基于候选基因策略的脓毒症遗传易感性研究
摘要
背景和目的：脓毒症(sepsis)是指由感染引起的全身性炎症反应综合征,是创伤、烧伤、术后感染和危重病的常见并发症,可进一步发展成严重脓毒症、脓毒性休克和器官功能障碍综合征,甚至导致死亡。通过对双胞胎和收养子的研究发现遗传因素在感染性疾病的发生、发展和转归中起着重要的作用。遗传关联研究显示多种炎症基因的单核苷酸多态性(single nucleotide polymorphism, SNP)和脓毒症易感性相关。如白细胞介素6(interleukin6, IL6)启动子区的-174G/C可产生新的转录因子结合位点,与脓毒症发病风险显著相关。纤溶酶原激活物抑制剂1(plasminogen activator inhibitor-1, PAI-1)基因启动子区的5G/4G多态性与脓毒性休克的转归相关,携带4G/4G基因型的脓毒症患者更易发生休克。可见,机体的遗传因素在脓毒症的发生、发展和临床转归中起着重要的作用。本研究旨在鉴定与脓毒症发生、发展和转归相关的易感基因和易感SNPs,并初步探讨它们的作用机制。
材料和方法：本研究基于候选基因的研究策略,采用回顾性病例-对照实验设计,对脓毒症的遗传因素进行了探讨。按照统一的入选和排除标准,招募了两个独立的脓毒症病例-对照人群,分别是辽宁人群和江苏人群。据本实验室前期的研究结果,确定了分布于23个基因上的66个SNPs作为脓毒症遗传易感性和严重程度关联研究的候选遗传标记,先在辽宁人群中进行关联研究,挑选显著关联的SNPs,再在江苏人群中进行重复验证,最后对在两个人群中均关联的SNPs进行了功能研究。
应用酚氯仿法从5mL EDTA抗凝的外周全血中提取基因组DNA。利用中通量的GenomeLab SNPStream分型平台、Sequenom MassARRAY分型平台和聚合酶链式反应-限制性片段长度多态性分型方法(Polymerase Chain Reaction-Restriction Fragment Length Polymorphism, PCR-RFLP)对SNPs进行了分型。
采用非条件logistic回归模型,在五种遗传模式中对脓毒症遗传易感性和严重程度与候选SNPs的相关性进行了探索性分析,同时校正了常住地、性别、年龄、吸烟、饮酒和慢性病五个混杂因素,严重程度分析还校正了APACHE Ⅱ和脓毒症病因两个混杂因素；在等位遗传模式中进行卡方统计检验。主要利用在线统计软件SNPStats (http://bioinfo. iconco logia.net/snpstats/start.htm)和SPSS (version13.0, SPSS Inc., Chicago, IL, USA)进行了统计分析。为有效地控制假阳性率,我们运用在线软件SNPSpD (http://gump.qimr.edu.au/general/daleN/SNPSpD),以基因为单位进行了多重检验的校正。
对多人群均显著关联的SNPs进行了功能研究。应用酶活性检测系统测定不同基因型对酶活性的影响；利用TaqMan实时定量PCR技术测定基因的转录水平,观察不同等位表达的差异。
结果：66个SNPs中有64个分型成功,其中6个SNPs的基因型频率分布不符合哈温平衡定律。遗传关联分析显示,有3个SNPs与脓毒症的遗传易感性或严重程度显著相关,分别是：
1.位于SELE基因3’侧翼序列的rs4656700,其与脓毒症导致的器官功能障碍关联,携带GA或AA基因型的患者发生功能障碍的器官数量更易超过3个(在合并人群的显性遗传模式下：GA+AA vs.GG,OR=2.44,95%CI=1.39-4.26,P=1.48×10-3).
