State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Changjiang Road 10, Yuzhong District, Chongqing, 400042, People's Republic of China.
Crit Care. 2011;15(6):R280. doi: 10.1186/cc10564. Epub 2011 Nov 23.
The nucleotide-binding oligomerization domain-like receptor (NLR) family has been recognized as comprising intracellular pattern recognition receptors in which NLRP3 (NLR family, pyrin domain containing 3) plays an important role in the initiation of host immune inflammatory responses. The genetic variants have been recognized to be critical determinants of interindividual differences in both inflammatory responses and clinical outcomes in critical illness. However, little is known about the clinical relevance of NLRP3 gene polymorphisms in critical illness.
A total of 718 patients with major blunt trauma were included in this study. Six tag SNPs (tSNPs) were selected from the entire NLRP3 gene through construction of haplotype bins, and they were genotyped using a pyrosequencing method. They were analyzed in relation to sepsis morbidity rate, multiple organ dysfunction (MOD) scores and IL-1β production. Moreover, the functionality of the rs2027432 polymorphism was assessed by the observation of its effect on transcriptional activities.
Among the six tSNPs genotyped in this study, two of them (rs2027432 and rs12048215) were significantly associated with sepsis morbidity rate and MOD scores. A significant association was also observed between these two polymorphisms and IL-1β production by peripheral leukocytes in response to ex vivo lipopolysaccharide stimulation. However, no combined effects were found between these two polymorphisms. In addition, the rs2027432 polymorphism could significantly enhance the promoter activities of the NLRP3 gene.
rs2027432 and rs12048215 polymorphisms might be used as relevant risk estimates for the development of sepsis and MOD syndrome in patients with major trauma, in which rs2027432 might be a functional SNP.
核苷酸结合寡聚化结构域样受体（NLR）家族已被认为包含细胞内模式识别受体，其中 NLRP3（NLR 家族，含有吡喃结构域 3）在启动宿主免疫炎症反应中发挥重要作用。遗传变异已被认为是个体间炎症反应和危重病临床结局差异的关键决定因素。然而，关于 NLRP3 基因多态性在危重病中的临床相关性知之甚少。
本研究共纳入 718 例主要钝性创伤患者。通过构建单倍型箱，从整个 NLRP3 基因中选择了 6 个标签单核苷酸多态性（tSNP），并使用焦磷酸测序法对其进行基因分型。分析它们与脓毒症发病率、多器官功能障碍（MOD）评分和 IL-1β 产生的关系。此外，通过观察 rs2027432 多态性对转录活性的影响来评估 rs2027432 多态性的功能。
在所研究的 6 个 tSNP 中，有 2 个（rs2027432 和 rs12048215）与脓毒症发病率和 MOD 评分显著相关。这两种多态性与外周白细胞对外源脂多糖刺激产生的 IL-1β 之间也存在显著相关性。然而，这两种多态性之间没有发现联合作用。此外，rs2027432 多态性可显著增强 NLRP3 基因的启动子活性。
rs2027432 和 rs12048215 多态性可能可作为主要创伤患者发生脓毒症和 MOD 综合征的相关风险估计，其中 rs2027432 可能是一个功能性 SNP。
