title: The UCP1 -3826A/G polymorphism is associated with diabetic retinopathy and increased UCP1 and MnSOD2 gene expression in human retina.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Endocrinology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Letícia A
authors.initials: LA
authors.lastname: Brondani
authors.forename: Bianca M
authors.initials: BM
authors.lastname: de Souza
authors.forename: Guilherme C K
authors.initials: GC
authors.lastname: Duarte
authors.forename: Lúcia M
authors.initials: LM
authors.lastname: Kliemann
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Esteves
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Marcon
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Gross
authors.forename: Luís H
authors.initials: LH
authors.lastname: Canani
authors.forename: Daisy
authors.initials: D
authors.lastname: Crispim
mesh_terms: D000328:Adult; D000483:Alleles; D018076:DNA, Complementary / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000378:metabolism*; D012189:Retrospective Studies; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics*; D000071256:Uncoupling Protein 1; D000099156:Superoxide Dismutase 2
chemical_list: D018076:DNA, Complementary; D007473:Ion Channels; D024101:Mitochondrial Proteins; D013482:Superoxide Dismutase; D000071256:Uncoupling Protein 1; D000099156:Superoxide Dismutase 2; C000604371:UCP1 protein, human