Bradykinin-Mediated Angioedema: An Update of the Genetic Causes and the Impact of Genomics

Abstract

Recurrent episodes of bradykinin-mediated angioedema (Bk-AE) can associate with acquired or hereditary conditions, the former most commonly developing secondarily to a pharmacological treatment. Despite successful genomic advances that have led to the identification of a large number of disease genes irrespective of disease prevalence, their application to Bk-AE has barely occurred. As a consequence, the genetic causes of Bk-AE remain poorly understood, obstructing the identification of patient subtypes and the development of precision medicine strategies. This review provides an update of the genetic studies completed to date on the acquired forms, which have almost exclusively focused on Bk-AE secondarily to the angiotensin-converting enzyme inhibitor treatment, and the blooming subdivision of the hereditary forms established by the identification of novel causal genes with next-generation sequencing (NGS) technology-based exome studies in genetically undiagnosed patients. Finally, based on the diverse benefits that are offered by the technology, we present arguments favoring the use of holistic NGS approaches as first-tier genetic tests as a promise to reduce the diagnostic odyssey of patients with suspected hereditary forms of Bk-AE.

Keywords: angioedema; diagnosis; inheritance; precision medicine; sequencing.

Figure 1

Schematic representation of bradykinin-mediated angioedema (AE) subtypes subdivided into acquired (AAE) and hereditary (HAE) forms. Two major groups of patients can be recognized within AAE forms based on the presence of a C1 inhibitor (C1-INH) deficiency or on a provocation by ACE inhibitors. Among the HAE forms, a major subdivision is made based on the existence of a C1-INH deficiency (caused by variants affecting function of SERPING1) or a normal C1-INH activity. The latter can be caused by diverse genes, most of them identified in recent whole-exome sequencing (WES) analyses of families. There remains a proportion of patients with unknown genetic causes where newly reported genes might explain disease causality. SERPING1, C1-inhibitor; ANGPT1, angiopoietin 1; PLG, plasminogen; KNG1, kininogen 1; TNFAIP3, tumor necrosis factor alpha-induced protein 3; SYTL2, synaptotagmin like 2.

Figure 2

Schematic representation of the complement and contact system with simplified interactions of the protein activities encoded by the known hereditary angioedema (HAE) genes. Overall, all gene deficiencies lead to an increase in activity of bradykinin, which is a potent vasodilator that leads to an increase of vascular permeability and, therefore, to the formation of edema. C1 inhibitor (C1-INH) is a protease inhibitor with regulatory functions on the complement system and fibrinolysis. It is a key negative regulatory protein of the contact system, and the encoding gene is usually affected in HAE patients. HAE can be caused also by defects in the F12 gene, causing a FXII proenzyme autoactivation and leading to an increase in all the mediators of the cascade. Recent exome studies have identified other causal genes of HAE, whose encoded products interact in the system, some of which are as follows: angiopoietin 1, where variants affecting function would reduce its binding capability to the receptor, leading to an enhanced vascular permeability by a variety of mediators [including vascular endothelial growth factor (VEGF)], rather than just by bradykinin; plasminogen, where variants translate into an enhanced binding to activators, triggering the fibrinolytic system with subsequent formation of bradykinin; and kininogen 1, where variants affecting function alter the generation of high-molecular-weight kininogen, increasing the half-life of bradykinin.

Figure 3

Schematic representation of the location of the pathogenic and likely pathogenic variants described so far in the SERPING1 gene, encoding the C1 inhibitor, among patients with hereditary angioedema. Pathogenicity was inferred according to the American College of Medical Genetics and Genomics (ACMG) classification. Represented vertical bars correspond to the variants, which have been categorized by the effect (frameshift, nonsense, and missense). Splicing variants are also represented by vertical bars outside the exons. Exons are represented by gray boxes with the exon number indicated. Untranslated regions from 5′ and 3′ are also represented as an extended horizontal green arrow.

Figure 4

Summary of the main advantages and disadvantages of using a first-tier holistic next-generation sequencing (NGS) approach for the diagnosis of hereditary angioedema (HAE). Among the advantages, this approach reduces manual intervention (and the possibility to introduce errors during sample processing) and improves standardization. The routine analyses link the detection to diverse quality metrics of the results and rich biological information. These help to facilitate interpretations and reduce the possibility of reporting false positives. Because it is an unbiased assay (without a focus on genes or types of variation), it has the potential to identify novel HAE genes. If novel genes or novel variants affecting function are described, these can be re-analyzed in preexisting results from previous studies. If personalized medicine approaches are pursued, the results also permit the evaluation of other traits such as pharmacogenetics and inflammatory responses. Among the disadvantages, the cost of the test per patient continues to be higher than that of the classical genetic screens. But these costs are not considering the persons/hour costs nor the health system burden because of the genetic odyssey to reach a precise diagnosis. NGS requires specialized and costly laboratory and computational equipment and trained personnel to process the large amount of data generated. However, cloud-based solutions are proliferating, and they can drastically reduce this burden. There is an active debate around the additional burden of genetic counseling linked to the incidental findings that are expected.