2.位于NOS2基因外显子上的rs2297518(S608L),其与脓毒性休克显著关联,联合基因型GA+AA显著增加了脓毒症患者发生休克的风险(在合并人群的显性遗传模式下：GA+AA vs.GG,OR=3.26,95%CI=1.84.5.79,P=3.45×10-5).NOS2活性检测实验显示,携带rs2297518不同基因型的个体间NOS2活性可能存在差异,与GG基因型携带者相比,GA基因型个体的NOS2活性有增高的趋势,但差异未达到统计学显著性检验水准(P=0.32)。
3.位于IRAK4基因内含子的rs4251569,其与脓毒症的遗传易感性显著相关,联合基因型TC+TT可显著降低脓毒症的发病风险(在合并人群的显性遗传模式下：TC+TT vs.CC,OR=0.68,95%CI=0.53-0.87,P=1.87×10-3)。在LPS刺激和非刺激条件下,等位表达不平衡实验显示,携带IRAK4-rs4251569T等位的内含子保留mRNA(IRAK4-009)的表达量显著高于含C等位的IRAK4-009的表达量(PLPS=5.74×10-9,PNormal=1.60×10-8)。
结论：我们的研究证实了遗传因素在脓毒症的发生、发展和转归过程中发挥着重要的作用。在携带SELE-rs4656700的GA或AA基因型的脓毒症患者中,4个或4个以上器官发生功能障碍的风险是GG基因型携带者的2.44倍。携带NOS2-rs2297518的GA或AA基因型的脓毒症患者与GG基因型携带者相比,脓毒性休克的发生风险增加了3.26倍。该位点可能会影响NOS2的活性,GA或AA基因型携带者体内NO生成增多,更易导致休克的发生。IRAK4的rs4251569与脓毒症易感性相关,携带T等位的人群具有较低的脓毒症发病率,功能研究提示该多态性位点可能影响基因转录后的剪接机制,使含T等位的IRAK4-009mRNA的表达量显著增高。由于IRAK4-009mRNA无法翻译成成熟的IRAK4蛋白,因此,介导IRAK4-009mRNA高表达的等位可能会相对减少成熟IRAK4蛋白的含量,减弱NF-KB炎症信号通路的活化,抑制炎症反应,进而降低了脓毒症的发病风险。总之,通过本项研究,我们新发现了3个与脓毒症遗传易感性或严重程度相关的易感基因和3个易感SNPs,并初步探讨了遗传机制在脓毒症病因学中的作用,为脓毒症的遗传病因学提供了新的机制性解释。
Background and Objects:Sepsis is a systemic inflammatory response to infection, which is a common complication followed by trauma, empyrosis, surgery and critical illness. Sepsis and its sequelae represent a continuum of clinical and pathophysiologic severity, including severe sepsis, septic shock, multiple organ dysfunction syndrome (MODS) and death. Studies on twins and adoptees showed that infection diseases had a strong genetic background. A large number of SNPs within genes have been reported to be associated with the risk of sepsis and its complications. For example,-174G/C in the IL6promoter could create a new transcription factors binding site and was significantly associated with sepsis risk. And, the polymorphism (5G/4G) in the plasminogen activator inhibitor-1promoter was associated with susceptibility to septic shock and patients with sepsis carrying4G/4G genotype were easier to suffer from shock. Taken together, the hereditary factors play an important role in the pathologic process of sepsis. The aim of this study is to identify novel genetic polymorphisms associated with susceptibility to or severity of sepsis in Chinese population.
Materials and methods:A candidate gene-based retrospective case-control design was used in this study. Under the unified inclusion and exclusion criteria, we have recruited two independent populations, Liaoning population and Jiangsu population. According to our previous study,66SNPs within23candidate genes were screened in Liaoning population. And then, the significanty associated SNPs were further replicated in Jiangsu population.
We extracted genomic DNA from5mL EDTA-anticoagulated peripheral blood samples using a standard phenol/chloroform protocol. GenomeLab SNPStream genotyping platform (Beckman Coulter Inc.), Sequenom's MassARRAY system (SEQUENOM Inc.) and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method were used for the SNPs genotyping.
