El impacto del polimorfismo en el Codón 72 del GEN TP53 en el pronóstico del ictus: participación de los mecanismos de muerte celular programada
[EN]The significance of apoptosis in the prognosis of stroke patients is not well known. The p53 tumor suppressor protein involved in regulation of apoptosis. The polymorphism at codon 72 of TP53 gene (Arg72Pro) determines the substitution of arginine for proline in the protein. p53-Arg conditions increased susceptibility to apoptosis. Clinical objective: to assess Arg72Pro as a prognostic marker in patients with cerebral infarction and in patients with intracerebral hemorrhage (ICH). Experimental Objective: To investigate the molecular mechanisms that mediate the apoptotic activity of different polymorphic variants. We studied two cohorts of patients collecting hospital clinical and codon 72 genotyping. Multivariate logistic regression to assess independent predictors of poor prognosis. The molecular mechanisms were investigated in cultured cortical neurons. Were expressed (lipofection) human variants: p53 or p53-Arg-Pro, and analyzed for: apoptosis, caspase-3 activity, effect of caspase inhibitors, mitochondrial membrane potential and response to stimulation with glutamate and experimental ischemia. Results: 408 patients with stroke: 57.6% Arg / Arg, 36% Arg / Pro and 6.4% Pro / Pro. 55.7% of patients Arg / Arg had a poor prognosis, compared with 17.3% of the Pro allele carriers (Pro +) (p <0.0001). After multivariate adjustment, Arg / Arg was a marker of poor prognosis (OR: 3.4, 95% CI 1.54 to 7.61). 128 patients with ICH: 52.3% Arg / Arg, 42.2% Arg / Proj 5.5% Pro / Pro. Poor prognosis in 92% Arg / Arg versus 7.9% of the Pro +. Arg / Arg was also an independent predictor of poor prognosis (OR: 320, 95% CI 36-2786). In neuronal cultures induced p53-Arg increased neuronal apoptosis, activation of the intrinsic pathway and interaction with the mitochondria and increased susceptibility to excitotoxicity and ischemia. Conclusion: The genotype Arg / Arg of Tp53 confers an increased risk of poor outcome after stroke and increased susceptibility to neuronal apoptosis mediated by mitochondria.
Tesis y disertaciones académicas, Universidad de Salamanca (España), Academic Dissertations, España, Spain, Neurología, Neurology, Genética, Genetics
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