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.

Figure  1

Cohorts included in variance-component linkage analysis. One member of each kindred, depicted in black, developed AE and/or AR associated with ACEi therapy. All available members were quantified for plasma APP activity, shown as numbers that represent units of arginine released per minute per milliliter of plasma. Genotypes of the C-2399A SNP upstream of XPNPEP2 are shown as C/C, C/A, or A/A for females, and C or A for males. a, DNA samples from cohort 1 were included in a genomewide microsatellite scan, which was analyzed for linkage using a variance-component method (SOLAR program). b, Eleven genome-scanned markers were genotyped in cohort 2 to further evaluate linkage. A large deletion (DEL) in XPNPEP2 segregates in pedigree VI.

Figure  2

Results of the variance-component QTL analyses in the five pedigrees of cohort 1. All results were corrected empirically for α ⩽ 0.05. a, String diagram of autosomal multipoint results, LODs >1, are shown next to a LOD scale. b, Two-point linkage analysis results including chromosome X.

Figure  3

Coding deletion in XPNPEP2. a, The deleted genomic region of 175 bp consists of 16 bp of exon 2 (in blue), the 3′ donor splice site (in green) and intronic sequences. b, The deleted allele (DEL) is present in four members of this pedigree who have negligible or reduced (in one female heterozygote) plasma APP activity. The two men with normal alleles (wt) both have high APP measurements. c, The deletion results in an abnormally spliced mRNA transcript coding for a premature stop codon that is predicted to translate into a severely truncated protein of 38 amino acids. This short peptide would not be membrane-bound because it lacks a glycosylphosphatidylinsitol (GPI) anchor attached to the alanine (A) at position 650.