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 1st 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.
Highlights
Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene (12p13) encoding the 55-kD receptor for tumor necrosis factor-a (TNF-a) (TNFRSF1A) [1]
TRAPS mutations can be distinguished into high-penetrance variants and low-penetrance variants: the former are mostly missense substitutions, mainly affecting the highly conserved cysteine residues of the extracellular cysteine-rich domains involved in disulfide bond formation and in the folding of the extracellular portion of TNFRSF1A [2], [3]
These mutations are associated with an earlier disease onset and with a more severe phenotype; patients may experience a higher number of fever episodes and a greater severity of attacks [11]
Summary
Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene (12p13) encoding the 55-kD receptor for tumor necrosis factor-a (TNF-a) (TNFRSF1A) [1]. TRAPS mutations can be distinguished into high-penetrance variants and low-penetrance variants: the former are mostly missense substitutions, mainly affecting the highly conserved cysteine residues of the extracellular cysteine-rich domains involved in disulfide bond formation and in the folding of the extracellular portion of TNFRSF1A [2], [3]. These mutations are associated with an earlier disease onset and with a more severe phenotype; patients may experience a higher number of fever episodes and a greater severity of attacks [11]. On the contrary low-penetrance variants seem to be associated with a milder phenotype, a later disease onset and a lower risk of amyloidosis [3,4,5,6,7,8,9], [13]
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