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.
Angiotensin-converting enzyme inhibitors (ACEIs) have been used in the treatment of various cardiovascular diseases. Despite the therapeutic benefits of ACEIs, there are several reported side effects, including chronic cough, angioedema and anaphylactoid reactions. These adverse events cannot be explained by the vasodilatory effects of this group of medications. Preliminary studies have shown that patients with a history of developing these side effects have a lower activity of an enzyme called aminopeptidase-P. This enzyme has an important role in degrading bradykinin. This defect in enzymatic activity can be partially explained by genetic variation. Using genome-wide screening strategies, the locus (loci), gene(s) and untimely polymorphisms that explain the low enzymatic activity and side effects can be identified.
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