A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors.
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.
Duan
Qing Ling
QL
Centre de recherche du CHUM, Hopital Notre-Dame, Montreal, Quebec, Canada.
Nikpoor
Borzoo
B
Dube
Marie-Pierre
MP
Molinaro
Giuseppe
G
Meijer
Inge A
IA
Dion
Patrick
P
Rochefort
Daniel
D
Saint-Onge
Judith
J
Flury
Leah
L
Brown
Nancy J
NJ
Gainer
James V
JV
Rouleau
Jean L
JL
Agostoni
Angelo
A
Cugno
Massimo
M
Simon
Pierre
P
Clavel
Pierre
P
Potier
Jacky
J
Wehbe
Bassem
B
Benarbia
Seddik
S
Marc-Aurele
Julien
J
Chanard
Jacques
J
Foroud
Tatiana
T
Adam
Albert
A
Rouleau
Guy A
GA
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
D000806:Angiotensin-Converting Enzyme Inhibitors; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase