Association of B₂ Receptor Polymorphisms and ACE Activity With ACE Inhibitor–Induced Angioedema in Black and Mixed‐Race South Africans

Abstract

4Angiotensin-converting enzyme (ACE) inhibitors are first-line therapy for the treatment of hypertension, congestive heart failure, and diabetic nephropathy. ACE inhibitors are associated with adverse side effects such as persistent dry cough (ACE-cough) and, rarely, life-threatening angioedema (ACE-AE). The authors investigated the influence of ACE I/D polymorphism in combination with serum ACE activity, B 2 receptor À9/+9 polymorphism, and B 2 receptor C-58T single nucleotide polymorphism (SNP) on the development of ACE-AE and ACE-cough. The frequencies of ACE I/D as well as B 2 receptor +9/À9 and C-58T polymorphisms were compared in patients with ACE-AE, ACE-cough, and ACE inhibitor-exposed controls, and serum ACE activity was measured. There were 52 cases of ACE-AE, 36 cases of ACE-cough, and 77 controls. The genotyping revealed a significant association between the B 2 À9 allele and ACE inhibitor-induced AE (62% vs 38%, P=.008), and ACE inhibitor-induced cough (61% vs 38%, P=.02) when compared with controls. There was no significant association between ACE I/D polymorphism as well as the B 2 C-58T

Pharmacogenetics of angiotensin‐converting enzyme inhibitor‐induced angioedema

“…109 However, three further case-control studies did not support these initial findings. [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. 96,97 No other variants in ACE gene have been studied in association with ACE-A.…”

“…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.…”

“…112 This indel variation, involving one of the three 9 bp tandem repeats, was identified as rs772945381 or rs71103505 and referred to by different names, 9+/9-or -21-29/ +21-29 or 2G/3G (Table 3). 98 The latter study also assessed the correlation of the -58C>T SNP (rs1799722) in the promoter region of the gene, which has been previously associated with ACEi-induced cough, 21 but found no association with ACEi-A. [113][114][115] This rsID has now been deleted from dbSNP and does not appear in the most recent human genome assembly (GRCh38/Hg38).…”

“…Bas et al (2010) found no association of the 9 + /9variant with ACEi-A, 97 whereas another study found a significant association. 98 The latter study also assessed the correlation of the -58C>T SNP (rs1799722) in the promoter region of the gene, which has been previously associated with ACEi-induced cough, 21 but found no association with ACEi-A. Most of these studies had a small sample size, and larger studies will be required to validate these initial findings.…”

Pharmacogenomics of off‐target adverse drug reactions

“…Genetic variants associated with ACEi angioedema are typically involved in the activity of or breakdown pathways for bradykinin and substance P. Variants in the bradykinin receptor 2 and neprilysin genes have been implicated as important in patients of African descent . Similarly, variants in the x‐linked X‐prolyl aminopeptidase 2 ( XPNPEP2 ) gene encoding the cytosolic form of aminopeptidase P, a metalloproteinase that degrades bradykinin, has been associated with ACEi angioedema in French Canadians and in both white and black men, but not women, from Tennessee .…”