First report of circulating microRNAs in tumour necrosis factor receptor-associated periodic syndrome (TRAPS)

Abstract

Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder characterized by recurrent episodes of long-lasting fever and inflammation in different regions of the body, such as the musculo-skeletal system, skin, gastrointestinal tract, serosal membranes and eye. Our aims were to evaluate circulating microRNAs (miRNAs) levels in patients with TRAPS, in comparison to controls without inflammatory diseases, and to correlate their levels with parameters of disease activity and/or disease severity. Expression levels of circulating miRNAs were measured by Agilent microarrays in 29 serum samples from 15 TRAPS patients carrying mutations known to be associated with high disease penetrance and from 8 controls without inflammatory diseases. Differentially expressed and clinically relevant miRNAs were detected using GeneSpring GX software. We identified a 6 miRNAs signature able to discriminate TRAPS from controls. Moreover, 4 miRNAs were differentially expressed between patients treated with the interleukin (IL)-1 receptor antagonist, anakinra, and untreated patients. Of these, miR-92a-3p and miR-150-3p expression was found to be significantly reduced in untreated patients, while their expression levels were similar to controls in samples obtained during anakinra treatment. MiR-92b levels were inversely correlated with the number of fever attacks/year during the 1(st) year from the index attack of TRAPS, while miR-377-5p levels were positively correlated with serum amyloid A (SAA) circulating levels. Our data suggest that serum miRNA levels show a baseline pattern in TRAPS, and may serve as potential markers of response to therapeutic intervention.

Figure 1. Hierarchical cluster representation of miRNAs modulated in TRAPS.

Cluster analysis groups samples and genes according to expression similarity. Genes are in rows, samples in columns. The colors of the genes represented on the heatmap correspond to the values normalized on miRNA average expression across all samples (see legends); up-regulated miRNAs are in red, down-regulated miRNAs in green. A) Cluster analysis of miRNAs modulated in TRAPS (blue) vs. controls (red) B) Four miRNAs are differentially expressed in samples from TRAPS patients during treatment with the interleukin (IL)-1 receptor antagonist anakinra. Treated patients (y) are colored in blue, whereas untreated patients (n) in red. One treated patient (S22) displays and intermediate expression profile.

Figure 2. Expression of miR-92-3p and miR-150-3p in controls and in treated and untreated TRAPS patients.

The expression levels of miR-93-3p and miR-150-3p, derived from the microarray experiment, were plotted in this graph using scatter plot distribution. ** p-value <0.001 at t-test; * p-value <0.05 at t-test.

Figure 3. MicroRNAs correlating with clinical and laboratory features.

A) correlation of miR-92b with the number of fever attacks/year during the 1^st year from the index attack of TRAPS. The levels of miR-92b correlate negatively with the number of fever attacks/year during the 1^st year from the index attack of TRAPS (p 0.0045, r = −0.5589) B) the levels of miR-377-5p are increased in patients presenting increased serum amyloid A (SAA) levels (p 0.0004, r = 0.66).