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

Lambden, S., Tomlinson, J., Piper, S., Gordon, A. C. and Leiper, J. (2018) 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. Critical Care, 22(1), 336. (doi: 10.1186/s13054-018-2277-5) (PMID:30538005) (PMCID:PMC6288902)

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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. TRIAL REGISTRATION:ISRCTN Registry, ISRCTN20769191 . Registered on 20 September 2012.

Item Type:Articles
Additional Information:This VANISH trial was funded by the UK National Institute for Health Research (NIHR) under its Research for Patient Benefit programme (grant number PB-PG-0610-22,350) and an NIHR Clinician Scientist Award held by Dr. Gordon. Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre. MRC intramurual funding, BJA/RCoA NIAA project grant. ACG is an NIHR Research Professor. SL is an NIHR Clinical Lecturer.
Keywords:Genetics, nitric oxide, sepsis, septic shock, nitric oxide synthase, clinical studies, translational studies, mortality/survival.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leiper, Professor James
Authors: Lambden, S., Tomlinson, J., Piper, S., Gordon, A. C., and Leiper, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Critical Care
Publisher:BioMed Central
ISSN:1364-8535
ISSN (Online):1466-609X
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Critical Care 22(1):336
Publisher Policy:Reproduced under a Creative Commons License

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