Determining biomarkers for evaluation and diagnosis of hereditary angioedema.
Clin Transl Allergy
; 12(10): e12202, 2022 Oct.
Article
in En
| MEDLINE
| ID: mdl-36254341
ABSTRACT
Rationale Kallikrein-bradykinin-forming cascade is known to cause hereditary angioedema (HAE) acute angioedema (AE) attacks. Further research of HAE attacks is needed to explain disease heterogeneity, predict treatment response and identify biomarkers for monitoring HAE attacks. Differential expression of the microvascular endothelial cell-surface receptors for example, g-C1qR, cytokeratin-1, and plasminogen-activator-urokinase-receptor (PLAUR) were hypothesized as biomarkers of AE attacks. Method:
To understand HAE attacks, the differentially expressed genes (DEGs) in RNAseq and mi-RNAseq data of total RNA extracted from skin biopsies of lesional versus non-lesional skin collected during and between attacks in Type-1 HAE patients (n = 11; FM = 83) were compared. To understand the HAE variants, DEGs in skin biopsies from HAE with normal C1 inhibitor (n = 5, FM = 50), and non-HAE (n = 7; FM = 34) patients were compared. Gene-set enrichment analyses and regulator effects analysis of these DEGs identified biological pathways in HAE attacks and their regulators.Results:
PLAUR gene, encoding urokinase-type plasminogen activator (u-PAR), was constitutively over-expressed in HAE-Type-1 versus non-HAE controls suggestive of overactive u-PAR-mediated signaling via binding to Factor-XII. Baseline PLAUR expression was associated with severe AE (p = 0.05). The 18 significant DEGs investigated between baseline and AE attack samples in Type1-HAE were enriched in beta1/beta3-integrin cell surface interactions and IL-6-mediated signaling. Regulator effects analysis suggests a role for IL-1b in HAE flares. AKT2, the mRNA regulated by the differentially-expressed miR-184A, was also associated with HAE attacks.Conclusion:
Angiopoetin-activated ß1-integrin signaling pathways causing endothelial destabilization, and avid binding of factor XII to u-PAR are possible novel mechanisms for progression of the endothelial kinin-bradykinin-forming cascade in HAE attacks.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Diagnostic_studies
/
Prognostic_studies
Language:
En
Journal:
Clin Transl Allergy
Year:
2022
Document type:
Article