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. 2018 Dec 11;22(1):336.
doi: 10.1186/s13054-018-2277-5.

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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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

Simon Lambden et al. Crit Care. .
Free PMC 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.

Trial registration: ISRCTN Registry, ISRCTN20769191 . Registered on 20 September 2012.

Keywords: Clinical studies; Genetics; Mortality/survival; Nitric oxide; Nitric oxide synthase; Sepsis; Septic shock; Translational studies.

Conflict of interest statement

Ethics approval and consent to participate

The study received ethics committee approval (Oxford A research ethics committee (12/SC/0014)) and was registered prior to the start of recruitment (ISRCTN20769191).

Consent for publication

Patient consent was secured for participation in this study and publication of relevant results.

Competing interests

JL and SL are founding directors of and consultants to Critical Pressure ltd.

ACG reports that outside of this work he has received speaker fees from Orion Corporation Orion Pharma and Amomed Pharma. He has consulted for Ferring Pharmaceuticals, Tenax Therapeutics, Baxter Healthcare, Bristol-Myers Squibb and GSK and received grant support from Orion Corporation Orion Pharma, Tenax Therapeutics and HCA International with funds paid to his institution.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Representative image of the synthesis and regulation of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) in sepsis. Protein arginine methyl transferases (PRMT) catalyse the methylation of arginine containing protein residues to ADMA and SDMA, which are released upon proteolysis. ADMA and SDMA are transported via the y+ cationic amino acid transporter into and out of the circulation. SDMA is not metabolised in most cell,s whereas ADMA is metabolised by the two isoforms of dimethylarginine dimethylaminohydrolase (DDAH) in a wide range of tissues. ADMA acts intracellularly to inhibit nitric oxide synthase (NOS), SDMA has no action on NOS isoforms. SDMA is cleared by the kidney largely unchanged and in small part through metabolism by AGXT2 (not shown). ADMA is largely metabolised by DDAH to dimethylamine (DMA); a small amount is cleared unchanged through the kidney. In sepsis, the synthesis of ADMA and SDMA may be increased through high protein-turnover in patients in a catabolic state and reduced renal clearance as a consequence of acute kidney injury. Differences in the relative concentrations of these methylarginines reflect their differential metabolism by DDAH isoforms as only ADMA is a DDAH substrate. Note, monomethylarginine (L-NMMA) is considered to have the same synthetic pathway, activity, metabolism and clearance as ADMA but is present in only 10% of the concentration
Fig. 2
Fig. 2
Temporal patterns in L-arginine and methylarginines over time in septic shock. Plasma L-arginine (a), asymmetric dimethylarginine (ADMA) (b) concentration changes over the first 7 days of inclusion in the VANISH trial; notation describes the number of samples available for analysis at each time point. Median and interquartile range plotted in red (both p < 0.001 over the time course (analysis of variance). Kaplan-Meier analysis of the association between methylarginine concentrations and outcome over time in septic shock following inclusion in the VANISH trial. A higher peak plasma ADMA (c) and symmetric dimethylarginine (SDMA) (d) concentration is associated with reduced survival in patients with septic shock. Data presented in quartiles (black line - top 25%, small-dotted grey line - 2nd quartile, dashed grey line - 3rd quartile, solid grey line - lowest quartile)
Fig. 3
Fig. 3
Associations between the rs805305 SNP of the dimethylarginine dimethylaminohydrolase (DDAH)2 promoter region and DDAH activity and outcome in septic shock. a Lower DDAH activity is associated with improved outcome in septic shock. Asymmetric dimethylarginine (ADMA):symmetric dimethylarginine (SDMA) ratio was employed as a marker of DDAH activity. Black line - patients with the lowest activity, dotted grey line - 2nd quartile, dashed grey line - 3rd Quartile, solid grey line – highest-activity quartile. The rs805305 SNP of the promoter region of the DDAH2 gene was sequenced in 284 participants in the VANISH trial. b Kaplan-Meier analysis of the impact of rs805305 SNP on 28-day survival in septic shock. The presence of the rare G:G homozygote (13.9%) was associated with improved survival compared to the common C:C homozygote (44.7), p = 0.02. Mean Sequential Organ Failure Assessment (SOFA) score (c) and shock duration (d) were lower in patients expressing the less common G:G genotype than the common C:C expression pattern, p = 0.04 and p = 0.02, respectively (analysis of variance)

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