title: 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, which 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). Earlier studies have provided conflicting data with regard to 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.
  
  
  OBJECTIVE
  To test the hypothesis that the relationship between XPNPEP2 C-2399A genotype and APP activity or ACE inhibitor-associated angioedema is sex-dependent and race-dependent.
  
  
  METHODS
  We compared C-2399A genotype frequencies in 169 cases with a history of ACE inhibitor-associated angioedema and 397 ACE inhibitor-exposed controls. Controls were prespecified to be 50% white, 50% black, and 50% women. Cases and controls were group matched for age and smoking.
  
  
  RESULTS
  XPNPEP2 C-2399A genotype associated with serum APP activity in both men and women. Serum APP activity was lower in men than in women, independent of genotype. XPNPEP2 -2399 A/ genotype was associated with an increased risk of angioedema in men [odds ratio 2.17 (1.09-4.32), P=0.03] in multivariate analysis. The A/ genotype was associated with angioedema in black men (P=0.03) but not in white men.
  
  
  CONCLUSIONS
  APP activity is lower in men and the XPNPEP2 C-2399A polymorphism associates with ACE inhibitor-associated angioedema in men but not women.
authors.affiliation: Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. alencia.v.woodard@vanderbilt.edu
authors.forename: Alencia V
authors.initials: AV
authors.lastname: Woodard-Grice
authors.forename: Amelia C
authors.initials: AC
authors.lastname: Lucisano
authors.forename: James B
authors.initials: JB
authors.lastname: Byrd
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Stone
authors.forename: William H
authors.initials: WH
authors.lastname: Simmons
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000626:Aminopeptidases / Q000235:genetics*; D000799:Angioedema / Q000139:chemically induced* / Q000201:enzymology / Q000208:ethnology* / Q000235:genetics; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000187:drug effects / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012727:Sex Characteristics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase