Profiling microRNAs in individuals at risk of progression to rheumatoid arthritis

Abstract

Background: Individuals at risk of rheumatoid arthritis (RA) demonstrate systemic autoimmunity in the form of anti-citrullinated peptide antibodies (ACPA). MicroRNAs (miRNAs) are implicated in established RA. This study aimed to (1) compare miRNA expression between healthy individuals and those at risk of and those that develop RA, (2) evaluate the change in expression of miRNA from "at-risk" to early RA and (3) explore whether these miRNAs could inform a signature predictive of progression from "at-risk" to RA.

Methods: We performed global profiling of 754 miRNAs per patient on a matched serum sample cohort of 12 anti-cyclic citrullinated peptide (CCP) + "at-risk" individuals that progressed to RA. Each individual had a serum sample from baseline and at time of detection of synovitis, forming the matched element. Healthy controls were also studied. miRNAs with a fold difference/fold change of four in expression level met our primary criterion for selection as candidate miRNAs. Validation of the miRNAs of interest was conducted using custom miRNA array cards on matched samples (baseline and follow up) in 24 CCP+ individuals; 12 RA progressors and 12 RA non-progressors.

Results: We report on the first study to use matched serum samples and a comprehensive miRNA array approach to identify in particular, three miRNAs (miR-22, miR-486-3p, and miR-382) associated with progression from systemic autoimmunity to RA inflammation. MiR-22 demonstrated significant fold difference between progressors and non-progressors indicating a potential biomarker role for at-risk individuals.

Conclusions: This first study using a cohort with matched serum samples provides important mechanistic insights in the transition from systemic autoimmunity to inflammatory disease for future investigation, and with further evaluation, might also serve as a predictive biomarker.

Trial registration: ClinicalTrials.gov NCT02012764.

Keywords: ACPA; At risk; Early RA; MicroRNA; Progression; Rheumatoid arthritis.

Conflict of interest statement

Ethics approval and consent to participate

Leeds Research Ethics Committee, UK (REC: reference 06/Q1205/169) approved the CCP observational cohort study (NCT02012764). All patients provided written informed consent for the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Candidate serum miRNA expression profiling. a MicroRNA heatmaps were generated using hierarchical clustering (Gene Cluster 3.0 and Java TreeView). Green indicates low expression; red indicates high expART ression levels. b Comparison of expression levels of miR-22, miR-382 and miR-486-3p in matched samples from anti-cyclic citrullinated peptide (CCP) + status to very early rheumatoid arthritis (VERA) (medians, 1st to 3rd quartiles). dCt, delta threshold cycle; HC, healthy controls. Of note, miR-22 was excluded from the healthy control cohort as it was not expressed in all 12 samples

Fig. 2

Validation-phase serum expression levels of candidate miRNAs. Baseline and follow-up relative expression in the progressor (P) and non-progressor (NP) cohorts of miR-486-3p, miR-22 and miR-382 (a) and miR-203 and miR-579 (b). HC, healthy controls; dCt, delta cycle threshold