Original Article| Volume 24, ISSUE 8, P1817-1822, August 2015

COX-2 rs20417 Polymorphism Is Associated with Stroke and White Matter Disease


      To investigate the effect of COX-2 polymorphism and its product, prostaglandin E2 (PGE2), on stroke risk in an endemic area for Chagas disease. In a separate cohort, to investigate the effect of COX-2 polymorphisms on the total burden of cerebral white matter disease.


      Cases were outpatients with ischemic stroke; controls were stroke-free subjects from 2 outpatient clinics (heart failure and caregivers of a movement disorders clinic). We extracted DNA from total blood to investigate the rs20417 COX-2 polymorphism. Serologic tests (Enzime-linked immunosorbent assay) were performed to confirm Trypanosoma cruzi infection and to quantify PGE2 levels. In the Boston cohort, white matter hyperintensity volume (WMHv) was quantified on the admission brain magnetic resonance images of subjects with ischemic stroke, who also donated DNA for the COX-2 gene region analysis.


      We studied 44 patients with stroke and 96 controls (46 with heart failure and 50 caregivers) in the Brazilian cohort; and 788 stroke patients (302 cardioembolic and 486 noncardioembolic) in the Boston cohort. In the Brazilian cohort, rs20417 polymorphism was associated with both stroke (P = 5 × 10−6) and decreased PGE2 levels (P = 4 × 10−5); similarly, Chagas was associated with stroke (P = 4 × 10−3) and decreased PGE2 levels (P = 7 × 10−3). In the Boston cohort, rs20417 polymorphism was associated with increased WMHv among noncardioembolic (P = .037), but not among cardioembolic stroke patients.


