Leucyl/Cystinyl Aminopeptidase Gene Variants in Septic Shock

Vasopressin is an essential peptide hormone regulating cardiovascular homeostasis and an adjunctive vasopressor therapy for septic shock.We tested for association between single nucleotide polymorphisms (SNPs) in vasopressin pathway genes and altered outcome in derivation (n = 589) and replication (n = 616) cohorts of patients with septic shock. The primary outcome was 28-day mortality and the secondary outcome was vasopressin clearance. In a third cardiac surgical cohort (n = 977), we tested for locus-specific heritability of serum sodium concentrations.Of 17 tested tag SNPs in five vasopressin pathway genes (arginine vasopressin [AVP], arginine vasopressin receptor 1A and 1B [AVPR1A, AVPR1B], leucyl/cystinyl aminopeptidase [LNPEP], and oxytocin receptor [OXTR]), rs18059 in LNPEP (also known as vasopressinase) was associated with 28-day mortality in the derivation cohort (P = .037). Therefore, we resequenced the 160-kb haplotype block encompassing the LNPEP gene, including rs18059, and genotyped the 230 identified SNPs in the derivation cohort. The strongest signal was found for LNPEP rs4869317 (adjusted P = .044). The rs4869317 TT genotype was associated with increased 28-day mortality in the derivation cohort (51.0% [TT] vs 34.5% [AA/AT]; adjusted hazard ratio [HR], 1.58; 95% CI, 1.21-2.06; P = .00073) and the replication cohort (38.6% vs 29.6%; HR, 1.36; 95% CI, 1.03-1.80; P = .030). We found that the TT genotype was associated with increased plasma vasopressin clearance (P = .028), and the rs4869317 genotype accounted for 80% of the variance of serum sodium concentrations (locus-specific heritability) in cardiac surgical patients.The genetic variation in LNPEP (vasopressinase) is associated with 28-day mortality in septic shock and is associated with biologic effects on vasopressin clearance and serum sodium regulation. Further confirmation in additional cohorts is required.