Unconditional logistic regression analysis was performed to explore the genetic associations between the polymorphisms and susceptibility to sepsis and its complications under five genetic models while adjusting for confounding factors, such as age, sex, status of smoking and drinking, APACHE II score, chronic disease status and cause of disease. Fisher's exact test was used to analyze the association between alleles and phenotypes. These analyses were performed by SNPStats (http://bioinfo.iconcologia.net/snpstats/start.htm) and SPSS (version13.0, SPSS Inc., USA). To assess the probability of a spurious association due to multiple comparisons, the online software, SNPSpD (http://gump.qimr.edu.au/general/daleN/SNPSpD), was used to calculate correction factor for multiple testing in gene unit.
To clarify the function of significantly associated SNPs, the activity of NOS2with different genotypes was detected by a NOS detection system kit. The allele expression imbalance assay was performed by TaqMan (ABI) real time quantitative PCR assay.
Results:Of the66selected SNPs,64were successfully genotyped. Three SNPs were shown to be significantly associated with susceptibility to or severity of sepsis:
1. The rs4656700within3'-flanking region of SELE was associated significantly with the susceptibility to dysfunction of organs caused by sepsis in a dominant genetic model (GA+AA vs. GG in the pooled population; OR=2.44,95%CI=1.39-4.26, P=1.48×10-3).
2. The rs2297518(S608L) within NOS2was significantly associated with susceptibility to septic shock in a dominant model (GA+AA vs. GG in the pooled population; OR=3.26,95%CI:1.84-5.79, P=3.45×10-5). The average relative activity of NOS2was higher in immortalized lymphocytes with GA genotype than those with GG genotype, although no significant difference was found between these two genotypes (P=0.32).
3. The rs4251569was significantly associated with susceptibility to sepsis in a dominant model (TC+TT vs. CC in the pooled population, OR=0.68,95%CI=0.53-0.87, P=1.87×10-3). There was a significantly higher expression of intron retention mRNA (IRAK4-009) marked by T allele than by C allele in lymphoblastoid cell lines under both LPS and non-LPS stimulation (PLps=5.74×10-9,PNormal=1-60×10-8).
Conclusion:This study verified that genetic factors played an important role in the occurrence, progression and outcome of sepsis. Sepsis patients with rs4656700GA or AA genotype suffered from dysfunction of multiple organs with a risk2.44fold greater than subjects with GG genotype. The polymorphism rs2297518(S608L) contributes to the risk of septic shock, which increased3.26-fold in sepsis patients with genotype GA+AA compared with GG carriers. The substitution of G to A allele might increase the NOS2activity to produce more NO. Subjects with the genotype TC or TT of rs4251569had a lower morbidity of sepsis than those with CC genotype. Higher expression of mRNA retaining intron marked by T allele was speculated to reduce protein level and weaken the function of IRAK4, which, in turn, inhibited the NF-κB inflammatory signaling pathway implicated in the development of sepsis. Taken together, this study highlighted the important role of genetic factors in determining the risk of sepsis and its sequelae and revolutionalized our understanding of sepsis pathogenesis in genetics.
材料和方法：本研究基于候选基因的研究策略,采用回顾性病例-对照实验设计,对脓毒症的遗传因素进行了探讨。按照统一的入选和排除标准,招募了两个独立的脓毒症病例-对照人群,分别是辽宁人群和江苏人群。据本实验室前期的研究结果,确定了分布于23个基因上的66个SNPs作为脓毒症遗传易感性和严重程度关联研究的候选遗传标记,先在辽宁人群中进行关联研究,挑选显著关联的SNPs,再在江苏人群中进行重复验证,最后对在两个人群中均关联的SNPs进行了功能研究。
应用酚氯仿法从5mL EDTA抗凝的外周全血中提取基因组DNA。利用中通量的GenomeLab SNPStream分型平台、Sequenom MassARRAY分型平台和聚合酶链式反应-限制性片段长度多态性分型方法(Polymerase Chain Reaction-Restriction Fragment Length Polymorphism, PCR-RFLP)对SNPs进行了分型。
采用非条件logistic回归模型,在五种遗传模式中对脓毒症遗传易感性和严重程度与候选SNPs的相关性进行了探索性分析,同时校正了常住地、性别、年龄、吸烟、饮酒和慢性病五个混杂因素,严重程度分析还校正了APACHE Ⅱ和脓毒症病因两个混杂因素；在等位遗传模式中进行卡方统计检验。主要利用在线统计软件SNPStats (http://bioinfo. iconco logia.net/snpstats/start.htm)和SPSS (version13.0, SPSS Inc., Chicago, IL, USA)进行了统计分析。为有效地控制假阳性率,我们运用在线软件SNPSpD (http://gump.qimr.edu.au/general/daleN/SNPSpD),以基因为单位进行了多重检验的校正。
对多人群均显著关联的SNPs进行了功能研究。应用酶活性检测系统测定不同基因型对酶活性的影响；利用TaqMan实时定量PCR技术测定基因的转录水平,观察不同等位表达的差异。
结果：66个SNPs中有64个分型成功,其中6个SNPs的基因型频率分布不符合哈温平衡定律。遗传关联分析显示,有3个SNPs与脓毒症的遗传易感性或严重程度显著相关,分别是：
1.位于SELE基因3’侧翼序列的rs4656700,其与脓毒症导致的器官功能障碍关联,携带GA或AA基因型的患者发生功能障碍的器官数量更易超过3个(在合并人群的显性遗传模式下：GA+AA vs.GG,OR=2.44,95%CI=1.39-4.26,P=1.48×10-3).
