Identification of Circulating Gene Expression Signatures of Intracranial Aneurysm in Peripheral Blood Mononuclear Cells

Abstract

Peripheral blood mononuclear cells (PBMCs) play an important role in the inflammation that accompanies intracranial aneurysm (IA) pathophysiology. We hypothesized that PBMCs have different transcriptional profiles in patients harboring IAs as compared to IA-free controls, which could be the basis for potential blood-based biomarkers for the disease. To test this, we isolated PBMC RNA from whole blood of 52 subjects (24 with IA, 28 without) and performed next-generation RNA sequencing to obtain their transcriptomes. In a randomly assigned discovery cohort of n = 39 patients, we performed differential expression analysis to define an IA-associated signature of 54 genes (q < 0.05 and an absolute fold-change ≥ 1.3). In the withheld validation dataset, these genes could delineate patients with IAs from controls, as the majority of them still had the same direction of expression difference. Bioinformatics analyses by gene ontology enrichment analysis and Ingenuity Pathway Analysis (IPA) demonstrated enrichment of structural regulation processes, intracellular signaling function, regulation of ion transport, and cell adhesion. IPA analysis showed that these processes were likely coordinated through NF-kB, cytokine signaling, growth factors, and TNF activity. Correlation analysis with aneurysm size and risk assessment metrics showed that 4/54 genes were associated with rupture risk. These findings highlight the potential to develop predictive biomarkers from PBMCs to identify patients harboring IAs.

High-Dimensional Immune Profiling by Mass Cytometry Revealed the Circulating Immune Cell Landscape in Patients With Intracranial Aneurysm

“…IA is increasingly recognized as a disease driven by chronic inflammation ( 5 , 7 , 14 , 15 ). Circulating immune cells may contribute to IA formation and progression by infiltrating the vessel walls, releasing proinflammatory molecules, mediating the destruction of the endothelium and the extracellular matrix and promoting the pathogenic proliferation of smooth muscle cells ( 10 , 16 , 17 ). In this study, we demonstrated that IA patients exhibited dysfunction of immunity, with dysregulation of CD4 + T-cell clusters, increased B cells and monocytes, and decreased CD8 + T cells, DNT cells, and DPT cells.…”

TNFRSF19 (TROY) as a plasma biomarker for diagnosing and monitoring intracranial aneurysms progression

“…Previous studies demonstrated DEGs in the circulating blood could serve as useful diagnostic markers in IAs. For example, neutrophil RNA expression pro le from blood samples could predict the presence of UIAs [33,34]. Raman et al [35] and Li et al [36] revealed that several different expression levels of serum miRNAs could discriminate patients with IAs from healthy individuals.…”

Aberrant Whole Blood Gene Expression in the Lumen of Human Intracranial Aneurysms

“…Any difference was considered statistically significant if p < 0.05. For correlation analyses, Pearson correlation was assessed as previously described [22]. To measure the degree of correlation, we assessed the Pearson correlation coefficient (PCC) and p-value from the Wald test.…”