核因子-κB家族基因内单倍型标签单核苷酸多态性的鉴定及其在严重创伤患者中的临床相关性。

Identification of haplotype tag single nucleotide polymorphisms within the nuclear factor-κB family genes and their clinical relevance in patients with major trauma.

作者信息

Pan Wei, Zhang An Qiang, Gu Wei, Gao Jun Wei, Du Ding Yuan, Zhang Lian Yang, Zeng Ling, Du Juan, Wang Hai Yan, Jiang Jian Xin

机构信息

State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Gaotanyan Street, Chongqing, 400038, China.

Chongqing Emergency Medical Center, Jiankang Road, Chongqing, 400042, China.

出版信息

Crit Care. 2015 Mar 20;19(1):95. doi: 10.1186/s13054-015-0836-6.

DOI:10.1186/s13054-015-0836-6

PMID:25880845

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4404128/

Abstract

INTRODUCTION

Nuclear factor-κB (NF-κB) family plays an important role in the development of sepsis in critically ill patients. Although several single nucleotide polymorphisms (SNPs) have been identified in the NF-κB family genes, only a few SNPs have been studied.

METHODS

A total of 753 patients with major blunt trauma were included in this study. Tag SNPs (tSNPs) were selected from the NF-κB family genes (NFKB1, NFKB2, RELA, RELB and REL) through construction of haplotype blocks. The SNPs selected from genes within the canonical NF-κB pathway (including NFKB1, RELA and REL), which played a critical role in innate immune responses were genotyped using pyrosequencing method and analyzed in relation to the risk of development of sepsis and multiple organ dysfunction (MOD) syndrome. Moreover, the rs842647 polymorphism was analyzed in relation to tumor necrosis factor α (TNF-α) production by peripheral blood leukocytes in response to bacterial lipoprotein stimulation.

RESULTS

Eight SNPs (rs28362491, rs3774932, rs4648068, rs7119750, rs4803789, rs12609547, rs1560725 and rs842647) were selected from the NF-κB family genes. All of them were shown to be high-frequency SNPs in this study cohort. Four SNPs (rs28362491, rs4648068, rs7119750 and rs842647) within the canonical NF-κB pathway were genotyped, and rs842647 was associated with sepsis morbidity rate and MOD scores. An association was also observed between the rs842647 A allele and lower TNF-α production.

CONCLUSIONS

rs842647 polymorphism might be used as relevant risk estimate for the development of sepsis and MOD syndrome in patients with major trauma.

摘要

引言

核因子-κB（NF-κB）家族在重症患者脓毒症的发生发展中起重要作用。尽管在NF-κB家族基因中已鉴定出若干单核苷酸多态性（SNP），但仅有少数SNP得到研究。

方法

本研究共纳入753例严重钝性创伤患者。通过构建单倍型模块，从NF-κB家族基因（NFKB1、NFKB2、RELA、RELB和REL）中选择标签SNP（tSNP）。采用焦磷酸测序法对从经典NF-κB途径（包括NFKB1、RELA和REL）中选择的、在先天免疫反应中起关键作用的基因内的SNP进行基因分型，并分析其与脓毒症发生风险及多器官功能障碍（MOD）综合征的关系。此外，分析rs842647多态性与外周血白细胞在细菌脂蛋白刺激下产生肿瘤坏死因子α（TNF-α）的关系。

结果

从NF-κB家族基因中选择了8个SNP（rs28362491、rs3774932,、rs4648068、rs7119750、rs4803789、rs12609547、rs1560725和rs842647）。在本研究队列中，所有这些SNP均显示为高频SNP。对经典NF-κB途径中的4个SNP（rs28362491、rs4648068、rs7119750和rs842647）进行基因分型，发现rs842647与脓毒症发病率及MOD评分相关。还观察到rs842647 A等位基因与较低的TNF-α产生之间存在关联。