Serum miRNA Signature in Rheumatoid Arthritis and "At-Risk Individuals".

Clare C Cunningham,Douglas J Veale,Trudy Mcgarry,Sarah Wade,Sian Cregan,Ursula Fearon,Carl Orr,Achilleas Floudas,Siobhan Wade

doi:10.3389/fimmu.2021.633201

Clare C Cunningham, Douglas J Veale + Show 7 more

Open Access

https://doi.org/10.3389/fimmu.2021.633201

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Abstract

BackgroundMicroRNAs (miRNAs) are small non-coding RNAs which have been implicated as potential biomarkers or therapeutic targets in autoimmune diseases. This study examines circulatory miRNAs in RA patients and further investigates if a serum miRNA signature precedes clinical manifestations of disease in arthralgia or “at-risk individuals”.MethodsSerum was collected from HC subjects (N = 20), RA patients (N = 50), and arthralgia subjects (N = 10), in addition to a subgroup of the RA patients post-methotrexate (MTX) (N = 18). The FirePlex miRNA Immunology-V2 panel was selected for multiplex analysis of 68 miRNAs in each sample. DNA intelligent analysis (DIANA)-mirPath and Ingenuity Pathway Analysis (IPA) software were used to predict pathways targeted by the dysregulated miRNAs.Results8 miRNA (miR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p, miR-339-5p, let-7i-5p) were significantly elevated in RA serum compared to HC (all p < 0.01) and 1 miRNA (miR-17-5p) was significantly lower in RA (p < 0.01). High specificity and sensitivity were determined by receiver operating characteristic (ROC) curve analysis. Both miR-339-5p and let-7i-5p were significantly reduced post-MTX (both p < 0.01). MiR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p were also significantly elevated in subjects “at risk” of developing RA (all p < 0.05) compared to HC. IPA analysis of this miRNA signature identified downstream targets including key transcription factors NF-κB, STAT-1, STAT-3, cytokines IL-1β, TNF-α, and matrix-metalloproteases all importantly associated with RA pathogenesis.ConclusionThis study identified six miRNAs that are altered in both RA and “at-risk individuals,” which potentially regulate key downstream pathways involved in regulating inflammation. These may have potential as predictive signature for disease onset and early progression.

Highlights

MicroRNAs are small non-coding RNAs which play an important role in numerous biological processes such as cell differentiation and homeostasis, through the regulation of gene expression [1]
This study identified eight miRNAs that are elevated and one that is decreased in the circulation of rheumatoid arthritis (RA) patients compared to healthy controls (HC) which may serve as prognostic biomarkers for disease development in “at-risk individuals” or may be predictive of response to MTX treatment
In order to compare the miRNA signature of RA and healthy sera, a specific panel of 68 miRNAs, known to be associated with immune dysfunction [14], was selected for multiplex miRNA analysis of serum from HC donors (N = 20) and RA patients that were naïve to treatment (N = 50)

Summary

Introduction

MicroRNAs (miRNAs) are small non-coding RNAs which play an important role in numerous biological processes such as cell differentiation and homeostasis, through the regulation of gene expression [1]. Since their discovery, they have been implicated in cancer, viral, neurodegenerative and autoimmune diseases [2]. While the genetic predisposition to rheumatoid arthritis (RA) has been recognized, new discoveries continue to reveal specific genes and mutations linked to RA pathogenesis and, in the last 10 years, miRNAs have been implicated [4]. MicroRNAs (miRNAs) are small non-coding RNAs which have been implicated as potential biomarkers or therapeutic targets in autoimmune diseases. This study examines circulatory miRNAs in RA patients and further investigates if a serum miRNA signature precedes clinical manifestations of disease in arthralgia or “at-risk individuals”

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Conclusion