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MicroRNAs as antiphospholipid syndrome biomarkers
AB
C
Figure 6. Specific miRNA signatures might identify subgroups of antiphospholipid syn- drome (APS) patients showing different thrombotic risk profiles: cluster analysis. (A) Clinical and laboratory parameters of the 3 clusters. (B) Comparison of the adjusted global anti-phospholipid syndrome score (aGAPSS) values among the different clus- ters. (C) Evaluation of different microRNA (miR) ratios expression among clusters. HTA: arterial hypertension; LA: lupus antico- agulant; aCL: anti-cardiolipin IgG/IgM; anti- β2GPI: anti-β2 glycoprotein 1 IgG/IgM.
this autoimmune disorder. Moreover, this signature could represent a useful tool to typify and stratify patients based on their thrombotic status and cardiovascular risk profile (Online Supplementary Figure S3).
Circulating miRNAs were firstly described in peripheral blood as promising specific biomarkers for a wide range of diseases, such as cancer and other inflammatory patholo- gies.25,26 Thereafter, several studies revealed the altered expression of numerous miRNAs in plasma, blood cells, and tissues of systemic autoimmune conditions, such as RA and SLE, which were directly associated to disease activity, making them potential useful biomarkers for clin- ical features and follow up.9,26-29 However, to date, the spe- cific profile of circulating miRNAs in APS patients has not been evaluated. In the present study, the profiling of miRNAs by PCR-array in plasma of APS patients has helped to identify a set of miRNAs differentially expressed and collectively associated to clinical features of the dis- ease, such as inflammatory response, reproductive system disease, and CVD, among others. Using logistic regres- sion, we further developed a model that identified 10 miRNA ratios, differentially expressed, that showed great potential as biomarkers of disease of APS patients.
Recent studies support the evidence that an miRNAs signature has a higher diagnostic value than individual miRNAs.14-19 The use of ratios is a feasible approach that overcomes the controversial question of normalizing plas- ma levels of miRNAs, given the lack of a reliable normal- izer for circulating miRNAs. In addition, the establishment
of these ratios allows the identification of a combination of expression profiles closer to reality in vivo in patients, where the interactions between miRNAs and their specific potential targets never occur in a unique or individualized way. In fact, it is likely that, in some cases, various miRNAs, whose concentrations are shifted in opposite directions in a particular pathology, contribute together and specifically to certain clinical profiles.
The signatures of circulating miRNAs identified in APS patients integrated miRNAs previously described to be altered in other autoimmune and CVD. Thus, miR-19b and miR-20a have been shown to be essential modulators of TF expression in APS and SLE patients,8 so that reduced expression of such miRNAs contributes to the overexpres- sion of TF in monocytes, which is directly associated with the occurrence of thrombotic events in APS.21 On the other hand, miR-124, found altered in APS, SLE and RA patients at both cellular and plasma levels, modulates the overexpression of MCP-1, a key chemokine directly involved in CVD associated to these autoimmune condi- tions.30-33 Likewise, miR-133b and miR-145 have been identified as the most promising biomarkers of the patho- genesis of CVD. Both miRNAs participate in the differen- tiation of vascular smooth muscle cells. In addition, miR- 133b regulates angiogenesis and endothelial function, while miR-145 participates in the stabilization of athero- matous plaque.34 The miR-34a is highly expressed in endothelial cells, and elevated circulating levels of this miRNA have been associated to myocardial infarction.35
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