title: 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.affiliation: University of British Columbia, Critical Care Research Laboratories, Heart and Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
authors.forename: Taka-Aki
authors.initials: TA
authors.lastname: Nakada
authors.affiliation: University of British Columbia, Critical Care Research Laboratories, Heart and Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.affiliation: Sirius Genomics Inc, Vancouver, BC, Canada.
authors.forename: Hugh
authors.initials: H
authors.lastname: Wellman
authors.affiliation: University of British Columbia, Critical Care Research Laboratories, Heart and Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
authors.forename: John H
authors.initials: JH
authors.lastname: Boyd
authors.affiliation: University of British Columbia, Critical Care Research Laboratories, Heart and Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
authors.forename: Emiri
authors.initials: E
authors.lastname: Nakada
authors.affiliation: University of British Columbia, Critical Care Research Laboratories, Heart and Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Thain
authors.affiliation: University of British Columbia, Critical Care Research Laboratories, Heart and Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Thair
authors.affiliation: Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirasawa
authors.affiliation: Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Oda
authors.affiliation: University of British Columbia, Critical Care Research Laboratories, Heart and Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada. Electronic address: Keith.Walley@hli.ubc.ca.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
mesh_terms: D000368:Aged; D006348:Cardiac Surgical Procedures; D010122:Cystinyl Aminopeptidase / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012772:Shock, Septic / Q000097:blood / Q000235:genetics*; D012964:Sodium / Q000097:blood; D014667:Vasopressins / Q000097:blood
chemical_list: D014667:Vasopressins; D012964:Sodium; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase