State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
Department of Cardiothoracic Surgery, The Affiliated Central Hospital of Chongqing University, Chongqing Emergency Medical Center, Chongqing, China.
Clin Exp Immunol. 2018 Oct;194(1):93-102. doi: 10.1111/cei.13160. Epub 2018 Sep 9.
Suppressor of cytokine signalling (SOCS) proteins are crucial negative regulators in many signalling pathways and are implicated in the pathogenesis of infectious diseases. The purpose of this study was to uncover possible associations of common polymorphisms within SOCS genes with infectious outcomes after traumatic injury. A total of 1087 trauma patients (Chongqing cohort 806 and Yunnan cohort 281) were recruited and followed-up for the development of infectious outcomes, such as sepsis and multiple organ dysfunction syndrome (MODS). Twelve selected single nucleotide polymorphisms (SNPs) were screened by pyrosequencing to determine their genotypes and associations with infectious complications. Among the 12 selected SNPs, only the cytokine-inducible Src homology (SH2) domain protein (CISH) promoter rs414171 polymorphism was found consistently to be associated statistically with the incidence of sepsis and MOD score in the two cohorts, despite analysing the SNPs independently or in combination. Further, patients with a T allele had significantly lower CISH expression and lower production of tumour necrosis factor (TNF)-α, but higher production of interleukin (IL)-10. Luciferase assay confirmed that the A→T variant in the rs414171 polymorphism inhibited the transcriptional activities of the CISH gene significantly. The CISH rs414171 polymorphism is associated significantly with susceptibility to sepsis and MODS in traumatic patients, which might prove to be a novel biomarker for indicating risk of infectious outcomes in critically injured patients.
细胞因子信号转导抑制蛋白（SOCS）是许多信号通路中重要的负调控因子，与感染性疾病的发病机制有关。本研究旨在揭示 SOCS 基因内常见多态性与创伤后感染性结局之间可能存在的关联。共招募了 1087 名创伤患者（重庆队列 806 名和云南队列 281 名），并对其感染结局（如脓毒症和多器官功能障碍综合征（MODS））进行了随访。通过焦磷酸测序筛选了 12 个选定的单核苷酸多态性（SNP），以确定其基因型及其与感染并发症的关联。在 12 个选定的 SNP 中，只有细胞因子诱导的Src 同源（SH2）结构域蛋白（CISH）启动子 rs414171 多态性在两个队列中均与脓毒症和 MOD 评分的发生率存在统计学关联，尽管独立或联合分析了这些 SNP。此外，携带 T 等位基因的患者 CISH 表达明显降低，肿瘤坏死因子（TNF）-α产生减少，但白细胞介素（IL）-10 产生增加。荧光素酶测定证实 rs414171 多态性中的 A→T 变异显著抑制了 CISH 基因的转录活性。CISH rs414171 多态性与创伤患者易患脓毒症和 MODS 显著相关，这可能成为预示重症创伤患者感染结局风险的新型生物标志物。
