title: Common polymorphisms of cyclooxygenase-2 and prostaglandin E2 receptor and increased risk for acute coronary syndrome in coronary artery disease.
abstract: The arachidonic acid metabolites participate in development of coronary artery disease (CAD) and the plaque's instability. We assessed two common genetic polymorphisms: of cyclooxygenase-2 (COX-2) (COX2.8473, rs5275) and prostaglandin EP2 receptor gene (uS5, rs708494) in patients with CAD. Out of 1,368 patients screened by coronary arteriography, two groups fulfilled the entry criteria and were studied: stable coronary disease (sCAD, n = 125) and acute coronary syndromes (ACS, n = 63). They did not differ in the main characteristics. All patients were on aspirin at least seven days prior to the study. In 70 control subjects, the same genotypes were ascertained, expression of cyclooxygenases in peripheral blood monocytes was assessed by flow cytometry, and in-vitro biosynthesis of PGE(2) was measured by mass spectrometry. COX-2 CC homozygotes (variant allele), were more common, while EP2 GG homozygotes (wild-type) were less common in ACS (p = 0.03 and p = 0.017) than in the sCAD group. A combined genotype characterized by the presence of the wild-type COX2.8743T allele and the wild type homozygous EP2uS5 genotype (TT or CT | GG) decreased risk ratio of ACS in CAD patients (relative risk 0.41; 95% confidence interval 0.21-0.81). COX-2 polymorphism in control subjects did not affect the enzyme expression or PGE(2) production by peripheral blood monocytes, but production of PGE(2) increased by 40.1% in the subjects homozygous for EP2 receptor allele uS5A following lipopolysaccharide stimulation. In conclusion, the combined COX-2 (COX2.8473) and the EP2 receptor (uS5) genotypes seem to influence CAD stability, but in peripheral blood monocytes only EP2 receptor modulates PGE(2) production.
authors.affiliation: Jagiellonian University, School of Medicine, Department of Medicine, ul. Skawinska 8, 31 - 066 Kraków, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szczeklik
authors.forename: Marek
authors.initials: M
authors.lastname: Sanak
authors.forename: Pawel
authors.initials: P
authors.lastname: Rostoff
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Piwowarska
authors.forename: Bogdan
authors.initials: B
authors.lastname: Jakiela
authors.forename: Andrew
authors.initials: A
authors.lastname: Szczeklik
mesh_terms: D054058:Acute Coronary Syndrome / Q000201:enzymology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D018078:Receptors, Prostaglandin E / Q000235:genetics* / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: C545644:PTGER2 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D015232:Dinoprostone