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Evidence for a protective role for the rs805305 single nucleotide polymorphism of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in septic shock through the regulation of DDAH activity

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Title: Evidence for a protective role for the rs805305 single nucleotide polymorphism of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in septic shock through the regulation of DDAH activity
Authors: Lambden, S
Tomlinson, J
Piper, S
Gordon, AC
Leiper, J
Item Type: Journal Article
Abstract: Background Dimethylarginine dimethylaminohydrolase 2 (DDAH2) regulates the synthesis of nitric oxide (NO) through the metabolism of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA). Pilot studies have associated the rs805305 SNP of DDAH2 with ADMA concentrations in sepsis. This study explored the impact of the rs805305 polymorphism on DDAH activity and outcome in septic shock. Methods We undertook a secondary analysis of data and samples collected during the Vasopressin versus noradrenaline as initial therapy in septic shock (VANISH) trial. Plasma and DNA samples isolated from 286 patients recruited into the VANISH trial were analysed. Concentrations of L-Arginine and the methylarginines ADMA and symmetric dimethylarginine (SDMA) were determined from plasma samples. Whole blood and buffy-coat samples were genotyped for polymorphisms of DDAH2. Clinical data collected during the study were used to explore the relationship between circulating methylarginines, genotype and outcome. Results Peak ADMA concentration over the study period was associated with a hazard ratio for death at 28 days of 3.3 (95% CI 2.0–5.4), p < 0.001. Reduced DDAH activity measured by an elevated ADMA:SDMA ratio was associated with a reduced risk of death in septic shock (p = 0.03). The rs805305 polymorphism of DDAH2 was associated with reduced DDAH activity (p = 0.004) and 28-day mortality (p = 0.02). Mean SOFA score and shock duration were also reduced in the less common G:G genotype compared to heterozygotes and C:C genotype patients (p = 0.04 and p = 0.02, respectively). Conclusions Plasma ADMA is a biomarker of outcome in septic shock, and reduced DDAH activity is associated with a protective effect. The polymorphism rs805305 SNP is associated with reduced mortality, which is potentially mediated by reduced DDAH2 activity.
Issue Date: 11-Dec-2018
Date of Acceptance: 26-Nov-2018
URI: http://hdl.handle.net/10044/1/65081
DOI: https://dx.doi.org/10.1186/s13054-018-2277-5
ISSN: 1364-8535
Publisher: BMC
Journal / Book Title: Critical Care
Volume: 22
Issue: 1
Copyright Statement: © 2018 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: National Institute for Health Research
National Institute for Health Research
Imperial College Healthcare NHS Trust
NIHR -RfPB
Funder's Grant Number: NIHR/CS/009/007
NIHR Fellowship
RDB17 79560
RD305
Keywords: Clinical studies
Genetics
Mortality/survival
Nitric oxide
Nitric oxide synthase
Sepsis
Septic shock
Translational studies
11 Medical And Health Sciences
Emergency & Critical Care Medicine
Publication Status: Published
Open Access location: https://ccforum.biomedcentral.com/track/pdf/10.1186/s13054-018-2277-5
Article Number: 336
Online Publication Date: 2018-12-11
Appears in Collections:Division of Surgery
Faculty of Medicine



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