Assessment of A379V (Ala379Val) Genetic Variant of Lipoprotein-Associated Phospholipase A2 Gene (PLA2G7) in Patients with Acute Ischemic Stroke

Abstract

SUMMARY AND CONCLUSION C erebrovascular stroke is the second most common cause of death (after ischemic heart diseases) and the leading cause of disability worldwide and one of the leading causes of death in Egypt, according to the WHO media center. Ischemic stroke is the most common type of stroke in Egypt, as in other countries, accounting for 43% to 79% of all stroke types. Acute Ischemic stroke is diagnosed by full history, clinical examination including general and neurological examinations, emergent brain imaging for confirming the diagnosis including CT and MRI, and the conventional baseline laboratory testing that is often limited to blood glucose, coagulation studies, complete blood count (CBC) and lipid profile. Additional laboratory tests may include cardiac biomarkers, homocysteine level, antinuclear antibody (ANA), & rheumatoid factor. Emerging studies of the genetic basis of enzymes like matrix metalloproteinases, Angiotensin converting enzyme and lipoprotein-associated phospholipase A2 (Lp-PLA2) maybe essential for early diagnosis and determining the prognosis of acute ischemic stroke. There are some traditional factors that increase the risk of ischemic stroke such as hypertension and hyperlipidemia, but genetic risk factors, suggested by evidence from inheritance-based studies, might contribute to a predisposition to ischemic stroke. Inflammation is an essential process in the pathogenesis of ischemic stroke. Therefore, genes involved in inflammatory responses are under investigation to look for variants predisposing to ischemic stroke. Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase (PAF-AH) is a calcium ion (Ca2+) independent phospholipase which belongs to phospholipase A2 superfamily and is composed of 441 amino acids. It is a phospholipid with a variety of biological functions. Lp-PLA2 was primarily recognized as an anti-inflammatory enzyme because of its capability of degrading platelet- activating factor. Intriguingly, this anti-inflammatory activity is gradually opposed by its pro-inflammatory action. It is involved in the signaling and activation of proinflammatory cells such as platelets, neutrophils, and macrophages and also it might inhibit the apoptosis of B cells. Furthermore, it has been reported to alter vascular permeability and to induce hypertension, platelet-dependent broncho-constriction and smooth-muscle contraction. Lp-PLA2 also paticipates in the oxidative modification of low-density lipoprotein (LDL) by cleaving oxidized phosphatidylcholines, generating lysophosphatidylcholine (lyso-PC) and oxidized non-esterified fatty acids (oxNEFAs), which are two important pro-inflammatory mediators and can promote atherosclerosis by increasing oxidative stress and the presence of oxidized LDL and other lipoproteins in the plasma and arterial walls, thereby initiating fatty streak formation. Genetic study of the human Lp-PLA2 shows that it is encoded by the PLA2G7 gene, which is located on chromosome 6p21-p12 originally assigned as the human leukocyte antigen region. One non-synonymous polymorphism A379V (Ala379Val) in exon 11, has previously been found to be associated with coronary artery disease & ischemic stroke in Chinese and USA population. However, little is known about whether the PLA2G7 gene polymorphism is associated with the risk of ischemic stroke in Egyptian population or not. So our study aimed at investigating the association of A379V (Ala 379 Val) genetic variant of PLA2G7 gene in patients with acute ischemic stroke. Our study was conducted on a group of twenty (20) patients presented with acute ischemic stroke in the first 48 hours and diagnosed according to clinical neurological and radiological examinations. The other group included in our study was a control group of eleven (11) apparently healthy, age and sex matching subjects. Assay of A379V genetic variant of PLA2G7 was by PCR- RFLP analysis. In this study, we found that the genotypic and allelic frequencies of A379V were found in higher percentages in patients with acute ischemic stroke than controls, yet they didn't show statistically significant association with the presence of acute ischemic stroke regarding the distributions of genotypes (P value = 0.115) of A379V between acute ischemic stroke patients and controls, indicating the inability to associate between A379V polymorphism and acute ischemic stroke. The AV genotype (35 % in patients and 9 % in controls) of A379V was represented at an increased frequency in the group of patients but the frequency of A379V V allele wasn't significantly higher in patients with acute ischemic stroke than in the control group (P value = 0.497). A379V variant was also found at higher percentages in female patients with AIS than in male patients, but A379V variant showed no statistically significant association with a certain age, sex, as well as hypertension, diabetes mellitus and hyperlipidemia in the Egyptian population. Thus, the ability of the Lp-PLA2 to cause acute ischemic stroke may be mediated through a mechanism that is at least partially independent of its polymorphic activity, although we cannot exclude the potential role of Lp-PLA2 gene in modulating the steps of atherosclerosis that contribute in the pathogenesis of acute ischemic stroke.