Long Non-Coding RNAs Gene Variants as Molecular Markers for Diabetic Retinopathy Risk and Response to Anti-VEGF Therapy

Background: Long non-coding RNAs (lncRNAs) play essential roles in molecular diagnosis and therapeutic response in several diseases. Purpose: For the first time, we aimed to evaluate the association of four lncRNAs TUG1 ( rs7284767G/A), MIAT (rs1061540T/C), MALAT1 (rs3200401C/T), and SENCR (rs12420823C/T) variants with susceptibility to diabetic retinopathy (DR), disease severity, and early therapeutic response to intravitreous anti-vascular endothelial growth factor aflibercept therapy. Patients and Methods: This case-control study enrolled 126 adult patients with type 2 diabetes. TaqMan assays using Real-Time PCR were run for genotyping. Multivariable regression analyses were applied to assess the role of each polymorphism after the adjustment of covariates. Results: Carriers of TUG1 A/G and MIAT T/C and C/C genotypes were more likely to develop DR [OR=3.15 (95% CI=1.15– 8.64), and OR=4.31 (95% CI=1.78– 10.47)], while MALAT1 T/C conferred protection (OR=0.40, 95% CI=0.16– 0.99). For TUG1, MALAT1, MIAT , and SENCR genotype combinations, GTCT and GCCC had a higher disease risk ( P =0.012). For disease severity, MIAT T/T homozygosity was associated with higher DR grade [33.3% (T/T) vs 10% (C/C) and 4.2% (C/T) carriers, P =0.012]. Otherwise, patients with the SENCR T variant exhibited better pre-treatment best-corrected visual acuity level ( p =0.021). Following aflibercept administration, carrying the TUG1 A or MIAT T/C was associated with a poor therapeutic response (OR=5.02, 95% CI=1.60– 15.76, and OR=10.23, 95% CI=1.51– 69.15, respectively). Conclusion: The lncRNAs TUG1 ( rs7284767G/A) and MIAT (rs1061540T/C) were associated with increased DR susceptibility and poor response to aflibercept treatment, while MALAT1 (rs3200401C/T) conferred protection to DR. These genetic determinants could be useful in DR risk stratification and pharmacogenetics after validation in large-scale studies.