2.位于NOS2基因外显子上的rs2297518(S608L),其与脓毒性休克显著关联,联合基因型GA+AA显著增加了脓毒症患者发生休克的风险(在合并人群的显性遗传模式下：GA+AA vs.GG,OR=3.26,95%CI=1.84.5.79,P=3.45×10-5).NOS2活性检测实验显示,携带rs2297518不同基因型的个体间NOS2活性可能存在差异,与GG基因型携带者相比,GA基因型个体的NOS2活性有增高的趋势,但差异未达到统计学显著性检验水准(P=0.32)。
3.位于IRAK4基因内含子的rs4251569,其与脓毒症的遗传易感性显著相关,联合基因型TC+TT可显著降低脓毒症的发病风险(在合并人群的显性遗传模式下：TC+TT vs.CC,OR=0.68,95%CI=0.53-0.87,P=1.87×10-3)。在LPS刺激和非刺激条件下,等位表达不平衡实验显示,携带IRAK4-rs4251569T等位的内含子保留mRNA(IRAK4-009)的表达量显著高于含C等位的IRAK4-009的表达量(PLPS=5.74×10-9,PNormal=1.60×10-8)。
结论：我们的研究证实了遗传因素在脓毒症的发生、发展和转归过程中发挥着重要的作用。在携带SELE-rs4656700的GA或AA基因型的脓毒症患者中,4个或4个以上器官发生功能障碍的风险是GG基因型携带者的2.44倍。携带NOS2-rs2297518的GA或AA基因型的脓毒症患者与GG基因型携带者相比,脓毒性休克的发生风险增加了3.26倍。该位点可能会影响NOS2的活性,GA或AA基因型携带者体内NO生成增多,更易导致休克的发生。IRAK4的rs4251569与脓毒症易感性相关,携带T等位的人群具有较低的脓毒症发病率,功能研究提示该多态性位点可能影响基因转录后的剪接机制,使含T等位的IRAK4-009mRNA的表达量显著增高。由于IRAK4-009mRNA无法翻译成成熟的IRAK4蛋白,因此,介导IRAK4-009mRNA高表达的等位可能会相对减少成熟IRAK4蛋白的含量,减弱NF-KB炎症信号通路的活化,抑制炎症反应,进而降低了脓毒症的发病风险。总之,通过本项研究,我们新发现了3个与脓毒症遗传易感性或严重程度相关的易感基因和3个易感SNPs,并初步探讨了遗传机制在脓毒症病因学中的作用,为脓毒症的遗传病因学提供了新的机制性解释。
Background and Objects:Sepsis is a systemic inflammatory response to infection, which is a common complication followed by trauma, empyrosis, surgery and critical illness. Sepsis and its sequelae represent a continuum of clinical and pathophysiologic severity, including severe sepsis, septic shock, multiple organ dysfunction syndrome (MODS) and death. Studies on twins and adoptees showed that infection diseases had a strong genetic background. A large number of SNPs within genes have been reported to be associated with the risk of sepsis and its complications. For example,-174G/C in the IL6promoter could create a new transcription factors binding site and was significantly associated with sepsis risk. And, the polymorphism (5G/4G) in the plasminogen activator inhibitor-1promoter was associated with susceptibility to septic shock and patients with sepsis carrying4G/4G genotype were easier to suffer from shock. Taken together, the hereditary factors play an important role in the pathologic process of sepsis. The aim of this study is to identify novel genetic polymorphisms associated with susceptibility to or severity of sepsis in Chinese population.
