Polymorphisms of prostaglandin-endoperoxide synthase 2 gene, and prostaglandin-E receptor 2 gene, C-reactive protein concentrations and risk of atherothrombosis: a nested case–control approach

Abstract

Summary. Objective: Recent data have shown an association between polymorphisms of prostaglandin-endoperoxide synthase-2 gene (PTGS2; alias COX-2), and prostaglandin-E receptor-2 gene (PTGER2) and risk of atherothrombotic disorders. Methods: We evaluated two PTGS2 (rs20417, rs689470), and three PTGER2 (rs708494/uS5, rs708495/uS7, and chr14: 50 764 013/uS10) gene polymorphisms among 600 Caucasian male participants of the PhysiciansÕ Health Study with incident myocardial infarction (MI) or ischemic stroke and 600 age-and smoking-matched controls who remained free of all reported cardiovascular disease. Results: Genotype distributions were in Hardy-Weinberg equilibrium in the control groups. Genotype and allele distribution were similar between cases and controls. The polymorphisms tested were in linkage disequilibrium. Results from the adjusted haplotype-based conditional logistic regression analysis showed a modest association of the PTGER2 2-1-1 haplotype with reduced risk of MI (odds ratio ¼ 0.50, 95% CI; CI ¼ 0.26-0.97, P ¼ 0.04), and the 2-2-1 haplotype with reduced risk of ischemic stroke (odds ratio ¼ 0.68, 95% CI ¼ 0.47-0.99, P ¼ 0.048). In contrast to prior data, we found no evidence for an association of the PTGS2 polymorphisms/haplotypes tested with risk of incident MI nor with ischemic stroke. However, we found suggestive evidence for an association of specific PTGER2 haplotypes with reduced risk of these outcomes. Conclusion: Although these prospective data implicate the potential involvement of prostaglandin-E receptor-2 gene variation in atherothrombosis, external validation of our findings is needed.

Cox-2 gene polymorphism and IL-6 levels in coronary artery disease

“…But contrary to those results, Hegener et al (2006) found no evidence of an association of the Cox-2 polymorphisms with risk of MI. Furthermore, Kohsaka et al (2008) recently reported that the Cox-2 (-765G > C) polymorphism was, in fact, a risk factor for incident stroke in African-Americans and the result was the same for diabetic stroke cases.…”

PTGS2 gene polymorphism -765G>C is associated with coronary artery disease: a meta-analysis

“…The C allele may also be associated with lower levels of inflammatory markers such as C-reactive protein and interleukin-6 in cardio/cerebrovascular and hypercholesterolemic patients (Sowers et al, 2005). In contrast to these prior data, Hegener et al (2006) found no evidence for an association of the polymorphism with risk of incident CAD (Delgado et al, 2004). Furthermore, Kohsaka et al (2008) have recently reported that the -765C allele is in fact a risk factor for incident stroke in African-Americans (Bresalier et al, 2005).…”

“…COX-2 has been found to be upregulated in atherosclerotic plaques (Kuge et al, 2007), and the polymorphisms of its gene, designated as PTGS2, have previously been associated with ischemic heart disease and risk of stroke (Colaizzo et al, 2006;Orbe et al, 2006). However, several studies indicated that there may be no association between PTGS2 polymorphism and CAD (Hegener et al, 2006;Lee et al, 2008). Therefore, we systematically reviewed the data published to date on the relationship between PTGS2 polymorphism and CAD risk and quantitatively summarized the available evidence by performing a formal meta-analysis.…”

“…Therefore, the identification of genetic determinants associated with CAD risk has tremendous importance from a public health perspective. Recently, a number of case-control studies have suggested that -765G>C polymorphism in the PTGS2 gene is associated with the risk of CAD (Cipollone et al, 2004(Cipollone et al, , 2009Hegener et al, 2006;Lee et al, 2008;Szczeklik et al, 2008;Kohsaka et al, 2008;Huuskonen et al, 2008;Li et al, 2009;Rudock et al, 2009;Sanak et al, 2010;McGettigan et al, 2011;Ol et al, 2011).…”

Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets

“…20 SNPs in genes from the fatty-acid biosynthetic and metabolic process pathways, particularly those participating in the synthesis of prostaglandins (eg, ALOX5, ALOX5AP, ALOX12, ALOX15, PTGS1, PTGS2, and COX2), have also been identified as risk factors for atherosclerotic plaque burden and CHD events. [21][22][23][24][25][26] SNPs in other genes from these pathways modulate CHD risk, presumably through their effects on lipids. [27][28][29][30][31] Thus, inclusion of these genes among enriched gene sets is supported by existing scientific literature.…”