A Polymorphism in the Promoter Region of the Survivin Gene is Related to Hemorrhagic Transformation in Patients with Acute Ischemic Stroke

Abstract

Hemorrhagic transformation (HT) of cerebral infarction is a common and serious occurrence following acute ischemic stroke. The expression of survivin, a member of the inhibitor of apoptosis protein family, has been shown to increase after cerebral ischemia. This protein has been mainly located at the microvasculature within the infarcted and peri-infarcted area, so we aimed to investigate whether survivin gene polymorphisms, also known as BIRC5 gene, were associated with HT of cerebral infarction. Polymorphism screening of the BIRC5 gene was performed in 107 patients with a hemispheric ischemic stroke and 93 controls by polymerase chain reaction, single-strand conformation polymorphism and sequencing analysis. Genotype-phenotype correlation was performed in patients. MRI was carried out within 12 h of symptoms onset and at 72 ± 12 h. The presence of HT was determined on the second DWI sequence and classified according to ECASS II criteria. MMP-9 levels were analyzed at admission. Forty-nine patients (45.8%) had HT. The -241 C/T (rs17878467) polymorphism was identified in the promoter region of the survivin gene. The prevalence of the mutant allele (T) was similar in patients and controls (14 vs. 16%, respectively; P = 0.37). However, 9 (29%) patients with allele T had HT compared to 40 (52.6%) of wild-type (P = 0.021). Logistic regression analysis showed that the polymorphism was associated with a lower risk of HT (OR 0.16; 95% CI 0.04-0.65; P = 0.01). The -241 C/T polymorphism in the promoter region of the survivin gene is associated with a lower risk of HT in patients with ischemic stroke. It has recently been reported that the -241 C/T polymorphism increases survivin promoter activity, reinforcing the hypothesis that patients with the mutant allele may have increased survivin expression in the brain. Different mechanisms, including BBB protection by the inhibition or activation of different angiogenic growth factors and the inhibition of apoptosis during angiogenesis, may explain the protective effect of this polymorphism on HT development in ischemic stroke. Further studies are needed to confirm our results and elucidate the mechanisms explaining this effect.

Association of Matrix Metalloproteinase 9 and Cellular Fibronectin and Outcome in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

“…One article was designed as a case-control study ( 36 ), and the others were cohort studies. Most studies enrolled patients with all types of acute ischemic stroke, except for three studies including patients without lacunar stroke ( 33 , 34 , 40 ), three studies including patients with cardioembolic stroke involving middle cerebral artery ( 33 – 35 ), and one study including patients with large-vessel occlusion treated with mechanical thrombectomy ( 54 ). Treatment with thrombolysis varied across studies: 10 studies included patients treated with thrombolysis ( 15 , 27 , 32 , 34 – 36 , 38 , 42 , 48 , 54 ), four studies had some patients who received thrombolysis ( 19 , 39 – 41 ), and the remaining 12 studies included patients who did not receive thrombolytic treatment.…”

“…A total of 19 studies comprising 2,631 patients reported on the relationship between MMP-9 levels and hemorrhagic transformation ( 6 , 8 , 15 , 19 , 27 , 32 – 43 , 45 , 54 ). Of the 19 studies, data from 11 studies with 1,709 patients were meta-analyzed to compare MMP-9 levels between patients with or without hemorrhagic transformation ( 6 , 8 , 15 , 27 , 32 – 34 , 37 , 38 , 40 , 45 ). The forest plot shows that MMP-9 levels were higher in the hemorrhagic transformation group than in the group without hemorrhagic transformation.…”

“…The SMD between the two groups was 1.00 (95% CI, 0.41–1.59, P = 0.001; heterogeneity: I 2 = 94.4%, P < 0.001; Figure 2 ). Among these 11 studies, seven of them reported ORs of association between MMP-9 levels and hemorrhagic transformation ( Supplementary Table 2 ) ( 8 , 15 , 33 , 34 , 37 , 40 , 45 ).…”

Association Between a Polymorphism (rs2071214) in Baculoviral IAP Repeat Containing 5 Gene (BIRC5) and Ischemic Stroke in Korean Population

“…Several polymorphisms have been described in the survivin gene. A recent study has demonstrated that rs17878467 polymorphism of survivin gene is associated with a lower risk of hemorrhagic transformation in patients with ischemic stroke [ 31 ]. The biologic role of amino acid alterations associated with SNPs in ischemic stroke remains unclear.…”

Hemorrhagic transformation of ischemic stroke

“…Stroke patients presenting this mutation show less severe HT if the HT occur and have lower risk for PH. Survivin is an anti-apoptotic molecule inhibiting caspase-3 [126].…”