Candidate Stress-Specific microRNA Expression in Pediatric Thrombosis and Healthy Children: A Comparative Analysis of Serum miR-34a-5p in Relation to Stress Levels and Inflammatory Genetic Traits

Background: Pediatric thrombosis (PT) is a rare clinical entity manifesting from neonatal life to adolescence with possibly severe clinical complications and increasing prevalence in the last decade. Its pathogenesis has been attributed to a multitude of factors, all of which share stress and inflammation as a common denominator. Although stress-induced inflammation, marked by the upregulation of proinflammatory interleukins, such as IL-1β, creates a prothrombotic environment, its relation with thrombosis remains incompletely defined, especially in the context of PT, which differs substantially from adult thrombosis. Here, we aimed to epigenetically explore the potential link between PT and stress-induced inflammation through a combinatorial approach. Methods: Initially, we bioinformatically identified candidate stress-specific miRNAs in childhood, followed by subsequent experimental assessment in serum samples of PT patients and healthy controls in relation to subjectively perceived stress levels and the functional +3953C/T genetic polymorphism of the IL1B gene, which affects the circulating levels of the proinflammatory and stress-induced interleukin 1beta (IL-1β). Results: The bioinformatic analysis identified miR-34a-5p as the most stress-specific candidate microRNA in childhood, exhibiting the highest gene-target coverage (80.6%) of the developed panel of adversity-related genes, but is also known to regulate IL1B expression. The expression of serum miR-34a-5p was not significantly influenced by subjectively perceived stress; however, its expression was significantly reduced in the presence of the T allele of the functional +3953C/T polymorphism of its target gene, IL1B, associated with increased levels of the stress-induced proinflammatory and simultaneously prothrombotic IL-1β cytokine (FC:0.57; p = 0.024). Conclusions: The observed downregulation of miR-34a-5p in the presence of the IL-1β-increasing T allele possibly indicates a dynamic regulatory relationship, which, alongside its previously established long-term downregulation in PT, renders miR-34a-5p a promising candidate molecule for bridging the biological processes of stress-associated inflammation and thrombosis. In addition, its bioinformatically yielded candidate stress-specific role holds great potential for the non-invasive evaluation of adversity-related stress in childhood.