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Study of Urinary Protein Biomarkers in Hereditary Angioedema

Wu J1,2*, Tang X1,3*, Zhou N4*, Wang X4, Liu P2, Zhang Z2, Zhang S2,5, Zhi Y4

1Institute of Clinical Medicine, National Infrastructure for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
3State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
4Department of Allergy and Clinical Immunology, National Clinical Research Center for Immunologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
5Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
*Jianqiang Wu, Xiaoyue Tang, and Nan Zhou contributed equally to this study.

J Investig Allergol Clin Immunol 2025; Vol. 35(5)
doi: 10.18176/jiaci.1032

Background: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease, and diagnosis is often missed or delayed. We aimed to identify noninvasive urinary protein biomarkers and to evaluate their potential roles in diagnosis and evaluation of disease severity.
Methods: Using data-independent acquisition (DIA)–based urinary proteomics, we identified proteins that were differentially expressed between patients with HAE and healthy control (HC) groups. Then, the parallel reaction monitoring (PRM)–targeted proteomics method was used to validate promising biomarker candidates in other HAE patients and HCs. Furthermore, enzyme-linked immunosorbent assay (ELISA) was conducted to verify levels of several key proteins in HAE, histamine-mediated angioedema, and HCs.
Results: Differential expression between HAE patients and HCs was observed in 269 of the 2562 urinary proteins identified. In the biofunction analysis, these differentially expressed proteins were significantly enriched in leukocyte migration, adhesion of immune cells, endothelial cell development, permeability of the vascular system, and death of immune cells. Moreover, a biomarker panel (C1 esterase inhibitor, pro-epidermal growth factor, and kininogen-1) was validated in 2 independent clinical cohorts with area under the curve values of 0.910 and 0.949 for a diagnosis of HAE. Additionally, the urinary clusterin level was found to be significantly correlated with HAE severity scores (R=–0.758, P<.01).
Conclusions: This study describes the first application of a DIA-PRM-ELISA workflow to identify noninvasive urine biomarkers of HAE. The results will contribute to our understanding of the pathogenesis of HAE and may also provide a potential alternative method for diagnosis and evaluation of disease severity.

Key words: Hereditary angioedema, Biomarkers, Urine, Proteomics, Pathogenesis