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A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema.

Abstract
Angiotensin I-converting enzyme inhibitors (ACEi) are widely used antihypertensive agents that are associated with a potentially life-threatening reaction, ACEi-angioedema. Impaired metabolism of bradykinin and des-Arg(9) -bradykinin by aminopeptidase P (APP) is a key contributor to ACEi-angioedema. This study aimed to characterize the genetic regulation of the XPNPEP2 gene and identify the genetic factors contributing to variance in plasma APP activity and ACEi-angioedema. Additive genetic factors accounted for 47.3% of variance in plasma APP activity in healthy individuals. Nested deletion analysis identified the minimal promoter (-338 bp to -147 bp) and an enhancer region (-2,502 bp to -2,238 bp). Three polymorphisms (c.-2399C>A, c.-1612G>T, and c.-393G>A) were significantly associated with plasma APP activity. Haplotype ATG was significantly associated with reduced reporter gene activity and with reduced plasma APP activity. The c.-2399C>A polymorphism was located in an enhancer region and was predicted to differentially bind hepatic nuclear factor 4 (HNF4). Over expression of HNF4 increased the activation of haplotype ATG compared with haplotype CGG. In a case control study of subjects with a history of ACEi-angioedema, haplotype ATG was significantly associated with ACEi-angioedema (OR 4.87 [1.78-13.35] P = 0.002). The ATG haplotype is functional and contributes to ACEi-angioedema through a reduction in APP.
AuthorsAmy L Cilia La Corte, Angela M Carter, Gillian I Rice, Qing Ling Duan, Guy A Rouleau, Albert Adam, Peter J Grant, Nigel M Hooper
JournalHuman mutation (Hum Mutat) Vol. 32 Issue 11 Pg. 1326-31 (Nov 2011) ISSN: 1098-1004 [Electronic] United States
PMID21898657 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2011 Wiley Periodicals, Inc.
Chemical References
  • Angiotensin-Converting Enzyme Inhibitors
  • Aminopeptidases
  • X-Pro aminopeptidase
Topics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aminopeptidases (blood, genetics)
  • Angioedema (chemically induced)
  • Angiotensin-Converting Enzyme Inhibitors (adverse effects)
  • Female
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Promoter Regions, Genetic
  • Regulatory Elements, Transcriptional

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