A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors

Qing Ling Duan, Borzoo Nikpoor, Marie Pierre Dubé, Giuseppe Molinaro, Inge A. Meijer, Patrick Dion, Daniel Rochefort, Judith Saint-Onge, Leah Flury, Nancy J. Brown, James V. Gainer, Jean L. Rouleau, Angelo Agostoni, Massimo Cugno, Pierre Simon, Pierre Clavel, Jacky Potier, Bassem Wehbe, Seddik Benarbia, Julien Marc-AurèleJacques Chanard, Tatiana Foroud, Albert Adam, Guy A. Rouleau

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97 Scopus citations


Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P = .0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.

Original languageEnglish (US)
Pages (from-to)617-626
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - Oct 2005


ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Duan, Q. L., Nikpoor, B., Dubé, M. P., Molinaro, G., Meijer, I. A., Dion, P., Rochefort, D., Saint-Onge, J., Flury, L., Brown, N. J., Gainer, J. V., Rouleau, J. L., Agostoni, A., Cugno, M., Simon, P., Clavel, P., Potier, J., Wehbe, B., Benarbia, S., ... Rouleau, G. A. (2005). A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors. American Journal of Human Genetics, 77(4), 617-626. https://doi.org/10.1086/496899