Chen Kaidian, Lin Yao, Liu Yuchun, Liao Shuanglin, Yang Ruoxuan, Huang Jiefeng, Xu Mingwei, He Junbing
The Intensive Care Unit, Jieyang Affiliated Hospital, Sun Yat-sen University, Jieyang, Guangdong, People's Republic of China.
The Intensive Care Unit, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, People's Republic of China.
J Inflamm Res. 2021 Dec 2;14:6461-6475. doi: 10.2147/JIR.S340446. eCollection 2021.
Complement 5 (C5) and C5a production play a pivotal role in the pathophysiology of sepsis. Strong evidence demonstrates an association of C5 gene polymorphisms with various inflammatory diseases. However, no current studies have explored the clinical relevance of C5 polymorphisms in sepsis.
Two C5 gene polymorphisms, rs17611 and rs2269067, were identified by genotyping in 636 sepsis patients and 753 controls in a Han Chinese population. C5 gene expression was detected via quantitative real-time PCR. C5a and proinflammatory cytokine production was measured by enzyme-linked immunosorbent assay. An Annexin V apoptosis assay was performed to assess cell apoptosis.
Our results showed significantly lower frequencies of rs2269067 GC/CC genotypes or C allele in sepsis patients than healthy controls. The frequencies of rs17611 CC/CT genotypes or C allele were significantly overrepresented in both the septic shock and non-survivor subgroups. Patients with this sepsis-associated high-risk rs17611 C allele exhibited a significant increase in C5a, TNF-α and IL-6 production. However, no significant difference in C5a and downstream proinflammatory cytokine production was observed among patients with different rs2269067 genotypes. In addition, in vitro experiments showed an effect of recombinant C5a on enhancing LPS-stimulated IL-1β, IL-6 and TNF-α production and cell apoptosis in THP-1 monocytes.
The rs2269067 polymorphism conferred protection against sepsis susceptibility. The rs17611 polymorphism was associated with increased C5a production, which ultimately potentiated the secretion of downstream proinflammatory cytokines and conferred susceptibility to sepsis progression and poor prognosis.
补体5（C5）及C5a的产生在脓毒症的病理生理学中起关键作用。有力证据表明C5基因多态性与多种炎症性疾病相关。然而，目前尚无研究探讨C5基因多态性在脓毒症中的临床相关性。
通过基因分型在636例脓毒症患者和753例汉族对照人群中鉴定了两个C5基因多态性位点rs17611和rs2269067。通过定量实时PCR检测C5基因表达。采用酶联免疫吸附测定法测定C5a和促炎细胞因子的产生。进行膜联蛋白V凋亡检测以评估细胞凋亡。
我们的结果显示，脓毒症患者中rs2269067 GC/CC基因型或C等位基因的频率显著低于健康对照。rs17611 CC/CT基因型或C等位基因的频率在感染性休克和非存活亚组中均显著过高。具有这种与脓毒症相关的高危rs17611 C等位基因的患者C5a、TNF-α和IL-6的产生显著增加。然而，不同rs2269067基因型患者的C5a和下游促炎细胞因子产生未见显著差异。此外，体外实验显示重组C5a对增强LPS刺激的THP-1单核细胞中IL-1β、IL-6和TNF-α的产生及细胞凋亡有作用。
rs2269067多态性赋予对脓毒症易感性的保护作用。rs17611多态性与C5a产生增加相关，这最终增强了下游促炎细胞因子的分泌，并赋予脓毒症进展易感性和不良预后。
