Table 1. Outcomes reported by studies investigating the relationship between ACEi-induced angioedema and gene polymorphisms.
| First author and year of publication | Study design | Country | Ethnicity | Age means ± SD (years) | Gender (F, %) | Participants (treatment duration with ACEi) | Genotyping | Polymorphisms | Main findings | The total score based on the Q-genie tool |
|---|---|---|---|---|---|---|---|---|---|---|
| Bas 2009 [16] | Case-control study | Germany | NS | 62 ± 1,6 |
47 | 65 cases (36,7 ± 4,8 months) 65 controls (49 ± 3,5 months) |
Allele-specific PCR |
ACE I/D (rs 4646994) BDKRB2 2/3 BDKRB2 c.C181T (BDKRB2 c.40> T rs1046248) |
No significant association was found between ACE I/D or BDKRB2 2/3 and c.C181T (BDKRB2 c.40> T rs1046248) gene polymorphism and ACEi-AE | 42 |
| Duan 2005 [22] | Case-control study | USA, Canada, Belgium | Caucasian | NS | NS | 20 cases (less than 8 years) 60 controls |
Allele-specific PCR |
XPNPEP2 C-2399A (XPNPEP2 c.-2400C>A rs3788853) |
XPNPEP2 C-2399A (XPNPEP2 c.-2400C>A rs3788853) is correlated with decreased APP activity and thus a greater incidence of ACEi-AE | 39 |
| Gulec 2008 [17] | Case-control study | Turkey | Caucasian | 58,06 ± 8,71 | 72,4 | 32 cases (less than 36 months) 46 controls (NS) |
PCR | ACE I/D | No association was found between ACE gene polymorphism and ACEi-AE or ATRB-AE | 36 |
| La Corte 2011 [20] | Case-control study | USA, Canada, Belgium | NS | NS | NS | 34 cases (NS) 127 controls (NS) |
TaqMan SNP genotyping |
XPNPEP2 C-2399A (XPNPEP2 c. C.-2400C>A rs3788853) |
A functional ATG haplotype was found in the 5’regulatory region of XPNPEP2; this region is correlated with an increased risk of ACEi-AE due to decreased APP activity. The ATG haplotype is more informative than the XPNPEP2 C-2399A polymorphism (XPNPEP2 c. C.-2400C>A rs3788853) |
37 |
| Moholisa 2013[21] | Case-control study | South Africa | Black, Caucasian and Cape mixed ancestry | 49 | 79 | 52 cases (NS) 77 controls (2 years) |
Allel-specific PCR and RFLP |
ACE I/D BDKRB2–9/+9 BDKRB2 C-58T (BDKRB2 c.-192T>C rs1799722) |
The association between Bradykinin receptor B2–9 /+ 9 and the development of ACEi-AE and ACE-cough was significant. No significant correlation shown between ACE I/D or BDKRB2 C-58T (BDKRB2 c.-192T>C rs1799722) polymorphism and ACEi-AE and ACE-cough |
40 |
| Pare[19] | Case-control study | USA | Black and Caucasian | 58,4 ± 14,1 |
54,9 | 175 cases 489 controls (at least 6 months) |
GWAS |
CPN MME XPNPEP2 DPP4 BDKRB1 BDKRB2 TACR1 |
A GWAS study investigated the relationship between the SNPs and ACEi-AE; no genome-wide significant connection was found. However, there was moderate evidence that 16 SNPs from African-Americans and 41 SNPs from European-Americans wew associated with ACEi-AE (p <10−4). In a candidate gene analyses, there was a significant correlation between MME and ACEi-AE |
55 |
| Woodard-Grice 2010 [18] | Case-control study | USA | Black and Caucasian | 57,3 ± 14,1 |
56,8 | 169 cases (median of 5 months) 397 controls (median of 42 months) |
Allele-specific PCR |
XPNPEP2 C-2399A (XPNPEP2 c.C-2400C>A rs3788853) |
The XPNPEP2 C-2399A (XPNPEP2 c.C-2400C>A rs3788853) genotype was correlated with a greater risk of ACEi-AE in men |
45 |
ACE: angiotension-converting enzyme; ACEi: ACE-inhibitor; ACEi-AE: ACE-inhibitor induced angioedema; ATRB-AE: Angiotensin II receptor blocker induced angioedema; ACE I/D: ACE insertion/deletion; APP: aminopeptidase P; ATRB: angiotensin receptor blocker; F: female; NS: not specified; OR: odds ratio; BDKRB2: bradykinin B2; BDKRB1: bradykinin B1; CPN: carboxypeptidase P; MME: neprilysin; XPNPEP2: aminopeptidase P; TACR1: NK1 receptor; GWAS: genome-wide association study; SD: standard deviation; Q-genie tool: quality of genetic association studies; RFLP: restriction fragment length polymorphism; PCR: polymerase chain reaction.