PMID- 21330387
OWN - NLM
STAT- MEDLINE
DCOM- 20110718
LR  - 20170521
IS  - 1931-3543 (Electronic)
IS  - 0012-3692 (Linking)
VI  - 139
IP  - 5
DP  - 2011 May
TI  - Leucyl/cystinyl aminopeptidase gene variants in septic shock.
PG  - 1042-1049
LID - S0012-3692(11)60228-6 [pii]
LID - 10.1378/chest.10-2517 [doi]
AB  - 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.
FAU - Nakada, Taka-Aki
AU  - Nakada TA
AD  - University of British Columbia, Critical Care Research Laboratories, Heart and 
      Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
FAU - Russell, James A
AU  - Russell JA
AD  - University of British Columbia, Critical Care Research Laboratories, Heart and 
      Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
FAU - Wellman, Hugh
AU  - Wellman H
AD  - Sirius Genomics Inc, Vancouver, BC, Canada.
FAU - Boyd, John H
AU  - Boyd JH
AD  - University of British Columbia, Critical Care Research Laboratories, Heart and 
      Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
FAU - Nakada, Emiri
AU  - Nakada E
AD  - University of British Columbia, Critical Care Research Laboratories, Heart and 
      Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
FAU - Thain, Katherine R
AU  - Thain KR
AD  - University of British Columbia, Critical Care Research Laboratories, Heart and 
      Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
FAU - Thair, Simone A
AU  - Thair SA
AD  - University of British Columbia, Critical Care Research Laboratories, Heart and 
      Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada.
FAU - Hirasawa, Hiroyuki
AU  - Hirasawa H
AD  - Department of Emergency and Critical Care Medicine, Chiba University Graduate 
      School of Medicine, Chiba, Japan.
FAU - Oda, Shigeto
AU  - Oda S
AD  - Department of Emergency and Critical Care Medicine, Chiba University Graduate 
      School of Medicine, Chiba, Japan.
FAU - Walley, Keith R
AU  - Walley KR
AD  - 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.
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110217
PL  - United States
TA  - Chest
JT  - Chest
JID - 0231335
RN  - 11000-17-2 (Vasopressins)
RN  - 9NEZ333N27 (Sodium)
RN  - EC 3.4.11.3 (Cystinyl Aminopeptidase)
RN  - EC 3.4.11.3 (leucyl-cystinyl aminopeptidase)
SB  - IM
MH  - Aged
MH  - Cardiac Surgical Procedures
MH  - Cystinyl Aminopeptidase/*genetics
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Polymorphism, Single Nucleotide
MH  - Shock, Septic/blood/*genetics
MH  - Sodium/blood
MH  - Vasopressins/blood
EDAT- 2011/02/19 06:00
MHDA- 2011/07/19 06:00
CRDT- 2011/02/19 06:00
PHST- 2011/02/19 06:00 [entrez]
PHST- 2011/02/19 06:00 [pubmed]
PHST- 2011/07/19 06:00 [medline]
AID - S0012-3692(11)60228-6 [pii]
AID - 10.1378/chest.10-2517 [doi]
PST - ppublish
SO  - Chest. 2011 May;139(5):1042-1049. doi: 10.1378/chest.10-2517. Epub 2011 Feb 17.