A Functional Variant of Lipopolysaccharide Binding Protein Predisposes to Sepsis and Organ Dysfunction in Patients with Major Trauma
A Functional Variant of Lipopolysaccharide Binding Protein Predisposes to Sepsis and Organ Dysfunction in Patients with Major Trauma
复制标题
脂多糖结合蛋白的功能变体易导致严重创伤患者败血症和器官功能障碍
DOI：
10.1097/sla.0b013e3182389515
复制
发表时间：
2012-01-01
影响因子：
9
通讯作者：
Jiang, Jian-Xin
中科院分区：
文献类型：
--
作者：
Zeng, Ling;Gu, Wei;Jiang, Jian-Xin
目的：探讨脂多糖结合蛋白（LBP）基因的遗传变异与严重创伤患者发生脓毒症和多器官功能障碍（MOD）的关系。背景：脂多糖结合蛋白在天然免疫应答中作为第一道防线发挥核心作用，并指导微生物诱导的炎症宿主应答的激活。尽管迄今为止在整个LBP基因中总共鉴定了112个单核苷酸多态性（SNP），但仅对少数SNP进行了研究。方法：利用中国汉族人群HapMap数据库，从51个次要等位基因频率≥5%的SNPs中筛选出9个单倍型标签SNPs（haplotype tagging SNPs，htSNPs）。招募了两个独立的严重创伤患者队列。使用焦磷酸测序方法对9个htSNPs进行基因分型，并分析其与脓毒症和MOD、LBP产生和脂多糖（LPS）诱导的外周血白细胞活化的发展风险的关系。此外，rs 2232618多态性的功能性通过观察其对LPS的结合和活化以及LBP-CD 14相互作用的影响来评估。结果：在9个htSNPs中，只有rs 2232618与中国西南和东部严重创伤患者的败血症和MOD易感性显著相关。该SNP也与LPS诱导的外周血白细胞活化显著相关。此外，rs 2232618多态性可以增强LBP蛋白的活性，在LBP蛋白变体的存在下，LPS与巨噬细胞的结合、LPS诱导的细胞活化和LBP-CD 14相互作用显著增加。结论：rs 2232618多态性是一个功能性SNP，并赋予宿主对严重创伤患者脓毒症和多器官功能障碍的易感性。
Objective:To determine the hypothesis that genetic variations of the lipopolysaccharide-binding protein (LBP) gene influence risk for the development of sepsis and multiple organ dysfunction (MOD) in patients with major trauma. Background:Lipopolysaccharide-binding protein plays a central role in innate immune response as the first line of defense and directing the microbial-induced activation of the inflammatory host response. Although a total of 112 single nucleotide polymorphisms (SNPs) have been identified so far within the entire LBP gene, only a few SNPs have been studied. Methods:Nine haplotype tagging SNPs (htSNPs) were selected from 51 SNPs with a minor allele frequency of ≥5% using the HapMap database for the Chinese Han population. Two independent cohorts of major trauma patients were recruited. The 9 htSNPs were genotyped using pyrosequencing method and analyzed in relation to the risk of development of sepsis and MOD, LBP production, and lipopolysaccharide (LPS)-induced activation of peripheral blood leukocytes. Moreover, the functionality of the rs2232618 polymorphism was assessed by the observation of its effects on the binding and activation of LPS and the LBP-CD14 interaction. Results:Among the 9 htSNPs, only the rs2232618 was significantly associated with higher susceptibility to sepsis and MOD in the 2 independent cohorts of major trauma patients recruited from southwest and eastern China. This SNP was also significantly associated with LPS-induced activation of peripheral blood leukocytes. In addition, the rs2232618 polymorphism could enhance LBP protein activities, showing significant increases in LPS binding to macrophages, LPS-induced cellular activation, and LBP-CD14 interaction at the presence of the variant LBP protein. Conclusions:The rs2232618 polymorphism is a functional SNP and confers host susceptibility to sepsis and multiple organ dysfunction in patients with major trauma.