■从受损细胞释放的细胞外ATP(eATP)激活周围细胞表面的P2X7受体(P2X7R)离子通道,导致钙流入,钾流出和炎性体激活。P2X7R基因(P2RX7)的遗传变化会影响eATP诱导的反应。P2RX7的单核苷酸多态性(SNP)影响受体的功能和信号,除了离子通量,还包括病原体控制和免疫。
■受试者(n=105)被送入乌尔姆大学医院的ICU,2018年6月至2019年8月之间的德国。其中,诊断为败血症的受试者(n=75),也被诊断为感染性休克(n=24),和/或肺炎(n=42)。患有肺炎的受试者(n=43)包括没有败血症的受试者(n=1),无休克的脓毒症(n=29)和感染性休克的肺炎(n=13)。在75例脓毒症/脓毒性休克患者中,33例患者未被诊断为肺炎。对照组(n=30)从创伤患者和无脓毒症的手术患者中招募到研究中,感染性休克,或者肺炎。SNP频率测定了16个已知影响P2X7R功能的P2RX7SNP,并在脓毒症中这些SNP的频率之间进行了关联研究,感染性休克,与对照组相比,肺炎。
■功能丧失(LOF)SNPrs17525809(T253C)在感染性休克患者中更为常见,与脓毒症相比,非脓毒症创伤患者。发现败血症和败血症性休克患者的LOFSNPrs2230911(C1096G)比非败血症性创伤患者更频繁。这些SNP的频率在脓毒症和脓毒症肺炎患者中甚至更高。本研究还证实了我们小组先前的一项研究,该研究显示了五个SNP组合,其中包括GOFSNPrs208294(C489T)和rs2230912(Q460R),被命名为#21211,与严重脓毒症的生存率增加有关。
■结果发现LOFP2RX7SNPs的表达与脓毒症患者进入ICU之间存在关联,与对照组ICU患者相比,感染性休克。此外,与无肺炎患者相比,有肺炎的脓毒症患者的LOFSNP频率更高.此外,5种SNPGOF组合与严重脓毒症患者生存率增加相关.这些结果表明,P2RX7是控制肺炎感染所必需的,并且LOF变体的遗传会增加与肺炎相关的败血症的风险。这项研究证实,肺炎中的P2RX7基因分型可以识别有发展为败血症风险的患者。该研究还将P2X7R鉴定为在具有GOFSNP组合的受试者中与过度免疫应答相关的脓毒症中的靶标。
UNASSIGNED: Extracellular ATP (eATP) released from damaged cells activates the P2X7 receptor (P2X7R) ion channel on the surface of surrounding cells, resulting in calcium influx, potassium efflux and inflammasome activation. Inherited changes in the P2X7R gene (
P2RX7) influence eATP induced responses. Single nucleotide polymorphisms (SNPs) of
P2RX7 influence both function and signaling of the receptor, that in addition to ion flux includes pathogen control and immunity.
UNASSIGNED: Subjects (n = 105) were admitted to the ICU at the University Hospital Ulm, Germany between June 2018 and August 2019. Of these, subjects with a diagnosis of sepsis (n = 75), were also diagnosed with septic shock (n = 24), and/or pneumonia (n = 42). Subjects with pneumonia (n = 43) included those without sepsis (n = 1), sepsis without shock (n = 29) and pneumonia with septic shock (n = 13). Out of the 75 sepsis/septic shock patients, 33 patients were not diagnosed with pneumonia. Controls (n = 30) were recruited to the study from trauma patients and surgical patients without sepsis, septic shock, or pneumonia. SNP frequencies were determined for 16
P2RX7 SNPs known to affect P2X7R function, and association studies were performed between frequencies of these SNPs in sepsis, septic shock, and pneumonia compared to controls.
UNASSIGNED: The loss-of-function (LOF) SNP rs17525809 (T253C) was found more frequently in patients with septic shock, and non-septic trauma patients when compared to sepsis. The LOF SNP rs2230911 (C1096G) was found to be more frequent in patients with sepsis and septic shock than in non-septic trauma patients. The frequencies of these SNPs were even higher in sepsis and septic patients with pneumonia. The current study also confirmed a previous study by our group that showed a five SNP combination that included the GOF SNPs rs208294 (C489T) and rs2230912 (Q460R) that was designated #21211 was associated with increased odds of survival in severe sepsis.
UNASSIGNED: The results found an association between expression of LOF P2RX7 SNPs and presentation to the ICU with sepsis, and septic shock compared to control ICU patients. Furthermore, frequencies of LOF SNPs were found to be higher in sepsis patients with pneumonia compared to those without pneumonia. In addition, a five SNP GOF combination was associated with increased odds of survival in severe sepsis. These results suggest that
P2RX7 is required to control infection in pneumonia and that inheritance of LOF variants increases the risk of sepsis when associated with pneumonia. This study confirms that
P2RX7 genotyping in pneumonia may identify patients at risk of developing sepsis. The study also identifies P2X7R as a target in sepsis associated with an excessive immune response in subjects with GOF SNP combinations.