rs805305 单核苷酸多态性的二甲基精氨酸二甲氨基水解酶 2（DDAH2）在脓毒症休克中通过调节 DDAH 活性发挥保护作用的证据。
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.
机构信息
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2OQQ, UK.
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.
出版信息
Crit Care. 2018 Dec 11;22(1):336. doi: 10.1186/s13054-018-2277-5.
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.
背景
二甲基精氨酸二甲氨基水解酶 2（DDAH2）通过代谢内源性一氧化氮合酶抑制剂不对称二甲基精氨酸（ADMA）来调节一氧化氮（NO）的合成。初步研究表明 DDAH2 的 rs805305 SNP 与败血症中的 ADMA 浓度有关。本研究探讨了 rs805305 多态性对败血症性休克中 DDAH 活性和结局的影响。
方法
我们对血管加压素与去甲肾上腺素作为败血症性休克初始治疗（VANISH）试验中收集的数据和样本进行了二次分析。从 VANISH 试验中招募的 286 名患者的血浆和 DNA 样本中进行分析。从血浆样本中测定 L-精氨酸和甲基精氨酸 ADMA 和对称二甲基精氨酸（SDMA）的浓度。对全血和白细胞层样本进行 DDAH2 多态性的基因分型。研究期间收集的临床数据用于探讨循环甲基精氨酸、基因型和结局之间的关系。
结果
研究期间的 ADMA 峰值浓度与 28 天死亡率的危险比为 3.3（95%CI 2.0-5.4），p<0.001。通过升高的 ADMA：SDMA 比值测量的降低的 DDAH 活性与败血症性休克死亡风险降低相关（p=0.03）。DDAH2 的 rs805305 多态性与降低的 DDAH 活性（p=0.004）和 28 天死亡率（p=0.02）相关。与杂合子和 C：C 基因型患者相比，DDAH2 的 rs805305 多态性也与较少的常见 G：G 基因型患者的平均 SOFA 评分和休克持续时间降低相关（p=0.04 和 p=0.02）。
结论
血浆 ADMA 是败血症性休克结局的生物标志物，降低的 DDAH 活性与保护作用相关。rs805305 SNP 与降低的死亡率相关，这可能是由降低的 DDAH2 活性介导的。
试验注册
ISRCTN 注册表，ISRCTN20769191。于 2012 年 9 月 20 日注册。
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