Although there has been great progress in understanding the genetic bases of ischemic stroke (IS), many of its aspects remain underexplored. These include the genetics of outcomes, as well as problems with the identification of real causative loci and their functional annotations. Therefore, analysis of the results obtained from animal models of brain ischemia could be helpful. We have developed a bioinformatic approach exploring single nucleotide polymorphisms (SNPs) in human orthologues of rat genes expressed differentially under conditions of induced brain ischemia. Using this approach, we identified and analyzed nine SNPs in 553 Russian individuals (331 patients with IS and 222 controls). We explored the association of SNPs with both IS outcomes and with the risk of IS. SNP rs66782529 (LGALS3) was associated with negative IS outcomes (p = 0.048). SNPs rs62278647 and rs2316710 (PTX3) were associated significantly with IS (p = 0.000029 and p = 0.0025, respectively). These correlations for rs62278647 and rs2316710 were found only in women, which suggests a sex-specific association of the PTX3 polymorphism. Thus, this research not only reveals some new genetic associations with IS and its outcomes but also shows how exploring variations in genes from a rat model of brain ischemia can be of use in searching for human genetic markers of this disorder.
To date, there has been great progress in understanding the genetic basis of ischemic stroke (IS); however, several aspects of the condition remain underexplored, including the influence of genetic factors on post-stroke outcomes and the identification of causative loci. We proposed that an analysis of the results obtained from animal models of brain ischemia could be helpful. To this end, we developed a bioinformatic approach for exploring single-nucleotide polymorphisms (SNPs) in human orthologs of rat genes expressed differentially after induced brain ischemia. Using this approach, we identified and analyzed 11 SNPs from 6 genes in 553 Russian individuals (331 patients with IS and 222 controls). We assessed the association of SNPs with the risk of IS and IS outcomes. We found that the SNPs rs858239 (GPNMB), rs907611 (LSP1), and rs494356 (TAGLN) were associated with different parameters of IS functional outcomes. In addition, the SNP rs1261025 (PDPN) was associated significantly with IS itself (p = 0.0188, recessive model). All these associations were demonstrated for the first time. Analysis of the literature suggests that they should be characterized as being inflammation related. This supports the pivotal role of inflammation in both the incidence of stroke and post-stroke outcomes. We believe the findings reported here will help with stroke prognosis in the future.
The impact of -5T/C polymorphism in the GP1BA gene on the risk of ischemic stroke (IS) was studied in patients younger than 50 years of age. Ninety-two patients (73 men and 19 women; mean age 42.6±6.7 years) with atherothrombotic, lacunar, and cryptogenic IS were examined on days 1-21 after its development. All the patients underwent brain magnetic resonance imaging or computed tomography, brachiocephalic artery duplex scanning, echocardiography, and laboratory studies (antiphospholipid antibodies, coagulogram and platelet aggregation, homocysteine, clinical and biochemical blood analyses, rheumatic tests, determination of -5T/C polymorphism in the GP1BA gene). An increased risk for IS was found in the young males versus the controls (healthy individuals; p = 0.03; OR 2.7; CI 1.14; 6.47). This association was not found in the women. Analysis of pathogenetic types ascertained that the lacunar IS men with CC and CT genotypes had a higher risk for stroke than the healthy individuals (p = 0.04, OR 3.5, CI 1.1; 10.9). In other subtypes of stroke, there was no association with this polymorphism. A group of patients with IS caused by thrombosis of the great arteries of the brain. In this group, the patients had CC and CT genotypes significantly more frequently than the controls (p = 0.003; OR 6.7; CI 2.0; 21.8), as well as C allele (p = 0.0008; OR 5.1; CI 1.97; 13.3). The -5T/C polymorphism in the GP1BA gene was associated with the development of IS in young males. The -5C allele and -5T/C and -5C/C genotypes are increased risk factors for lacunar and arterial thrombosis-induced IS in men.
The article, which is a review-lecture, reflects the historical milestones in the description and study of cerebral edema (CE) from ancient times to the present. Great attention is paid to the Monroe–Kellie doctrine, without which it is impossible to understand the mechanism of development of a vitally significant complication of CE – intracranial hypertension. The importance of the Monroe–Kellie doctrine in substantiating the symptomatic treatment of increased intracranial pressure is emphasized. The possible involvement of the glymphatic system in both the decrease and the increase in increased intracranial pressure is discussed. The modern ideas about the blood-brain barrier (BBB), its role in the development of CE and an increase in intracranial volume are analyzed. With the study of the molecular mechanisms of BBB damage and the development of targeted therapy, the researchers associate future advances in the treatment of CE. The great interest of modern authors in the state of the BBB in various diseases, as well as in the violation of its integrity in COVID-19 is reflected. It is noted that the main and only, today, method for diagnosing CE is neuroimaging. Development has begun on the isolation of potential biochemical markers of CE from blood.
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