title: A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors.
abstract: 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.
authors.affiliation: Centre de recherche du CHUM, Hopital Notre-Dame, Montreal, Quebec, Canada.
authors.forename: Qing Ling
authors.initials: QL
authors.lastname: Duan
authors.forename: Borzoo
authors.initials: B
authors.lastname: Nikpoor
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dube
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Molinaro
authors.forename: Inge A
authors.initials: IA
authors.lastname: Meijer
authors.forename: Patrick
authors.initials: P
authors.lastname: Dion
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.forename: Judith
authors.initials: J
authors.lastname: Saint-Onge
authors.forename: Leah
authors.initials: L
authors.lastname: Flury
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
authors.forename: James V
authors.initials: JV
authors.lastname: Gainer
authors.forename: Jean L
authors.initials: JL
authors.lastname: Rouleau
authors.forename: Angelo
authors.initials: A
authors.lastname: Agostoni
authors.forename: Massimo
authors.initials: M
authors.lastname: Cugno
authors.forename: Pierre
authors.initials: P
authors.lastname: Simon
authors.forename: Pierre
authors.initials: P
authors.lastname: Clavel
authors.forename: Jacky
authors.initials: J
authors.lastname: Potier
authors.forename: Bassem
authors.initials: B
authors.lastname: Wehbe
authors.forename: Seddik
authors.initials: S
authors.lastname: Benarbia
authors.forename: Julien
authors.initials: J
authors.lastname: Marc-Aurele
authors.forename: Jacques
authors.initials: J
authors.lastname: Chanard
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Albert
authors.initials: A
authors.lastname: Adam
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000626:Aminopeptidases / Q000097:blood / Q000235:genetics*; D000799:Angioedema / Q000139:chemically induced* / Q000235:genetics*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D015331:Cohort Studies; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D040641:Quantitative Trait Loci
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase