Genetic susceptibility to angiotensin-converting enzyme-inhibitor induced angioedema: A systematic review and evaluation of methodological approaches

by Haivin Aziz Ali, Anne Fog Lomholt, Seyed Hamidreza Mahmoudpour, Thorbjørn Hermanrud, Anette Bygum, Christian von Buchwald, Marianne Antonius Jakobsen, Eva Rye Rasmussen

Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II which causes vasoconstriction. ACE inhibitors reduce blood pressure by inhibiting ACE. A well-known adverse drug reaction to ACE inhibitors is ACE inhibitor-induced angioedema (ACEi-AE). Angioedema is a swelling of skin and mucosa, which can be fatal if the airway is compromised. We have performed a systematic review of the evidence suggesting that genetic polymorphisms are associated with ACEi-AE and evaluated the methodological approaches of the included studies. The Cochrane Database of Systematic Reviews, Google Scholar, and PubMed were searched. Studies investigating the association between genetic markers and ACEi-AE were included. The Q-genie tool was used to evaluate the quality of the study methodologies. Seven studies were included. With the exception of one whole genome study, all of the included studies were candidate gene association studies. Study quality assessment scores ranged from 36 to 55. One study was found to be of good quality, suggesting that the detected associations may be unreliable. The inferior quality of some studies was due to poor organization, lack of analyses and missing information. Polymorphisms within XPEPNP2, BDKRB2–9/+ 9 and neprilysin genes, were reported to be associated with increased risk of ACEi-AE. However, due to low quality, these associations need to be confirmed in larger studies.