title: 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.
authors: Institute of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
authors: Amy L
authors: AL
authors: Cilia La Corte
authors: Angela M
authors: AM
authors: Carter
authors: Gillian I
authors: GI
authors: Rice
authors: Qing Ling
authors: QL
authors: Duan
authors: Guy A
authors: GA
authors: Rouleau
authors: Albert
authors: A
authors: Adam
authors: Peter J
authors: PJ
authors: Grant
authors: Nigel M
authors: NM
authors: Hooper
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000626:Aminopeptidases / Q000097:blood* / Q000235:genetics*; D000799:Angioedema / Q000139:chemically induced*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011401:Promoter Regions, Genetic; D050436:Regulatory Elements, Transcriptional
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase