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.

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Two groups of patients with congestive heart failure were studied, one with elevated (Group I) and another (Group II) with suppressed plasma concentrations of vasopressin. The mean plasma arginine vasopressin (AVP) concentration in the 17 patients in group I was 3.1 +/- 0.4 pg/mliter whereas the eight patients in group II had plasma concentration less than 0.5 pg/mliter. Platelet AVP concentrations were also higher in the Group I than Group II patients (7.8 +/- 1.5 vs. 2.2 +/- 0.7 pg/mliter, P less than 0.001). Plasma effective osmolality (262 vs. 268 mOsm/kg H2O, P less than 0.05) and plasma sodium concentration (134 vs. 137 mEq/liter, P less than 0.05) were lower in Group I. The Group I patients had a lower cardiac index (CI, 1.9 vs. 2.5 liter/min/m2, P less than 0.05) and higher pulmonary capillary wedge pressure (PCWP, 30 vs. 22 mm Hg, P less than 0.02), plasma renin activity (4.4 vs. 2.0 ng/mliter/hr, P less than 0.01), and plasma aldosterone (74 vs. 10 ng/dliter, P less than 0.001) than the Group II patients. The Group I patients also excreted a smaller percentage of a 15 mliter/kg waterload (31 vs. 57%, P less than 0.005). Group I patients then were treated with agents to decrease cardiac afterload, either captopril or prazosin. CI increased (1.9 to 2.1 liter/min/m2, P less than 0.001) and PCWP decreased (30 to 27 mm Hg, P less than 0.001). This improved cardiac performance was associated with enhanced water excretion (31 vs. 52%, P less than 0.001) and decreased minimal urinary osmolality (375 vs. 208 mOsm/kg H2O, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)