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

Autoři: Haivin Aziz Ali aff001;  Anne Fog Lomholt aff002;  Seyed Hamidreza Mahmoudpour aff003;  Thorbjørn Hermanrud aff002;  Anette Bygum aff004;  Christian von Buchwald aff002;  Marianne Antonius Jakobsen aff005;  Eva Rye Rasmussen aff002
Působiště autorů: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark aff001;  Department of Oto-Rhino-Laryngology—Head and Neck Surgery and Audiology, Denmark aff002;  IMBEI—Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg, CTH -Center for Thrombosis and Hemostasis Mainz, Mainz, Germany aff003;  Department of Dermatology I and Allergy Center, Odense University Hospital, Indgang, Odense C, Denmark aff004;  Department of Clinical Immunology, Odense University Hospital, Denmark, Odense C, Denmark aff005
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224858


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.

Klíčová slova:

Adverse reactions – Case-control studies – Database searching – Genetic polymorphism – Genome-wide association studies – Haplotypes – Systematic reviews – ACE inhibitors


1. Peng H, Carretero OA, Vuljaj N, Liao T-D, Motivala A, Peterson EL, et al. Angiotensin-Converting Enzyme Inhibitors. Circulation. 2005;112: 2436–2445. doi: 10.1161/CIRCULATIONAHA.104.528695 16216963

2. Khalil M, Basher A, Brown E, Alhaddad I. A remarkable medical story: benefits of angiotensin-converting enzyme inhibitors in cardiac patients. J Am Coll Cardiol. 2001;37: 1757–1764. doi: 10.1016/s0735-1097(01)01229-3 11401108

3. Sulpizio AC, Pullen M a, Edwards RM, Brooks DP. The effect of acute angiotensin-converting enzyme and neutral endopeptidase 24.11 inhibition on plasma extravasation in the rat. J Pharmacol Exp Ther. 2004;309: 1141–1147. doi: 10.1124/jpet.103.064105 14769834

4. Byrd JB, Touzin K, Sile S, Gainer J V, Yu C, Nadeau J, et al. Dipeptidyl Peptidase IV in Angiotensin-Converting Enzyme Inhibitor–Associated Angioedema. Hypertension. 2009;51: 141–147. doi: 10.1161/HYPERTENSIONAHA.107.096552.Dipeptidyl

5. Kim SJ, Brooks JC, Sheikh J, Kaplan MS, Goldberg BJ. Angioedema deaths in the United States, 1979–2010. Ann Allergy Asthma Immunol. 2014;113: 630–634. doi: 10.1016/j.anai.2014.09.003 25280464

6. Agostoni A, Cicardi M, Cugno M, Zingale LC. Angioedema due to angiotensin-converting enzyme inhibitors. Immunopharmacology. 1999;44: 21–25. doi: 10.1016/s0162-3109(99)00107-1 10604520

7. Krogh Nielsen T, Bygum A, Rasmussen ER. Life-threatening angio-oedema after the first dose of an ACE inhibitor—not an anaphylactic reaction. BMJ Case Rep. 2016; bcr2016214364. doi: 10.1136/bcr-2016-214364 27229746

8. Boura A, Svolmanis A. Converting enzyme inhibition in the rat by captopril is accompanied by potentiation of carrageenin-induced inflammation. Brit J Pharmacol. 1984;82: 3–8. Available: = 1987256&tool = pmcentrez&rendertype = abstract

9. Emanueli C, Grady EF, Madeddu P, Figini M, Bunnett NW, Parisi D, et al. Acute ACE inhibition causes plasma extravasation in mice that is mediated by bradykinin and substance P. Hypertension. 1998;31: 1299–1304. doi: 10.1161/01.hyp.31.6.1299 9622145

10. Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G. Nonallergic angioedema: role of bradykinin. Allergy. 2007;62: 842–56. doi: 10.1111/j.1398-9995.2007.01427.x 17620062

11. Wang L, Sadoun E, Stephens RE, Ward PE. Metabolism of substance P and neurokinin A by human vascular endothelium and smooth muscle. Peptides. 1994;15: 497–503. Available: doi: 10.1016/0196-9781(94)90212-7 7524048

12. Kaplan AP, Ghebrehiwet B. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol. 2010;47: 2161–9. doi: 10.1016/j.molimm.2010.05.010 20580091

13. Ahmad S, Wang L, Ward P. Dipeptidyl (amino) peptidase IV and Aminopeptidase M metabolize circulating Substance P in vivo. J Pharmacol Exp Ther. 1992;260: 1257–61. 1372050

14. Rasmussen ER, von Buchwald C, Wadelius M, Prasad SC, Kamaleswaran S, Ajgeiy KK, et al. Assessment of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema. Int J Otolaryngol. 2017;2017: 1–7. doi: 10.1155/2017/1476402 28286522

