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

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

    Research output: Contribution to journalArticlepeer-review

    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.
    Original languageEnglish
    Pages (from-to)1326-1331
    Number of pages5
    JournalHuman Mutation
    Volume32
    Issue number11
    DOIs
    Publication statusPublished - Nov 2011

    Keywords

    • ACE inhibitor angioedema
    • Aminopeptidase P
    • Bradykinin
    • Haplotype
    • Hepatic nuclear factor 4
    • Transcription regulatory elements

    Research Beacons, Institutes and Platforms

    • Dementia@Manchester

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