Leveraging Genetics for Hereditary Angioedema: A Road Map to Precision Medicine

Abstract

Biochemical studies performed during the last decades resulted in the development of various innovative medicinal products for hereditary angioedema (HAE). These therapeutic agents target the production or the function of bradykinin—the main mediator of HAE due to C1-inhibitor (C1-INH) deficiency. However, despite these remarkable achievements, current knowledge cannot provide convincing explanations for the clinical variability of the disease. As a consequence, treatment indications apply for drugs available for C1-INH deficiency. The advent of high-throughput next-generation sequencing technologies may assist in covering the missing part of our understanding of HAE pathogenesis. During the last 3 years alone, several new entities were added to the already described genotypes. The recent discovery of four novel target genes expands our understanding of other causes which may explain recurrent angioedema in individuals and families with normal C1-INH activity. Furthermore, new genetic technologies allowed the recognition of deep intronic variants associated with the disease, and elegant functional studies characterized new variants for the C1-INH gene. Thus, evidence has been provided regarding pathogenetic aspects remaining obscure for many years, such as the defective intracellular transport of mutant C1-INH, and environmental effect on the disease expression. Therefore, it seems that the stage for Precision Medicine era in HAE management is ready. Disease endotypes are expected to be uncovered and specified targets for therapeutic intervention will be detected, promising a more effective, individualized management of the disease.

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Fig. 1

Abbreviations

ACE-I :

Angiotensin convertase enzyme inhibitors

ANGPT1 :

Angiopoietin gene

APP :

Aminopeptidase P

BK :

Bradykinin

C1-INH :

C1-inhibitor

CS:

Contact-activating system

GWAS :

Genome-wide association studies

FXII:

Coagulation factor 12

HAE :

Hereditary angioedema

KKS :

Kallikrein-kinin system

KNG1:

Kininogen 1

MYOF :

Myoferlin gene

nC1-INH-HAE :

Normal C1 inhibitor HAE

NGS:

Next-generation sequencing

SERPING1 :

Serine-protease inhibitor 1 gene

PLG :

Plasminogen gene

U-HAE :

HAE with unknown mechanism

WES :

Whole-exome sequencing

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Correspondence to Anastasios E. Germenis.

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Germenis, A.E., Rijavec, M. & Veronez, C.L. Leveraging Genetics for Hereditary Angioedema: A Road Map to Precision Medicine. Clinic Rev Allerg Immunol (2021). https://doi.org/10.1007/s12016-021-08836-7

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Keywords

  • Acquired angioedema
  • C1-inhibitor deficiency
  • Genomics
  • Hereditary angioedema
  • Next-generation sequencing
  • Precision medicine