The Mdm2 309T>G polymorphism modulates the MDM2-p53 signaling pathway and conditions the functional outcome of stroke patients

Abstract

The highly variable prediction of functional outcome after stroke could be the effect of different genetic backgrounds to apoptosis. MDM2 protein is the main negative regulator of p53, which plays an important role on neuronal apoptosis after cerebral ischemia. Recently, we found that the Arg72Pro single nucleotide polymorphism (SNP) of p53 regulates the pro-apoptotic activity of the protein and conditions neuronal vulnerability to ischemia-induced apoptosis and functional outcome of stroke patients. In MDM2 a SNP in the promoter gene (309T>G) modulates levels of Mdm2 expression. However, the role of Mdm2 309T>G SNP in stroke prognosis remains unknown. Here we study the association of the Mdm2 309T>G SNP and the functional prognosis after stroke in blood samples from 408 patients with ischemic stroke and 206 with intracerebral hemorrhage. Functional outcome at 3 and 12 months was evaluated by the modified Rankin scale. Mononuclear cells from healthy individuals were collected to measure levels of MDM2 mRNA and protein. We found that mononuclear cells harboring the Mdm2 TT genotype have lower levels of MDM2 mRNA and protein than those with the Mdm2 GG and Mdm2 TG genotypes, which may affect p53 stabilization and then cell vulnerability to ischemia-induced apoptosis. Furthermore, patients harboring the Mdm2 TT genotype showed poor functional outcome at 3 and 12 months following ischemic (p=0.003) and hemorrhagic (p<0.0001) stroke. Our results suggest that the Mdm2 309T>G SNP modulates the MMD2p53 signaling pathway and then cell susceptibility to apoptosis, which conditions the functional outcome of patients after stroke.