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Circulating microRNAs (miRNAs/miRs) have emerged as potential disease biomarkers; however, their expression in diabetic retinopathy (DR) has been evaluated only recently in humans. Whilst it is recognized that sequence variants in miRNA genes (miRSNPs) can alter the miRNA-mediated regulation of gene expression, there are almost no studies on the association of miRSNPs with DR. In this case-control study, we investigated whether the functional polymorphisms rs531564 G>C (MIR124-1), rs4636297 A>G (MIR126) and 2910164 C>G (MIR146A) are associated with DR in 1,025 Brazilians with type 2 diabetes. We also evaluated whether the plasma levels of miR-124, miR-126 and miR-146a are associated with DR and with miRSNPs in 182 patients. Blood donors were included to determine the prevalence of miRSNPs (n = 104) and miRNA expression (n = 20) in the general population. Genotyping was done by real-time PCR and plasma levels were quantified by RT-qPCR. Genotype and allele frequencies in diabetic subjects did not significantly differ from those of blood donors, and the minor allele frequencies were similar to those reported in other populations. The MIR126 heterozygous genotype was more frequent in patients without DR than in those with DR (52% versus 44%, respectively, p = 0.040), and remained associated with this complication after controlling for clinical covariates. MiR-126 was markedly downregulated in diabetic subjects as compared to blood donors and even more reduced among those with DR (mean log2 fold-change of -0.7 ± 1.7, -1.1 ± 2.0 and -1.7 ± 1.6 for subjects without DR, with nonproliferative DR or with proliferative DR, p = 0.002). Patients carrying the A allele of the rs4636297 polymorphism had almost twice higher levels of miR-126 than patients with GG genotype. MiR-126 and miR-146a were strongly correlated and the levels of miR-146a were also lower in diabetic subjects than in blood donors. Overall, our findings reinforce that gene variants and expression of miRNAs are associated with DR in type 2 diabetes. Disclosure: E.R. Polina: None. R.C. Sbruzzi: None. F.M. de Oliveira: None. D. Crispim: None. M.D. Enoia: None. L.H. Canani: Research Support; Self; Novo Nordisk Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. K.G. Santos: None. Funding: Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (1994-2551/13-4); Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre (14-0645) [ABSTRACT FROM AUTHOR]