title: 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.
authors.affiliation: Cerebrovascular Pathology Research Group, Department of Neurology, Girona Biomedical Research Institute (IdIBGi), Dr. Josep Trueta University Hospital, Av França s/n, 17007, Girona, Spain, judithmallolas@cofgi.org.
authors.forename: Judith
authors.initials: J
authors.lastname: Mallolas
authors.forename: Rocío
authors.initials: R
authors.lastname: Rodríguez
authors.forename: Carme
authors.initials: C
authors.lastname: Gubern
authors.forename: Susanna
authors.initials: S
authors.lastname: Camós
authors.forename: Joaquín
authors.initials: J
authors.lastname: Serena
authors.forename: Mar
authors.initials: M
authors.lastname: Castellanos
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000150:complications*; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000453:epidemiology / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002544:Cerebral Infarction / Q000150:complications; D015897:Comorbidity; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012306:Risk; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D016037:Single-Blind Method; D013030:Spain / Q000453:epidemiology; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9