Leucyl/cystinyl aminopeptidase gene variants in septic shock.

Abstract

BACKGROUND:

Vasopressin is an essential peptide hormone regulating cardiovascular homeostasis and an adjunctive vasopressor therapy for septic shock.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Taka-Aki Nakada, James A Russell, Hugh Wellman, John H Boyd, Emiri Nakada, Katherine R Thain, Simone A Thair, Hiroyuki Hirasawa, Shigeto Oda, Keith R Walley
• Journal: Chest (Chest) Vol. 139 Issue 5 Pg. 1042-1049 (May 2011) ISSN: 1931-3543 [Electronic] United States
• PMID: 21330387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vasopressins
• Sodium
• Cystinyl Aminopeptidase
• leucyl-cystinyl aminopeptidase

Topics

• Aged
• Cardiac Surgical Procedures
• Cystinyl Aminopeptidase (genetics)
• Female
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Shock, Septic (blood, genetics)
• Sodium (blood)
• Vasopressins (blood)