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

Abstract

Goals 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. Methods Cases were outpatients with ischemic stroke; controls were stroke-free subjects from two 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 (ELISA) were performed to confirm T. cruzi infection and to quantify PGE2 levels. In the Boston cohort, white matter hyperintensity volume (WMHv) was quantified on the admission brain MRIs of subjects with ischemic stroke, who also donated DNA for the COX-2 gene region analysis. Findings 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, 486 non-cardioembolic) in the Boston cohort. In the Brazilian cohort, rs20417 polymorphism was associated with both stroke (p=5x10−6) and decreased PGE2 levels (p=4x10−5); similarly, Chagas was associated with stroke (p=4x10−3) and decreased PGE2 levels (p=7x10−3). In the Boston cohort, rs20417 polymorphism was associated with increased WMHv among non-cardioembolic (p=0.037), but not among cardioembolic stroke patients. Conclusions 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.

Silencing of PTGS2 exerts promoting effects on angiogenesis endothelial progenitor cells in mice with ischemic stroke via repression of the NF‐κB signaling pathway

“…Prostaglandin-endoperoxide synthase (PTGS2), also known as COX-2, is a primary response gene that is associated with maintenance of homeostasis in normal tissues and regulation of inflammation (S. L. Ma et al, 2008). The association of COX-2 gene polymorphism with ischemic stroke was explained in a variety of research (Oliveira-Filho et al, 2015;Wu et al, 2016). It is common knowledge that NF-κB mediates genes encoding cytokine receptors and cytokines, as well as cell adhesion molecules which contribute to immunity and inflammation (St-Germain, Gagnon, Parent, & Asselin, 2004).…”

Genetic variants of PTGS2, TXA2R and TXAS1 are associated with carotid plaque vulnerability, platelet activation and TXA2 levels in ischemic stroke patients

“…In the Atherosclerosis Risk in Communities (ARIC) study and one other study, the C allele of PTGS2 rs20417 was reported to be associated with higher risk of stroke in African Americans or Brazilian population [16,32]. In contrast, the C allele was associated with lower risks of myocardial infarction, ischemic stroke and carotid intima-media thickness in an Italian population [15,33].…”

“…Several studies have investigated the association of a functional polymorphism of PTGS2 rs20417 and TXA2R rs1131882 with the risk of cardiovascular disease or ischemic stroke [ 14 – 18 , 21 , 22 ]. In the Atherosclerosis Risk in Communities (ARIC) study and one other study, the C allele of PTGS2 rs20417 was reported to be associated with higher risk of stroke in African Americans or Brazilian population [ 16 , 32 ]. In contrast, the C allele was associated with lower risks of myocardial infarction, ischemic stroke and carotid intima-media thickness in an Italian population [ 15 , 33 ].…”

“…Numerous genetic polymorphisms in PTGS2 have been identified and characterized [ 41 ]. The C allele of PTGS2 rs20417 was reported to be associated with COX-2 activity and higher risk of stroke in African Americans [ 16 , 32 ]. Up to date, the association of TBXAS1 variation with cardiovascular disease and ischemic stroke has not been well addressed.…”

Genetic Variation of Inflammatory Genes to Ischemic Stroke Risk in a Chinese Han Population

“…17 Multiple studies reported an association between PTGS2 genetic polymorphisms and IS risk. 18,19 Matrix metalloproteinases (MMPs), as a category of proteolytic zinc-dependent enzymes, play an important role in the degradation of the extracellular matrix and take part in the progression of atherosclerosis by triggering the migration and proliferation of smooth muscle cells and by causing destabilization of atherosclerotic plaques. 20 Previously, studies have reported that the MMPs protein levels elevate result in blood-brain barrier dysfunction and impact the extent of the infarct, [21][22][23] and the polymorphisms of MMPs have been evaluated in IS.…”