A Variant in XPNPEP2 Is Associated with Angioedema Induced by Angiotensin I–Converting Enzyme Inhibitors

Abstract

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P=.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.

The Development of a Novel Molecular Assay Examining the Role of Aminopeptidase P Polymorphisms in Acute Hypotensive Transfusion Reactions

“…More importantly, APP is the enzyme primarily responsible for the degradation of desArg 9 -bradykinin, the active metabolite of bradykinin. 3,[13][14][15] Notably, the XPNPEP2 gene responsible for coding membrane-bound APP is polymorphic.…”

“…15 In fact, several studies have demonstrated that the C-2399A SNP in XPNPEP2 is associated with decreased APP activity and angioedema in selected populations.…”

“…More importantly, APP is the enzyme primarily responsible for the degradation of desArg 9 -bradykinin, the active metabolite of bradykinin. 3,[13][14][15] Notably, the XPNPEP2 gene responsible for coding membrane-bound APP is polymorphic. 14,15 The C-2399A single-nucleotide polymorphism (SNP) in XPNPEP2 results in a substantially truncated APP protein that cannot adequately bind to the membrane of host epithelial cells, thereby reducing its ability to participate in bradykinin/bradykinin metabolite degradation.…”

“…3,[13][14][15] Notably, the XPNPEP2 gene responsible for coding membrane-bound APP is polymorphic. 14,15 The C-2399A single-nucleotide polymorphism (SNP) in XPNPEP2 results in a substantially truncated APP protein that cannot adequately bind to the membrane of host epithelial cells, thereby reducing its ability to participate in bradykinin/bradykinin metabolite degradation. 15 In fact, several studies have demonstrated that the C-2399A SNP in XPNPEP2 is associated with decreased APP activity and angioedema in selected populations.…”

“…14,15 The C-2399A single-nucleotide polymorphism (SNP) in XPNPEP2 results in a substantially truncated APP protein that cannot adequately bind to the membrane of host epithelial cells, thereby reducing its ability to participate in bradykinin/bradykinin metabolite degradation. 15 In fact, several studies have demonstrated that the C-2399A SNP in XPNPEP2 is associated with decreased APP activity and angioedema in selected populations. [14][15][16] To date, however, few studies have investigated the role of APP in acute hypotensive transfusion reactions, 9,11 and no studies have determined whether the C-2399A SNP may be a contributing factor to acute hypotensive transfusion reactions in patients not taking ACE-Is.…”