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Letícia A. Brondani, Bianca M. de Souza, Guilherme C. K. Duarte, Lúcia M. Kliemann, Jorge F. Esteves, Alexandre S. Marcon, Jorge L. Gross, Luís H. Canani, Daisy Crispim; The UCP1 −3826A/G Polymorphism Is Associated with Diabetic Retinopathy and Increased UCP1 and MnSOD2 Gene Expression in Human Retina. Invest. Ophthalmol. Vis. Sci. 2012;53(12):7449-7457. doi: 10.1167/iovs.12-10660.
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Uncoupling protein 1 (UCP1) reduces mitochondrial production of reactive oxygen species (ROS). ROS overproduction is related to diabetic retinopathy (DR), a chronic complication of diabetes mellitus (DM). Therefore, deleterious polymorphisms in the UCP1 gene are candidate risk factors for DR. We investigated the relationships between the UCP1 −3826A/G polymorphism and risk of DR and UCP1 gene expression in human retina. Considering that superoxide dismutase-2 (MnSOD2) enzyme is the first line of defense against oxidative stress in mitochondria, we also analyzed MnSOD2 gene expression in retinal samples according to different UCP1 −3826A/G genotypes.
In a case-control study, frequencies of −3826A/G polymorphisms were analyzed in 257 type 1 DM patients (154 cases with DR and 103 controls without DR). In a cross-sectional study comprising cadaveric cornea donors, UCP1 and MnSOD2 gene expressions were evaluated in 107 retinal samples differentiated according to different −3826A/G genotypes.
In the type 1 DM group, multivariate analysis confirmed that the G/G genotype was an independent risk factor for DR (OR = 3.503; P = 0.043). In cornea donors, G allele carriers had higher UCP1 cDNA and protein concentrations than A/A carriers (P = 0.034 and P = 0.039, respectively). Interestingly, G allele carriers exhibited increased MnSOD2 expression (P = 0.001).
This study suggests that the −3826A/G polymorphism is associated with DR in type 1 DM patients. This is the first report demonstrating UCP1 gene expression in human retinas and indicates that the −3826A/G polymorphism influences its expression. In addition, the −3826G allele was associated with increased MnSOD2 expression; thus, suggesting that this allele could be a marker of oxidative stress.
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