Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema

Abstract

Background-Angioedema is a rare adverse effect of angiotensin converting enzyme (ACE) inhibitors that occurs more commonly in women and black Americans. Angioedema is thought to result from decreased degradation of vasoactive peptides. During ACE inhibition, bradykinin is primarily inactivated by aminopeptidase P (APP). Previous studies have provided conflicting data regarding serum APP activity in patients with a history of ACE inhibitor-associated angioedema. A single nucleotide polymorphism, −2399C>A (rs3788853, C-2399A), in XPNPEP2, the X-linked gene that encodes membranous APP, has been reported to associate with APP activity.

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.…”

“…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.…”

“…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.…”

“…This hypothesis is focused on the C-2399A polymorphism because previous studies have shown that this SNP reduces APP activity and thereby potentially prolongs the half-life of bradykinin and/or its active metabolites. [13][14][15] As such, the primary aim of this study is to develop an assay for the C-2399A SNP. After validation of this assay we will attempt, via a small pilot study, to examine the few cases of acute hypotensive transfusion reactions in patients not taking ACE-Is noted at our facility to determine if any initial associations between this reaction and the C-2399A polymorphism in XPNPEP2 can be found.…”