Materials and methods:A candidate gene-based retrospective case-control design was used in this study. Under the unified inclusion and exclusion criteria, we have recruited two independent populations, Liaoning population and Jiangsu population. According to our previous study,66SNPs within23candidate genes were screened in Liaoning population. And then, the significanty associated SNPs were further replicated in Jiangsu population.
We extracted genomic DNA from5mL EDTA-anticoagulated peripheral blood samples using a standard phenol/chloroform protocol. GenomeLab SNPStream genotyping platform (Beckman Coulter Inc.), Sequenom's MassARRAY system (SEQUENOM Inc.) and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method were used for the SNPs genotyping.
Unconditional logistic regression analysis was performed to explore the genetic associations between the polymorphisms and susceptibility to sepsis and its complications under five genetic models while adjusting for confounding factors, such as age, sex, status of smoking and drinking, APACHE II score, chronic disease status and cause of disease. Fisher's exact test was used to analyze the association between alleles and phenotypes. These analyses were performed by SNPStats (http://bioinfo.iconcologia.net/snpstats/start.htm) and SPSS (version13.0, SPSS Inc., USA). To assess the probability of a spurious association due to multiple comparisons, the online software, SNPSpD (http://gump.qimr.edu.au/general/daleN/SNPSpD), was used to calculate correction factor for multiple testing in gene unit.
To clarify the function of significantly associated SNPs, the activity of NOS2with different genotypes was detected by a NOS detection system kit. The allele expression imbalance assay was performed by TaqMan (ABI) real time quantitative PCR assay.
Results:Of the66selected SNPs,64were successfully genotyped. Three SNPs were shown to be significantly associated with susceptibility to or severity of sepsis:
1. The rs4656700within3'-flanking region of SELE was associated significantly with the susceptibility to dysfunction of organs caused by sepsis in a dominant genetic model (GA+AA vs. GG in the pooled population; OR=2.44,95%CI=1.39-4.26, P=1.48×10-3).
2. The rs2297518(S608L) within NOS2was significantly associated with susceptibility to septic shock in a dominant model (GA+AA vs. GG in the pooled population; OR=3.26,95%CI:1.84-5.79, P=3.45×10-5). The average relative activity of NOS2was higher in immortalized lymphocytes with GA genotype than those with GG genotype, although no significant difference was found between these two genotypes (P=0.32).
3. The rs4251569was significantly associated with susceptibility to sepsis in a dominant model (TC+TT vs. CC in the pooled population, OR=0.68,95%CI=0.53-0.87, P=1.87×10-3). There was a significantly higher expression of intron retention mRNA (IRAK4-009) marked by T allele than by C allele in lymphoblastoid cell lines under both LPS and non-LPS stimulation (PLps=5.74×10-9,PNormal=1-60×10-8).
Conclusion:This study verified that genetic factors played an important role in the occurrence, progression and outcome of sepsis. Sepsis patients with rs4656700GA or AA genotype suffered from dysfunction of multiple organs with a risk2.44fold greater than subjects with GG genotype. The polymorphism rs2297518(S608L) contributes to the risk of septic shock, which increased3.26-fold in sepsis patients with genotype GA+AA compared with GG carriers. The substitution of G to A allele might increase the NOS2activity to produce more NO. Subjects with the genotype TC or TT of rs4251569had a lower morbidity of sepsis than those with CC genotype. Higher expression of mRNA retaining intron marked by T allele was speculated to reduce protein level and weaken the function of IRAK4, which, in turn, inhibited the NF-κB inflammatory signaling pathway implicated in the development of sepsis. Taken together, this study highlighted the important role of genetic factors in determining the risk of sepsis and its sequelae and revolutionalized our understanding of sepsis pathogenesis in genetics.
