the arterial wall plays a crucial role in the pathogenesis of atherosclerosis. Cyclooxygenase-2 (COX-2) is a key enzyme in the synthesis of proinflammatory prostanoids. At least two of the common genetic polymorphisms of the COX-2 gene have phenotypic effects: G-765C (rs20417) and T8473C (rs5275). AIM: To assess the relation of G-765C and T8473C COX-2 polymorphisms to clinical and angiographic characteristics of patients with coronary artery disease (CAD). MATERIAL AND METHODS: The study comprised 186 consecutive patients with angiographically defined CAD (> or =70% stenosis of > or =1 coronary artery). The study population were divided into two groups: A-123 patients with stable angina (mean age, 62.6 +/- 11.2 years; 30.1% women), and B-63 patients with unstable angina (mean age, 64.0 +/- 10.8 years; 19.0% women). The controls comprised 70 individuals without symptoms of CAD (mean age, 37.6 +/- 9.9 years; 57.1% women). Results: No significant differences were observed in -765C and 8473C allele frequencies between the patients with CAD and control subjects. In CAD patients, the studied COX-2 polymorphisms were not significantly associated with the age of the onset of symptoms and clinical presentation of CAD. In the B group, a difference was observed within the frequency of significant (>50%) left main coronary artery stenosis (LMCAS) and/or three-vessel CAD (3-CAD) between the -765C allele carriers and 765G 765G homozygotes (14.3% vs. 49.0%; p=0.044). In the CAD patients (group A and group B) the prevalence of LMCAS and/or 3-CAD was significantly lower among 365C allele carriers (22.8% vs. 40.3%: CONCLUSIONS: There were no significant differences in -765C and 8473C allele frequencies between patients with CAD and subjects without symptoms of CAD; In patients with CAD, COX-2 G-765C and T8473C polymorphisms had no significant association with the age of the onset of symptoms and clinical presentation of ischaemic heart disease; The G-765C COX-2 polymorphism is associated with less frequent occurrence of multivessel CAD in the studied population. p=0.021.
    Full-text · Article · Oct 2014 · Przegla̧d lekarski
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    • "The role of COX-2 has previously been studied in relation to advanced atherosclerosis with clinical complications, such as coronary artery disease [7,8] myocardial infarction and ischemic stroke [9]. However, atherosclerosis begins in childhood and progresses for decades until clinical complications such as myocardial infarction appear [10]. "
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    ABSTRACT: BACKGROUD: The role of cyclooxygenase-2 (COX-2) single nucleotide polymorphisms has mostly been studied in relation to advanced atherosclerosis, but little is known how they contribute to preclinical disease. In the present study we analyzed whether COX-2 gene variants associate independently with the early subclinical markers of atherosclerosis, carotid intima-media thickness and carotid artery distensibility in a population of young healthy Caucasian adults. SNPs for association analysis were collected from the COX-2 gene and 5 kb up- and downstream of it. There were 19 SNPs available for analysis, four genotyped and fifteen imputed. Genotype data was available for 2442 individuals participating in the Cardiovascular Risk in Young Finns Study. Genotype imputation was performed using MACH 1.0 and HapMap II CEU (release 22) samples as reference. Association analysis was performed using linear regression with an additive model. PLINK was used for true genotyped SNPs and ProbABEL for imputed genotype dosages. False discovery rate was used to take into account multiple testing bias. Two of the COX-2 variants (rs689470, rs689462) associated with distensibility (p = 0.005) under the linear regression additive model. After adjustment with gender, age, body mass index and smoking status, association between these SNPs and distensibility remained significant (p = 0.031). Subjects carrying the minor alleles had higher value of carotid artery distensibility compared to the major allele homozygotes. However, after correcting p-values for multiple testing bias using false discovery rate, association was lost. Another COX-2 variant rs4648261 associated with mean carotid intima-media thickness (p = 0.046) and maximal carotid intima-media thickness (p = 0.048) in the linear regression model. Subjects carrying the minor allele of rs4648261 had lower values of mean and maximal carotid intima-media thickness compared to subjects homozygote for major allele. After adjustments the associations were lost with both mean and maximal carotid intima-media thickness. Thus, no statistically significant associations of the studied COX-2 variants with carotid artery distensibility or carotid intima-media thickness were found. Our results suggest that in a Finnish population, there are no significant associations between COX-2 variants and early atherosclerotic changes in young adulthood.
    Full-text · Article · May 2012 · BMC Medical Genetics
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    • "Cox-2 expression has been detected in endothelial cells, smooth muscle cells, monocytes, and macrophages within human atherosclerotic lesions. Many PGs produced by the Cox-2 enzyme, including thromboxane, stimulate vasoconstriction, platelet aggregation, and leukocyte-endothelial cell adhesion and so contribute to the formation of thrombosis and atherosclerosis (Huuskonen et al., 2008). Cox-2, which is normally undetectable in most tissues, can be upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters, suggesting its relevance to inflammation (Prescott and Fitzpatrick, 2000; Pisetsky and St. Clair, 2001). "
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    ABSTRACT: Coronary artery disease is one of the leading causes of mortality and diabetes mellitus is one of its main risk factors due to microvascular and macrovascular complications, such as atherosclerosis. Atherosclerosis is now known to be an inflammatory process mediated by prostaglandins and several interleukins. As both are important in inflammatory processes, we examined Cox-2 (-765G > C) polymorphism and interleukin-6 levels in coronary artery disease patients compared to healthy controls. We also divided the patients into diabetic and non-diabetic groups to check the effects of diabetes mellitus separately. We found that the GG allele frequency was significantly higher in the patient group. Patients with the GG genotype had an approximately 2.78-fold higher risk of coronary artery disease. We also found that the Cox-2 (-765G > C) polymorphism is associated with lower interleukin-6 levels, which decreased in the order: GG > GC > CC.
    Full-text · Article · Jan 2011 · Genetics and molecular research: GMR
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