Potential genetic risk factors in angiotensin‐converting enzyme‐inhibitor‐induced angio‐oedema

Abstract

KeywordsACE I/D polymorphism, angio-oedema, bradykinin, bradykinin B2 receptor polymorphism, serum ACE activity ---------------------------------------------------------------------- WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Angiotensin-converting enzyme inhibitor (ACEi)-induced angio-oedema is an underestimated clinical life-threatening problem.• The incidence of this non-allergic, bradykinin-induced drug side-effect is 1 : 4000.• Although most ACEi-treated patients probably have an increased bradykinin plasma concentration, only 0.5% of them develop an angio-oedema and nothing is known about potential risk factors. WHAT THIS STUDY ADDS• In our attempt to elucidate the unpredictable character of ACEi-induced angio-oedema, we investigated bradykinin B2 receptor 2/3 and c.C181T polymorphisms as well as the ACE insertion/deletion polymorphism in combination with serum ACE activity in 65 patients.• ACE insertion/deletion and bradykinin B2 receptor polymorphisms are not involved in the development of ACEi-induced angio-oedema.• Further studies should be carried out to clarify whether a combination of these polymorphisms might be a risk factor for ACEi-induced angio-oedema. AIMSThe pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)-induced angio-oedema remains unclear. We have investigated the impact of ACE insertion/deletion (I/D) polymorphism in combination with serum ACE activity as well as the bradykinin B2 receptor 2/3 and c.C181T polymorphisms. METHODSWe analysed the ACE I/D as well as bradykinin B2 (2/3 and C181T) receptor polymorphisms in 65 patients with documented episodes of ACEi-induced angio-oedema and 65 patients matched for age and sex being under ACEi treatment without history of angio-oedema. Furthermore, we determined serum ACE activity in 47 of the 65 angio-oedema patients 3 months after the angio-oedema attack and compared these values with 51 healthy individuals (control II). ; P = 0.9). RESULTS No risk association was identified between ACE CONCLUSIONSOur data suggest that polymorphism of ACE I/D and the bradykinin B2 receptor polymorphisms are not involved in the development of ACEi-induced angio-oedema when considered individually. Further studies should be carried out to clarify whether a combination of these polymorphisms might be a risk factor for ACEi-induced angio-oedema.

Molecular Genetic Mechanisms of Chronic Urticaria

“…Intradermal injection of substance P induces wheal and flare reactions in normal human skin 90, 91. Genetic variation in the ACE gene has been studied in patients with angioedema and CU patients with angioedema 92-94. Insertion/deletion polymorphisms of the ACE gene showed statistically significant associations with angioedema in CU in a Turkish cohort 94.…”

Stroke Pharmacogenetics

“…This association has been replicated in a larger cohort ( n = 169), and the C-2399A genotype was associated with an increased risk of angioedema in men only (OR 2.17 1.09-4.32, p = 0.03) [ 163 ] . Studies that have investigated whether ACE or bradykinin B 2 gene polymorphisms are associated with development of angioedema have, to date, found no causal association [ 164,165 ] . Due to the rarity of this condition, the sample sizes were small (maximum 65), and hence, a larger population would be required to de fi nitively exclude this association and identify new associations.…”

Pharmacogenetics of angiotensin‐converting enzyme inhibitor‐induced angioedema

“…106 The risk associated with the haplotype is higher compared to the rs3788853 alone (4.9-fold vs 3.0-fold) 95 Moholisa (2013) genotype, in which both copies of the ACE gene lack the 287 base-pair indel region, is associated with higher ACE activity, but not with higher risk of ACEi-A. [96][97][98] One of these studies reported a 50% lower ACE activity in ACEi-A cases compared to controls taking the same drug, and independent of the presence of the insertion/deletion variation 98 and, the two other studies failed to replicate this finding. 109 However, three further case-control studies did not support these initial findings.…”