Whole Exome Sequencing in Drug-Induced Angioedema Caused by Angiotensin-Converting Enzyme Inhibitors: A Pilot Study in Five Patients

Abstract

Background and Objectives: One of the most common causes of drug-induced angioedema (AE-DI) is related to reduced bradykinin breakdown after the use of certain medications. This is the case for forms of AE-DI due to the use of angiotensin-converting enzyme inhibitors (ACEi), which are used for the treatment of cardiovascular conditions. The causes of AE are not clear in these patients. Given the limited number of AE-ACEi genetic loci identified by genome-wide association studies, we opted to assess the utility of NGS of a panel of relevant genes to identify candidate genetic risk factors in severely affected patients. Methods: Five hypertensive patients from unrelated families with clinical AE-ACEi were included in the study. Whole-exome sequencing, variant calling, and annotation techniques were used. ANNOVAR v18.04.16 was used to annotate the variant calls. The resulting variants for each patient were assessed using the Hereditary Angioedema Database Annotation tool and Franklin genomic platform for variant prioritization and clinical impact interpretation. Results: The genetic variant rs6025 in the F5 gene was identified in all recruited samples, which has been associated with an increase in blood clotting in AE-ACEi patients. In two patients, a common synonymous genetic variant of the ACE gene was found (rs4343). Finally, we identified the ACE genetic variant rs142947404 in only one patient. This variant has not been assessed in AE-ACEi. Conclusions: More studies will be needed to clarify the genetics involved in AE-DI. In this way, we will be able to try to predict future episodes of angioedema due to the use of ACEi.

Keywords: ACEi; NGS; acquired angioedema; bradykinin; exome.

Figure 1

Overview of DNA sequencing and data processing for AE-ACEi candidate genetic variant prioritization.