引文
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17 Matsuda, N. and Hattori, Y., Vascular biology in sepsis:pathophysiological and therapeutic significance of vascular dysfunction. J Smooth Muscle Res 43 (4),117 (2007).
18 Vigorito, E. et al, microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27 (6),847 (2007).
19 Rodriguez, A. et al., Requirement of bic/microRNA-155 for normal immune function. Science 316 (5824),608 (2007).
20 Cheng, B. et al., Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med 35 (11),2538 (2007).
21 Tsokos, M., Fehlauer, F. and Puschel, K., Immunohistochemical expression of E-selectin in sepsis-induced lung injury. Int J Legal Med 113 (6),338 (2000).
22 Engelberts, I. et al., Generalized inflammation during peritonitis evidenced by intracutaneous E-selectin expression. Clin Immunol Immunopathol 65 (3),330 (1992).
23 Newman, W. et al., Soluble E-selectin is found in supernatants of activated endothelial cells and is elevated in the serum of patients with septic shock. J Immunol 150(2),644(1993).
24 Cummings, C. J. et al., Soluble E-selectin levels in sepsis and critical illness. Correlation with infection and hemodynamic dysfunction. Am J Respir Crit Care Med 156 (2 Pt 1),431 (1997).
25 Cowley, H. C. et al., Increased circulating adhesion molecule concentrations in patients with the systemic inflammatory response syndrome:a prospective cohort study. Crit Care Med 22 (4),651 (1994).
26 Stavarachi, M. et al., Investigation of P213S SELL gene polymorphism in type 2 diabetes mellitus and related end stage renal disease. A case-control study. Rom J Morphol Embryol 52 (3 Suppl),995 (2011).
27 Chen, H. et al., The common variants of E-selectin gene in Graves'disease. Genes Immun 9 (2),182 (2008).
28 Chang, Y. P. et al., Multiple genes for essential-hypertension susceptibility on chromosome 1q. Am J Hum Genet 80 (2),253 (2007).
29 Wang, Z. et al., E-selectin gene polymorphisms are associated with essential hypertension:a case-control pilot study in a Chinese population. BMC Med Genet 11, 127 (2010).
30 Pacher, P., Beckman, J. S. and Liaudet, L., Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87 (1),315 (2007).
31 Petros, A., Bennett, D. and Vallance, P., Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 338 (8782-8783),1557 (1991).
32 Nava, E., Palmer, R. M. and Moncada, S., Inhibition of nitric oxide synthesis in septic shock:how much is beneficial? Lancet 338 (8782-8783),1555 (1991).
33 Qidwai, T. and Jamal, F., Inducible nitric oxide synthase (iNOS) gene polymorphism and disease prevalence. Scand J Immunol 72 (5),375 (2010).
34 Abraham, E., Alterations in cell signaling in sepsis. Clin Infect Dis 41 Suppl 7, S459 (2005).
35 Medvedev, A. E. et al, Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 198 (4),521 (2003).
[1]Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference[J]. Crit Care Med,2003, 31(4):1250-1256.
[2]Riedemann NC, Ward PA. Oxidized lipid protects against sepsis[J]. Nat Med,2002, 8(10):1084-1085.
[3]Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans[J]. J Immunol,2001,166(11):6952-6963.
[4]Shi M, Guo N. MicroRNA expression and its implications for the diagnosis and therapeutic strategies of breast cancer[J]. Cancer Treat Rev,2009,35(4):328-334.
[5]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function[J]. Cell,2004,116(2):281-297.
[6]Stern-Ginossar N, Elefant N, Zimmermann A, et al. Host immune system gene targeting by a viral miRNA[J]. Science,2007, 317(5836):376-381.
[7]Tili E, Michaille JJ, Cimino A, et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock[J]. J Immunol,2007, 179(8):5082-5089.
