AMPD1基因34C>T变异对脓毒症患者免疫功能、多器官功能障碍及死亡率的影响

Effects of the 34C>T Variant of the AMPD1 Gene on Immune Function, Multi-Organ Dysfunction, and Mortality in Sepsis Patients.

作者信息

Ramakers Bart P, Giamarellos-Bourboulis Evangelos J, Tasioudis Chronis, Coenen Marieke J H, Kox Matthijs, Vermeulen Sita H, Groothuismink Johanne M, van der Hoeven Johannes G, Routsi Christina, Savva Athina, Prekates Athanassios, Diamantea Filia, Sinapidis Dimitrios, Smits Paul, Toutouzas Konstantinos, Riksen Niels P, Pickkers Peter

机构信息

*Department of Pharmacology and Toxicology †Intensive Care Medicine ‡Internal Medicine §Human Genetics ¶Anesthesiology ||Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands #4th Department of Internal Medicine, University of Athens, Medical School, Athens **Intensive Care Unit, "G. Gennimatas" General Hospital, Thessaloniki ††1st Department of Critical Care Medicine, University of Athens, Medical School ‡‡Intensive Care Unit, Tzaneion General Hospital of Piraeus §§Department of Respiratory Medicine, "Sismanogleion" General Hospital ¶¶Department of Therapeutics, Alexandra General Hospital ||||1st Department of Propedeutic Surgery, University of Athens, Medical School, Athens, Greece.

出版信息

Shock. 2015 Dec;44(6):542-7. doi: 10.1097/SHK.0000000000000456.

DOI:10.1097/SHK.0000000000000456

PMID:26529652

Abstract

INTRODUCTION

Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C>T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown.

METHODS

The effects of the presence of the 34C>T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n = 285; replication cohort n = 212) and ventilator-associated pneumonia (VAP, n = 117; n = 33) and control patients without infection (n = 101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort.

RESULTS

The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P = 0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P = 0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P = 0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-α by LPS-stimulated monocytes was attenuated (P = 0.005), indicative of a more pronounced immunoparalytic state in these patients.

CONCLUSIONS

Presence of the AMPD1 34C>T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation.

摘要

引言

腺苷在全身炎症反应中发挥抗炎和组织保护作用。虽然组织保护作用可能会限制器官损伤，但其抗炎特性可能会导致免疫麻痹并阻碍细菌清除。AMPD1常见的34C>T功能丧失变异（rs17602729）与腺苷生成增加有关，但对脓毒症患者免疫功能和预后的影响尚不清楚。

方法

研究了34C>T变异的存在对脓毒症患者脓毒症易感性、免疫功能、多器官功能障碍和死亡率的影响。纳入社区获得性肺炎（CAP，初始队列n = 285；重复队列n = 212）、呼吸机相关性肺炎（VAP，n = 117；n = 33）患者以及无感染的对照患者（n = 101）。在初始队列中，AMPD1单核苷酸多态性的基因分布为CC 76%、CT 22%、TT 2%，在重复队列中为CC 80%、CT 18%、TT 2%。

结果

在初始队列中，CT基因型患者发生脓毒症性CAP的几率高于CC基因型患者，但脓毒症性VAP患者并非如此（比值比（95%置信区间）2.0（1.1 - 3.7）；P = 0.02）。在重复队列中也观察到CT基因型相对于CC基因型的风险增加，但未达到统计学显著性（P = 0.38），导致整个组的比值比为1.7（95%置信区间1.0 - 3.1），P = 0.07。在携带CT基因型的脓毒症患者中，脂多糖刺激的单核细胞体外产生肿瘤坏死因子-α的能力减弱（P = 0.005），表明这些患者的免疫麻痹状态更为明显。