The Role Of MDM2 SNP T309G In Retinal Neovascular Diseases And Epimacular Membrane

Background:The proto-oncogene mouse double minute 2 gene(MDM2)encodes the MDM2 oncoprotein,a primary negative regulator of the tumor suppressor p53.The MDM2-p53 axis regulates critical cellular events,including cell cycle arrest,apoptosis,DNA damage repair and malignant transformation.In addition,it interacts with the hypoxia-inducible factor1-vascular endothelial growth factor signaling pathway to regulate biological neovascularization.The MDM2 single nucleotide polymorphism T309G(MDM2 SNP T309G)enhances the binding of the transcription factor Sp1 to the MDM2 P2 promoter and stimulates P2-driven inducible expression of MDM2,which has been proven to be correlated with multiple malignancies.Since studies have shown that MDM2 promotes intratumor neovascularization,we speculate that MDM2 SNP T309G may also be implicated in retinal neovascular diseases.Moreover,the MDM2 SNP T309 G increases the risk of proliferative vitreoretinopathy(PVR)by enhancing the proliferation and migration of retinal pigment epithelial cells.It is possible that epimacular membranes(EMMs),a group of commonly seen retinal gliosis(mainly Müller glial cells)diseases,are also related to MDM2 SNP T309 G.Purposes:To investigate the role of MDM2 SNP T309 G in retinal neovascular diseases and epimacular membranes.Methods:(1)We compared the percentages of retinal vaso-obliteration area(%VO)and retinal neovascular area(% NV)and the relative retinal MDM2 expression levels between the oxygen-induced retinopathy(OIR)model of MDM2 SNP309 T/T,T/G,and G/G mice.(2)We collected and genotyped PVR membranes/EMMs,internal limiting membranes(PVR-ILMs/EMM-ILMs)and blood samples(PVRblood/EMM-blood)from patients.The genotype distribution of MDM2 SNP T309G,the allelic frequency of the MDM2 SNP309 G allele(% G)and the somatic mutation rate at the MDM2 SNP T309 G locus(% M)were analyzed and compared in paired membrane-blood samples between the PVR,EMM and healthy Chinese donor groups.Results:(1)MDM2 SNP309 T/G and G/G mice had significantly higher % VO and % NV than MDM2 SNP309 T/T mice.However,no significant differences were found between MDM2 SNP309 T/T and T/G mice.In addition,the relative retinal MDM2 expression level of MDM2 SNP309G/G mice was significantly higher than that of MDM2 SNP309 T/T mice.(2)MDM2 SNP309 G allele carriers were at a higher risk of developing EMMs than non-G allele carriers.Moreover,EMM-blood exhibited a significantly higher % G than blood samples from healthy Chinese donors.Moreover,EMMs were significantly higher in % M than PVR membranes,in contrast to ILMs in both groups,which showed a considerable % M.Furthermore,EMMs and EMM-ILMs from patients with preoperative macular holes were more predisposed toward somatic mutations at the MDM2 SNP T309 G locus than those from patients without preoperative macular holes.Conclusions:(1)MDM2 SNP T309 G drives abnormally high expression of retinal MDM2,which is correlated with neovascularization in oxygen-induced retinopathy.The MDM2 SNP309 G allele may be a pathogenic factor for retinal neovascular diseases in humans.(2)MDM2 SNP T309 G is associated with the development of EMMs.The MDM2 SNP309 G allele is an associated factor of EMMs in a Chinese population.Furthermore,EMMs and EMM-ILMs are genetically unstable at the MDM2 SNP T309 G locus,especially in patients with preoperative macular holes.