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.
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Authors | Amy L Cilia La Corte, Angela M Carter, Gillian I Rice, Qing Ling Duan, Guy A Rouleau, Albert Adam, Peter J Grant, Nigel M Hooper |
Journal | Human mutation
(Hum Mutat)
Vol. 32
Issue 11
Pg. 1326-31
(Nov 2011)
ISSN: 1098-1004 [Electronic] United States |
PMID | 21898657
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2011 Wiley Periodicals, Inc. |
Chemical References |
- Angiotensin-Converting Enzyme Inhibitors
- Aminopeptidases
- X-Pro aminopeptidase
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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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