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

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‐Arg9‐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. Hum Mutat 32:1326–1331, 2011. ©2011 Wiley Periodicals, Inc.