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

机译:AMPD1基因的34C> T变异对败血症患者的免疫功能,多器官功能障碍和死亡率的影响

摘要

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-alpha 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.
机译:简介:腺苷在全身性炎症过程中发挥抗炎和组织保护作用。尽管组织保护作用可能会限制器官损伤,但其抗炎特性可能会引起免疫麻痹并阻碍细菌清除。常见的AMPD1的34C> T功能丧失变异体(rs17602729)与腺苷形成增加有关,但对败血症患者的免疫功能和预后的影响尚不清楚。方法:研究了34C> T变异体的存在对败血症患者败血症易感性,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;复制队列n = 212)和呼吸机相关性肺炎(VAP,n = 117; n = 33)的患者以及未感染的对照组(n = 101)。 AMPD1 SNP的遗传分布在初始队列中为CC 76%,CT 22%和TT 2%,在复制队列中CC为80%,CT 18%和TT 2%。结果:在最初队列中,CT vs CC基因型(OR(95%CI)2.0(1.1-3.7); P = 0.02)增加了感染性CAP的发生,而不是感染性VAP的发生。在复制队列中也观察到CT和CC基因型的风险增加,但在那里没有达到统计学显着性(P = 0.38),导致总组的OR为1.7(95%CI 1.0-3.1),P = 0.07。在携带CT基因型的脓毒症患者中,LPS刺激的单核细胞离体产生TNF-α的作用减弱(P = 0.005),表明这些患者的免疫麻痹状态更为明显。结论:AMPD1 34C> T变体的存在与CAP而不是VAP的较高感染易感性有关。在这些患者中,由腺苷的抗炎作用介导的更明显的免疫麻痹可以解释这一现象。

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