15. Gainer J V, Nadeau JH, Ryder D, Brown NJ. Increased sensitivity to bradykinin among African Americans. J Allergy Clin Immunol. 1996;98: 283–287. doi: 10.1016/s0091-6749(96)70151-3 8757204

16. Bas M, Hoffmann TK, Tiemann B, Dao VTV, Bantis C, Balz V, et al. Potential genetic risk factors in angiotensin-converting enzyme-inhibitor-induced angio-oedema. Brit J Clin Pharmacol. 2010;69: 179–186. doi: 10.1111/j.1365-2125.2009.03567.x 20233181

17. Gulec M, Caliskaner Z, Tunca Y, Ozturk S, Bozoglu E, Gul D, et al. The role of ace gene polymorphism in the development of angioedema secondary to angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Allergol et Immunopathol. 2008;36: 134–40. Available:

18. Woodard-Grice A V., Lucisano AC, Byrd JB, Stone ER, Simmons WH, Brown NJ. Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics. 2010;20: 532–536. doi: 10.1097/FPC.0b013e32833d3acb

19. Pare G, Kubo M, Byrd JB, McCarty C a, Woodard-Grice A, Teo KK, et al. Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics. 2013;23: 470–478. doi: 10.1097/FPC.0b013e328363c137 23838604

20. Cilia La Corte AL, Carter AM, Rice GI, Duan QL, Rouleau GA, Adam A, et al. A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema. Hum Mutat. 2011;32: 1326–1331. doi: 10.1002/humu.21579 21898657

21. Moholisa RR, Rayner BR, Patricia Owen E, Schwager SLU, Stark JS, Badri M, et al. Association of B2 receptor polymorphisms and ACE activity with ACE inhibitor-induced angioedema in black and mixed-race south africans. J Clin Hypertens. 2013;15: 413–419. doi: 10.1111/jch.12104 23730990

22. Duan QL, Nikpoor B, Dube M, Molinaro G, Meijer IA, Dion P, et al. A variant in XPNPEP2 is associated with angioedema induced by angiotensin I–converting enzyme inhibitors. Am J Hum Genet. 2005;77: 617–626. doi: 10.1086/496899 16175507

23. Sohani ZN, Meyre D, de Souza RJ, Joseph PG, Gandhi M, Dennis BB, et al. Assessing the quality of published genetic association studies in meta-analyses: The quality of genetic studies (Q-Genie) tool. BMC Genet. 2015;16: 1–8. doi: 10.1186/s12863-014-0153-0

24. Moher D, Liberati A, Tetzlaff J, Altman DG. Systematic Reviews and Meta-Analyses: The PRISMA Statement. Annu Intern Med. 2009;151: 264–269. doi: 10.1371/journal.pmed1000097

25. Rasmussen E, Bygum A. Genetic polymorphisms in angiotension converting enzyme inhibitor-induced angioedema: a systematic review. In: CRD42018087063. 2017 p.

26. Adam A, Cugno M, Molinaro G, Perez M, Lepage Y, Agostoni A. Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors. Lancet. 2002;359: 2088–2089. doi: 10.1016/S0140-6736(02)08914-6 12086766

27. Wadelius M, Marshall SE, Islander G, Nordang L, Karawajczyk M, Yue Q-Y, et al. Phenotype standardization of angioedema in the head and neck region caused by agents acting on the angiotensin system. Clin Pharmacol Ther. 2014;96: 477–481. doi: 10.1038/clpt.2014.138 24960520

28. Hubers SA, Kohm K, Wei S, Yu C, Nian H, Grabert R, et al. Endogenous bradykinin and B1-B5 during angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2018;142: 1636–1639.e5. doi: 10.1016/j.jaci.2018.06.037 30036596

29. Kaplan AP, Ghebrehiwet B. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol immunol. 2010;47: 2161–9. doi: 10.1016/j.molimm.2010.05.010 20580091

30. Joseph K, Tholanikunnel BG, Bygum A, Ghebrehiwet B, Kaplan AP. Factor XII-independent activation of the bradykinin-forming cascade: Implications for the pathogenesis of hereditary angioedema types I and II. J Allergy Clin Immunol. 2013;132: 470–5. doi: 10.1016/j.jaci.2013.03.026 23672780

31. Veronez CL, Serpa FS, Pesquero JB. A rare mutation in the F12 gene in a patient with ACE inhibitor-induced angioedema. Ann Allergy Asthma Immunol. 2017;118: 743–745. doi: 10.1016/j.anai.2017.04.014 28483295

32. Human Genome Variation Society. No Title. In:

33. Q-genie tool. In: 2015.

Článek vyšel v časopise


2019 Číslo 11