LncRNA GAS5 and miR-137 Polymorphisms and Expression are Associated with Multiple Sclerosis Risk: Mechanistic Insights and Potential Clinical Impact

Abstract

The pathogenesis of multiple sclerosis (MS) is influenced by the interaction of genetic and epigenetic mechanisms. The long noncoding RNA GAS5 acts as a competing endogenous RNA for microRNA-137 and is involved in demyelination. We investigated the association of GAS5 and miR-137 expression and their polymorphisms with MS susceptibility. One hundred and eight MS patients and 104 healthy controls were included. Expression analysis and genotyping of GAS5-rs2067079 and miR-137-rs1625579 single nucleotide polymorphisms were performed by qPCR. Serum GAS5 was upregulated, while serum miR-137 was downregulated in MS compared with the controls. Serum miR-137 was an excellent discriminator of MS patients from the controls (AUC = 0.97) and a negative independent predictor of MS in multivariate logistic analysis. Serum GAS5 expression was positively correlated with the expanded disability status scale scores in the relapsing–remitting MS patients. The rs2067079TT minor homozygote genotype was associated with an increased MS risk, while the rs1625579G minor allele was protective. rs1625579 showed an age-specific effect, while the rs2067079 affected the MS risk in gender- and age-specific manners. In MS patients, rs2067079TT was associated with a higher serum GAS5 than other genotypes, while serum miR-137 did not differ between rs1625579 genotypes. Our results suggest serum GAS5 and miR-137 as MS biomarkers, with miR-137 as a negative predictor of MS risk and GAS5 as a marker of MS severity. We propose rs2067079 and rs1625579 as novel genetic markers of MS susceptibility, and at least, rs2067079 possibly impacts the crosstalk between GAS5 and miR-137.

Meta-Analysis of miRNA Variants Associated with Susceptibility to Autoimmune Disease

“…Most of the mutations are typically located in either coding gene regions with an influence on protein function or noncoding gene regions, potentially affecting a targeted gene transcript. Additionally, recent studies suggested that functional variants occurring in microRNA sequences were associated with susceptibility to AD [6][7][8][9][10][11][12][13][14][15]. These findings indicate that variants in common miRNAs could be genetic markers of AD such as multiple sclerosis, rheumatoid arthritis, and ankylosing spondylitis, which highlighted a new paradigm for genetic susceptibility.…”

“…Among them, 56 studies were eliminated since they did not contain sufficient genotype results (n = 18) or for not investigating an association between miRNA-SNP and AD risk (n = 17) or for being a review or meta-analysis (n = 13), expert opinion (n = 3), or case report (n = 5). Ultimately, 94 articles met all the inclusion criteria for our meta-analysis, of which 87 were eligible for quantitative analysis of risk estimates [6][7][8][9][10][11][12][13][14][15]. Assessment of interinvestigator agreement using kappa values for the selected articles yielded values of 0.84 for PubMed, 0.88 for Embase, 0.90 for Web of Science, 0.91 for Google Scholar, and 1.0 for CNKI, suggesting a high level of agreement between our two reviewers.…”

Serum a proliferation-inducing ligand and MicroRNA-223 are associated with rheumatoid arthritis: diagnostic and prognostic implications

“…miRNAs can control many immune processes, including T- and B-cell development and maturation, antigen presentation, Toll-like receptor signaling and pro-inflammatory cytokine production, immunoglobulin class-switch recombination in B-cells, and T-cell receptor signaling (Ceribelli et al 2012 ). Differential expression of non-coding RNAs, including miRNAs were found in patients affected by several autoimmune diseases, and were linked to the pathogenesis of these conditions (Senousy et al 2019 ; Senousy et al 2020 ; Abd-Elmawla et al 2020 ). Indeed, dysregulated miRNA expression has been shown to be implicated into the molecular mechanisms of RA (Tavasolian et al 2018 ).…”

Serum A Proliferation-Inducing Ligand and MicroRNA-223 are Associated with Rheumatoid Arthritis: Diagnostic and Prognostic Implications

“…miRNAs can control many immune processes, including T-and B-cell development and maturation, antigen presentation, Toll-like receptor signaling and pro-inflammatory cytokine production, immunoglobulin class-switch recombination in B-cells, and Tcell receptor signaling (Ceribelli et al 2012). Differential expression of non-coding RNAs, including miRNAs were found in patients affected by several autoimmune diseases, and were linked to the pathogenesis of these conditions (Senousy et al 2019;Senousy et al 2020;Abd-Elmawla et al 2020). Indeed, dysregulated miRNA expression has been shown to be implicated into the molecular mechanisms of RA (Tavasolian et al 2018).…”