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Original Research: CRITICAL CARE |

Leucyl/Cystinyl Aminopeptidase Gene Variants in Septic Shock

Taka-aki Nakada, MD, PhD; James A. Russell, MD; Hugh Wellman, MSc; John H. Boyd, MD; Emiri Nakada, MD; Katherine R. Thain, BSc; Simone A. Thair, BSc; Hiroyuki Hirasawa, MD, PhD; Shigeto Oda, MD, PhD; Keith R. Walley, MD; Dieter Ayers for the Vasopressin and Septic Shock Trial Investigators
Author and Funding Information

From the University of British Columbia (Drs T. Nakada, Russell, Boyd, E. Nakada, and Walley, and Mss Thain and Thair), Critical Care Research Laboratories, Heart and Lung Institute, St. Paul’s Hospital; and Sirius Genomics Inc (Mr Wellman), Vancouver, BC, Canada; and the Department of Emergency and Critical Care Medicine (Drs Hirasawa and Oda), Chiba University Graduate School of Medicine, Chiba, Japan.

Correspondence to: Keith R. Walley, MD, Heart and Lung Institute, University of British Columbia, 1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada; e-mail: Keith.Walley@hli.ubc.ca


Funding/Support: This study was funded by the Heart and Stroke Foundation and Sirius Genomics Inc. Dr T. Nakada is a CIHR IMPACT Postdoctoral Fellow and is supported in part by a research fellowship from Yamada Science Foundation.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(5):1042-1049. doi:10.1378/chest.10-2517
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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.

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