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

Abstract

Eicosanoids may play a role in ischemic stroke. However, the associations of variants in cyclooxygenase (COX) pathway genes and interaction among these variants with carotid plaque vulnerability are not fully understood. In present study, twelve variants in COX pathway genes were examined using matrix-assisted laser desorption ionization time-of-flight mass spectrometry method in 396 patients with ischemic stroke and 291 controls. Platelet aggregation, platelet-leukocyte aggregates, and urine 11-dehydrothromboxane B2 (11-dTxB2) were also measured. According to the results of carotid high-resolution B-mode ultrasound, the patients were stratified into the following groups [i.e., non-carotid plaque and carotid plaque. The carotid plaque was further classified into subgroups of echolucent plaque (ELP) and echogenic plaque (EGP)]. Additionally, gene-gene interactions were analyzed to assess whether there was any interactive role for assessed variants in affecting carotid plaque vulnerability, platelet activation and 11-dTxB2 levels. There were no significant differences in the frequencies of genotypes of the twelve variants between patients and controls. Among 396 patients, 294 cases (74.2%) had carotid plaques (106 had ELP, 188 had EGP). Frequency of PTGS2 rs20417CC, TXAS1 rs2267679TT, TXAS1 rs41708TT, PTGIS rs5602CC, and TXA2R rs1131882TT genotype was significantly higher in patients with plaque compared with patients without plaque, or in patients with ELP compared with patients with EGP. 11-dTxB2 levels, platelet aggregation and platelet-leukocyte aggregates were significantly higher in patients with ELP compared with patients without plaque or with EGP. Multivariate logistic regression analysis revealed that PTGS2 rs20417CC, TXA2R rs1131882TT, and high-risk interaction among variants in PTGS2 rs20417, TXA2R rs1131882 and TXAS1 rs41708 were independently associated with the risk of ELP after adjusting for confounding variables. The variants in COX pathway genes and the high-risk interactions among variants in PTGS2 rs20417, TXA2R rs1131882 and TXAS1 rs41708 were associated with high 11-dTxB2 and platelet activation, and independently associated with the risk of carotid plaque vulnerability. These variants might be potential markers for plaque instability.

Inflammation and Endothelial Function Relevant Genetic Polymorphisms and Carotid Plaque in Chinese Population

“…Therefore, genetic variants in inflammation and endothelial function relevant genes may influence metabolism of lipids and affect atherogenesis. Several studies have investigated the association between carotid atherosclerosis and inflammation-and endothelial function-related genetic variants [10][11][12][13] . However, information about specific genetic determinants of carotid plaque is lacking, particularly among Chinese populations.…”

“…It is known that atherosclerosis as a common complex trait does not follow the Mendelian pattern of inheritance 14) . Gene-gene and gene-environment interactions may be responsible for the complex trait 12,13) . It has been emphasized that assessment of multiple genes is necessary to identify the genetic mechanisms for carotid plaque using the generalized multifactor dimensionality reduction (GMDR) approach 15) .…”

“…Carotid characteristics, including intima-media thickness (IMT), plaque morphology, and degree of carotid stenosis, were evaluated. The detailed procedures for evaluating plaques, types of plaques, degree of carotid stenosis, intraobserver, and interobserver coefficients were described in our previous study 12,13,19) . Briefly, bilateral internal and common carotid arteries, as well as bifurcations, were examined for the presence of atherosclerotic plaque.…”

“…Furthermore, according to plaque echogenicity and surface structure, carotid plaque was further graded from class I to class IV as echolucent, predominantly echolucent, predominantly echogenic, and echogenic, respectively 20) . Plaque of class I or class II was defined as vulnerable plaque, and plaque of class III or class IV was defined as stable plaque 12,13) . Carotid characteristics were graded independently by one ultrasound imaging doctor blinded to clinical status.…”

C1q/TNF‐related protein 9: A novel therapeutic target in ischemic stroke?

“…Besides, platelet activation may interact with lipid peroxidation (van Kooten, Ciabattoni, Patrono, Dippel, & Koudstaal, ), leukocytes (Schmalbach et al, ), fibrinolysis (Wang, Li, & Liu, ) and EC (Shantikumar, Grant, Catto, Bamford, & Carter, ) in the pathogenesis of ischemic stroke. In particular, some genetic variants associated with platelet activation have been revealed in the past two years (Postula et al, ; Yi, Lin, Luo, Wang, & Liu, ).…”