      Variation in COX-2 gene is associated with both symptomatic and silent brain cerebrovascular disease. This candidate gene region should be tested in population-based samples.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Stroke and Cerebrovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Helgadottir A.
        • Manolescu A.
        • Thorleifsson G.
        • et al.
        The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.
        Nat Genet. 2004; 36: 233-239
        • Li W.
        • Xu J.
        • Wang X.
        • et al.
        Cyclooxygenase-2 (COX-2) G-765C is a protective factor for coronary artery disease but not for ischemic stroke: a meta-analysis.
        Atherosclerosis. 2009; 207: 492-495
        • Wang H.
        • Fu Y.
        • Liu D.
        • et al.
        The COX-2 rs20417 polymorphism and risk of coronary artery disease: evidence from 17,621 subjects.
        Heart Lung Circ. 2014; 23: 572-577
        • Funk C.D.
        • FitzGerald G.A.
        COX-2 inhibitors and cardiovascular risk.
        J Cardiovasc Pharmacol. 2007; 50: 470-479
        • Carod-Artal F.J.
        Stroke: a neglected complication of American trypanosomiasis (Chagas' disease).
        Trans R Soc Trop Med Hyg. 2007; 101: 1075-1080
        • Carod-Artal F.J.
        • Gascon J.
        Chagas disease and stroke.
        Lancet Neurol. 2010; 9: 533-542
        • Bern C.
        • Montgomery S.P.
        An estimate of the burden of Chagas disease in the United States.
        Clin Infect Dis. 2009; 49: e52-e54
        • Oliveira-Filho J.
        • Viana L.C.
        • Vieira-de-Melo R.M.
        • et al.
        Chagas disease is an independent risk factor for stroke: baseline characteristics of a Chagas Disease cohort.
        Stroke. 2005; 36: 2015-2017
        • Paixao L.C.
        • Ribeiro A.L.
        • Valacio R.A.
        • et al.
        Chagas disease: independent risk factor for stroke.
        Stroke. 2009; 40: 3691-3694
        • Corral R.S.
        • Guerrero N.A.
        • Cuervo H.
        • et al.
        Trypanosoma cruzi infection and endothelin-1 cooperatively activate pathogenic inflammatory pathways in cardiomyocytes.
        PLoS Negl Trop Dis. 2013; 7: e2034
        • Abdalla G.K.
        • Faria G.E.
        • Silva K.T.
        • et al.
        Trypanosoma cruzi: the role of PGE2 in immune response during the acute phase of experimental infection.
        Exp Parasitol. 2008; 118: 514-521
        • Rost N.S.
        • Rahman R.M.
        • Biffi A.
        • et al.
        White matter hyperintensity volume is increased in small vessel stroke subtypes.
        Neurology. 2010; 75: 1670-1677
        • Chutinet A.
        • Rost N.S.
        White matter disease as a biomarker for long-term cerebrovascular disease and dementia.
        Curr Treat Options Cardiovasc Med. 2014; 16: 292
        • Adib-Samii P.
        • Rost N.
        • Traylor M.
        • et al.
        17q25 Locus is associated with white matter hyperintensity volume in ischemic stroke, but not with lacunar stroke status.
        Stroke. 2013; 44: 1609-1615
        • Jones W.J.
        • Williams L.S.
        • Meschia J.F.
        Validating the Questionnaire for Verifying Stroke-Free Status (QVSFS) by neurological history and examination.
        Stroke. 2001; 32: 2232-2236
        • Ay H.
        • Benner T.
        • Arsava E.M.
        • et al.
        A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System.
        Stroke. 2007; 38: 2979-2984
        • Gordon D.L.
        • Bendixen B.H.
        • Adams Jr., H.P.
        • et al.
        Interphysician agreement in the diagnosis of subtypes of acute ischemic stroke: implications for clinical trials. The TOAST Investigators.
        Neurology. 1993; 43: 1021-1027
        • Rost N.S.
        • Rahman R.
        • Sonni S.
        • et al.
        Determinants of white matter hyperintensity volume in patients with acute ischemic stroke.
        J Stroke Cerebrovasc Dis. 2010; 19: 230-235
        • Kohsaka S.
        • Volcik K.A.
        • Folsom A.R.
        • et al.
        Increased risk of incident stroke associated with the cyclooxygenase 2 (COX-2) G-765C polymorphism in African-Americans: the Atherosclerosis Risk in Communities Study.
        Atherosclerosis. 2008; 196: 926-930
        • Lee C.R.
        • North K.E.
        • Bray M.S.
        • et al.
        Cyclooxygenase polymorphisms and risk of cardiovascular events: the Atherosclerosis Risk in Communities (ARIC) study.
        Clin Pharmacol Ther. 2008; 83: 52-60
        • Yi X.Y.
        • Zhou Q.
        • Lin J.
        • et al.
        Interaction between ALOX5AP-SG13S114A/T and COX-2-765G/C increases susceptibility to cerebral infarction in a Chinese population.
        Genet Mol Res. 2013; 12: 1660-1669
        • Chen G.Z.
        • Shan X.Y.
        • Cheng G.P.
        • et al.
        Cyclooxygenase-2 genetic polymorphism and stroke subtypes in Chinese.
        J Mol Neurosci. 2013; 51: 467-473
        • Shan X.Y.
        • Chen G.Z.
        • Cheng G.P.
        • et al.
        Cyclooxygenase 2 genetic polymorphism may increase the risk of developing leukoaraiosis in Chinese.
        J Mol Neurosci. 2013; 51: 461-466
        • Cheng Y.
        • Austin S.C.
        • Rocca B.
        • et al.
        Role of prostacyclin in the cardiovascular response to thromboxane A2.
        Science. 2002; 296: 539-541
        • Liang X.
        • Lin L.
        • Woodling N.S.
        • et al.
        Signaling via the prostaglandin E(2) receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia.
        J Clin Invest. 2011; 121: 4362-4371
        • Li J.
        • Liang X.
        • Wang Q.
        • et al.
        Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia.
        Neurosci Lett. 2008; 438: 210-215
        • Sharma J.
        • Eickhoff C.S.
        • Hoft D.F.
        • et al.
        The absence of myocardial calcium-independent phospholipase A2gamma results in impaired prostaglandin E2 production and decreased survival in mice with acute Trypanosoma cruzi infection.
        Infect Immun. 2013; 81: 2278-2287
        • Ganzinelli S.
        • Borda E.
        • Joensen L.
        • et al.
        Chagasic antibodies induce cardiac COX-2/iNOS mRNA expression with PGE2/NO production.
        Int J Cardiol. 2009; 134: 212-223
        • Kozora E.
        • Filley C.M.
        Cognitive dysfunction and white matter abnormalities in systemic lupus erythematosus.
        J Int Neuropsychol Soc. 2011; 17: 385-392
        • Tektonidou M.G.
        • Varsou N.
        • Kotoulas G.
        • et al.
        Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings.
        Arch Intern Med. 2006; 166: 2278-2284