AB0096 FCER1G GENE METHYLATION AND MIR-106/MIR-17 AS A NEW POTENTIAL EPIGENETIC MARKERS IN RHEUMATOID ARTHRITIS
Authors: M. Ciesla, B. Kolarz, M. Dryglewska, M. Majdan
Journal: Annals of the Rheumatic Diseases (2020)

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joints destruction. One of the most important cytokine responsible for this process is interleukin 6 (IL-6). Fc receptor gamma chain (FcRγ), encoded by FCER1G gene, is responsible for neutrophils activation, phagocytosis, cell surface signaling pathway as well as IL-4, IL-6, IL-10 and tumor necrosis factor production. Epigenetic factors, including DNA methylation and micro-RNAs (miRs) expression regulate the genes expression on transcriptional and post-transcriptional mechanisms. There are miRs responsible for cytokines production, for example GU rich miRs, miR-106b and miR-155 were reported as associated with IL-6 overproduction. Objectives: The aim of our study was to evaluate FCER1G gene methylation and miR-17 family members as epigenetic markers associated with RA, disease activity and IL-6 expression. Methods: Bioinformatics analysis were applied to select the miRs with a possible target sites in a promoter region of FCER1G gene. The MiR-17 family members, including miR-17, miR-93 and miR-106b were selected for investigation. A total of 74 individuals, 50 RA patients, 84% female, aged 53,7±12,3 years (mean±SD) and 24 healthy controls (HC), 87,5% female, aged 53±8,49 years were enrolled. RA patients were selected based on DAS-28 scoring. RA patients with high disease activity (DAS28 &gt;5,1; 58%) and remission (≤2,6; 42%) were included in the analysis. DNA was extracted from a whole blood and miRs were extracted from plasma. Quantitative real-time PCR was use for analyze both methylation and expression levels. In a randomly selected samples (16 from high disease activity group; 9 from remission and 19 from HC) the level of IL-6 in serum was evaluated. Results: Patients with RA in comparison to HC have had a lower FCER1G methylation (0.98 [0.73-1.46] vs 1.96 [1.44-3], p&lt;0.00001; median [interquartile range]) and miR-106b (0.79 [0.49-1.68] vs 1.54 [0.88-2.51], p=0.008) and miR-17 (1.26 [0.41-2.04] vs 2.44 [2.09-3.47], p=0.0001) expressions. No difference in methylation between high and remission RA groups was found. MiR-106b and miR-17 expressions were different between RA patients with high disease activity and remission (p=0.009 and p=0.003, respectively), however a high disease activity group was not different to HC (p=0.82 and p=0.12, respectively). Detailed results are presented in Table 1. A strong correlation between IL-6 levels and FCER1G methylation (r s = -0.46) was found. Table 1. Methylation and expression between patients divided by disease activity in compare to controls. High disease activity, n=29 Remission, n=21 HC, n=24 FCER1G methylation 1.11 [0.83-1.52] 0.96 [0.61-1.18] 1.96 [1.44-3] miR-106b expression 1.36 [0.63-1.76] 0.54 [0.19-1.19] 1.54 [0.88-2.51] miR-93 expression 0.63 [0.49-1.21] 0.59 [0.15-1.5] 1.03 [0.65-1.38] miR-17 expression 1.46 [1.05-2.54] 0.34 [0.11-1.26] 2.44 [2.09-3.47] Data are given by median [interquartile range]. FCER1G, Fc receptor gamma chain gene; HC, healthy controls; miR, micro-RNA; RA, rheumatoid arthritis patients. Conclusion: FCER1G methylation was found as a new epigenetic marker of RA, which is independent of disease activity and may be associated with IL-6 production. Plasma miR-17 and miR-106b can be considered as a novel molecular biomarkers of disease severity in RA. FcRγ may plays a significant role in RA pathogenesis and FCER1G gene methylation was found as a new, epigenetic and promising marker of RA. References: [1]Németh T, Futosi K, Szabó M, Aradi P, Saito T, Mócsai A, Jakus Z. Importance of Fc Receptor γ-Chain ITAM Tyrosines in Neutrophil Activation and in vivo Autoimmune Arthritis. Front Immunol. 2019 Feb 25;10:252. [2]Cunningham F et al. Ensembl 2019. Nucleic Acids Res. 2019 Jan 8;47(D1):D745-D751. [3]Salvi V, Gianello V, Tiberio L, Sozzani S, Bosisio D. Cytokine Targeting by miRNAs in Autoimmune Diseases. Front Immunol. 2019 Jan 29;10:15. Disclosure of Interests: Marek Ciesla: None declared, Bogdan Kolarz: None declared, Magdalena Dryglewska: None declared, Maria Majdan Consultant of: Roche, Amgen, Speakers bureau: Roche, Amgen