Abstract
Purpose: To investigate the role of the mouse double minute 2 (MDM2) gene single-nucleotide polymorphism (SNP) T309G in the development of epimacular membranes (EMMs) by analyzing the genotype distribution and consistency of the polymorphism in paired membrane-blood samples. Methods: This was a cross–sectional genetic association study of patients with proliferative vitreoretinopathy (PVR) or EMMs. PVR membranes (PVRMs), internal limiting membranes (ILMs) (PVR-ILMs) and blood samples (PVR-blood) from patients with PVR, and EMMs, EMM-ILMs and EMM-blood from patients with EMMs were collected. The genotype of all samples was determined by Sanger sequencing. Sex composition, mean age, the genotype distribution of MDM2 T309G, the allelic frequency of the MDM2 SNP309 G allele (% G) and the somatic mutation rate at the MDM2 T309G locus (% M) were analyzed and compared. The PVR and healthy Chinese donor groups were used as controls for different comparisons. Results: The EMM group of 62 patients was older than the PVR group of 61 patients by an average of 8.87 years (p < 0.0001), but the two groups were statistically similar in the sex composition (p = 0.1754). Importantly, G allele carriers were at a higher risk of developing EMMs than non-G allele carriers (p = 0.0479; OR = 2.047). Moreover, EMM-blood exhibited a significantly higher % G than blood samples from healthy Chinese donors (EMM-blood: 56.78%, donors: 45.61%; p = 0.0256; OR = 1.567). Regarding membrane-blood consistency, % M was significantly different between PVRMs and EMMs (PVRMs: 2.63%, EMMs: 21.57%; p = 0.0097; OR = 10.18) but not between different types of ILMs (PVR-ILMs: 18.18%, EMM-ILMs: 29.17%; p = 0.6855). Furthermore, EMMs (p = 0.0053; OR = 8.250) and EMM-ILMs (p = 0.0233; OR = 14.40) from patients with preoperative macular holes were more predisposed toward somatic mutations at the MDM2 T309G locus than those from patients without preoperative macular holes. Conclusions: MDM2 T309G is associated with the development of EMMs. Herein, the MDM2 SNP309 G allele is first reported as an associated factor of EMMs in a Chinese population. In addition, EMMs and ILMs are genetically unstable at the MDM2 T309G locus, especially when complicated with preoperative macular holes.
Highlights
The tumor suppressor p53 is a pivotal component of cells that monitors and controls the most important cellular events, including cell cycle arrest, apoptosis, senescence, metabolism, DNA repair and malignant transformation. p53 acts as a switch between life and death and determines the fate of cells in response to cellular stress (Carvajal and Manfredi, 2013)
We aimed to investigate the role of mouse double minute 2 (MDM2) T309G in epimacular membrane (EMM) formation by comparing the genotype distribution and consistency of the polymorphism in paired membrane-blood samples between the proliferative vitreoretinopathy (PVR), EMM and healthy Chinese donor groups
The study population was divided into a PVR group and an EMM group
Summary
The tumor suppressor p53 is a pivotal component of cells that monitors and controls the most important cellular events, including cell cycle arrest, apoptosis, senescence, metabolism, DNA repair and malignant transformation. p53 acts as a switch between life (cell cycle arrest and attendant DNA repair) and death (apoptosis) and determines the fate of cells in response to cellular stress (Carvajal and Manfredi, 2013). The tumor suppressor p53 is a pivotal component of cells that monitors and controls the most important cellular events, including cell cycle arrest, apoptosis, senescence, metabolism, DNA repair and malignant transformation. P53 acts as a switch between life (cell cycle arrest and attendant DNA repair) and death (apoptosis) and determines the fate of cells in response to cellular stress (Carvajal and Manfredi, 2013). A naturally occurring singlenucleotide polymorphism (SNP) in the P2 promoter, MDM2 T309G (rs2279744, a thymine-to-guanine change at the 309th nucleotide in the first intron), enhances binding of the transcriptional activator Sp1 to the P2 promoter and stimulates P2-driven inducible expression of MDM2 under stress, with subsequent attenuation of p53 signaling (Bond et al, 2004). Post et al (2010) corroborated the correlation between MDM2 T309G and increased tumor risk using two cohorts of genetically engineered mice carrying either the humanized MDM2 SNP309 G allele or T allele
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