Hereditary angioedema: Research of genetic etiology

Project Details

Description

Hereditary angioedema (HAE) is a rare, life-threatening, autosomal dominant inborn error of immunity, characterized by recurrent episodes of subcutaneous or submucosal edema mostly of the extremities, face, airway and gastrointestinal tract. There are three types of hereditary angioedema: types I, II, and non-C1 INH associated HAE, which can be distinguished by levels and functional activity of a C1-esterase inhibitor.

C1-INH-associated HAE (types I and II) are mainly caused by pathogenic variations in the SERPING1 gene, that results in deficient or dysfunctional C1 esterase inhibitor (C1-INH), leading to overproduction of bradykinin and the development of massive local edema. Although pathogenic variations in SERPING1 is the only known cause of the development of HAE types I and II, there are ~15% of symptomatic HAE patients with reduced C1-INH levels and/or functional activity in whom pathogenic variations cannot be found even after carrying out a thorough genetic examination (including the entire SERPING1 gene sequencing of the coding and non-coding parts of the gene and analysis of copy number variants). Given the specific C1-INH-associated biochemical phenotype, we hypothesize that intragenic and extragenic non-coding point and structural variations in the SERPING1 gene are the cause of type I and II HAE in patients with a negative genetic finding because they cannot be detected by standard genetic diagnostic methods (Sanger sequencing, MLPA, exome sequencing). Currently, only whole genome sequencing (WGS) can unbiasedly detect all genetic variant classes. In contrast, the etiology and pathogenesis of non-C1-INH-associated HAE (type III) is more complex and is associated with gain-of-function pathogenic variants in genes involved in the quinine (incl. bradykinin) system (F12, PLG, ANGPT1, KNG1). The diagnosis of non-C1-INH-associated HAE can only be confirmed by genetic analysis. However, despite advances in novel gene discoveries, for most of the non-C1-INH HAE patients the genetic cause remains unknown. Patients with HAE need to clarify the genetic etiology of the disease because it is important for the diagnosis, prognosis, family planning, prevention and the optimization of treatment. Additionally, identification of the novel causes improves our understanding of the pathogenesis which could lead to the development of new drugs or alternative use of the existing ones.
StatusActive
Effective start/end date12/07/2111/07/22

Funding

  • Riga Stradins University: €20,000.00

Keywords

  • Hereditary angioedema
  • primary immunodeficiency
  • metabolome
  • biomarkers
  • whole genome sequencing

Field of Science

  • 3.2 Clinical medicine

Smart Specialization Area

  • Biomedicine, medical technologies and biotechnology

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