Omics analysis reveals galectin-3 to be a potential key regulator of allergic inflammation in hereditary angioedema

Hereditary angioedema (HAE) is a rare inherited disorder that predisposes an individual to develop vasogenic edema. Bradykinin release, which increases vascular permeability, results in angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes involved in bradykinin generation and mutations in genes that encode the C1 inhibitor of complement factor 1, which prevent its synthesis (type I HAE), form a dysfunctional protein (type II HAE), or have normal functioning C1-INH (type III HAE, aka HAE-III).

The goals of this study were to use a systems biology analysis to identify novel biomarkers to aid in the diagnosis of HAE-III and to elucidate its underlying pathogenic mechanisms.

Blood samples were obtained from HAE-III subjects and age- and sex-matched healthy controls. DNA, RNA, and protein purified from the samples were subjected to multiomics analysis using a 1-shot liquid chromatography-mass spectrometry-based multiomics platform (Omni-MS, Dalton Bioanalytics) to profile proteins, lipids, electrolytes, and metabolites enabling concurrent analysis of diverse analyte classes.

A total of 1647 novel identifications that included genes, proteins, and metabolites were made when comparing HAE-III samples to control samples. Our identification library included MSFragger for protein identification, LipiDex for lipid identification, and Compound Discoverer for metabolite identification, enabling differential expression analysis. Key findings included a significant increase in the expression levels of galectin-3, lysosomal α-glucosidase, platelet factor 4, and platelet-derived growth factor subunit A in HAE-III subjects compared to controls, all of which generate an immunomodulatory response.

Galectin-3 plays a critical role in eosinophil recruitment and airway allergic inflammation. It may contribute to chronic inflammation and fibrosis resulting in leaky vasculature, and it could be a potential therapeutic target in HAE-III.