[8]Rodriguez A, Vigorito E, Clare S, et al. Requirement of bic/microRNA-155 for normal immune function[J]. Science, 2007,316(5824):608-611.
[9]Thai TH, Calado DP, Casola S, et al. Regulation of the germinal center response by microRNA-155[J]. Science, 2007,316(5824):604-608.
[10]Vasilescu C, Rossi S, Shimizu M, et al. MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis[J], PLoS One,2009, 4(10):e7405.
[11]Schmidt WM, Spiel AO, Jilma B, et al. In vivo profile of the human leukocyte microRNA response to endotoxemia[J]. Biochem Biophys Res Commun,2009, 380(3):437-441.
[12]Taganov KD, Boldin MP, Chang KJ, et al. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses[J]. Proc Natl Acad Sci U S A,2006,103(33):12481-12486.
[13]Nahid MA, Pauley KM, Satoh M, et al. miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY[J]. J Biol Chem,2009, 284(50):34590-34599.
[14]Baltimore D, Boldin MP, O'Connell RM, et al. MicroRNAs:new regulators of immune cell development and function[J]. Nat Immunol,2008,9(8):839-845.
[15]Chen XM, Splinter PL, O'Hara SP, et al. A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection[J]. J Biol Chem,2007, 282(39):28929-28938.
[16]Neilson JR, Zheng GX, Burge CB, et al. Dynamic regulation of miRNA expression in ordered stages of cellular development[J]. Genes Dev,2007, 21(5):578-589.
[17]Wu H, Neilson JR, Kumar P, et al. miRNA profiling of naive, effector and memory CD8 T cells[J]. PLoS One,2007, 2(10):e1020.
[18]Chen CZ, Li L, Lodish HF, et al. MicroRNAs modulate hematopoietic lineage differentiation[J]. Science,2004, 303(5654):83-86.
[19]Li QJ, Chau J, Ebert PJ, et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection[J]. Cell,2007, 129(1):147-161.
[20]Teng G, Hakimpour P, Landgraf P, et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase[J]. Immunity,2008,28(5):621-629.
[21]Vigorito E, Perks KL, Abreu-Goodger C, et al. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells[J]. Immunity, 2007,27(6):847-859.
[22]Turner M, Vigorito E. Regulation of B-and T-cell differentiation by a single microRNA[J]. Biochem Soc Trans,2008, 36(Pt3):531-533.
[23]Zhou B, Wang S, Mayr C, et al. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely[J]. Proc Natl Acad Sci U S A,2007, 104(17):7080-7085.
[24]Cheng AM, Byrom MW, Shelton J, et al. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis[J]. Nucleic Acids Res,2005, 33(4):1290-1297.
[25]Moschos SA, Williams AE, Perry MM, et al. Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids[J]. BMC Genomics,2007, 8:240.
[26]El G M, Church A, Liu T, et al. MicroRNA-146a regulates both transcription silencing and translation disruption of TNF-{alpha} during TLR4-induced gene reprogramming[J]. J Leukoc Biol,2011,90(3):509-519.
[27]Lagos D, Pollara G, Henderson S, et al. miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator [J]. Nat Cell Biol,2010,12(5):513-519.
[28]Jing Q, Huang S, Guth S, et al. Involvement of microRNA in AU-rich element-mediated mRNA instability[J]. Cell,2005,120(5):623-634.
[29]Sheedy F J, Palsson-Mcdermott E, Hennessy EJ, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21[J]. Nat Immunol,2010,11(2):141-147.
[30]Kim SW, Ramasamy K, Bouamar H, et al. MicroRNAs miR-125a and miR-125b constitutively activate the NF-kappaB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20)[J]. Proc Natl Acad Sci U S A,2012,109(20):7865-7870.
[31]Chaudhuri AA, So AY, Mehta A, et al. Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A[J]. Proc Natl Acad Sci U S A, 2012,109(11):4233-4238.
[32]Shaked I, Meerson A, Wolf Y, et al. MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase[J]. Immunity,2009, 31(6):965-973.
[33]Sun Y, Varambally S, Maher CA, et al. Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality[J]. Blood, 2011,117(23):6172-6183.
[34]Cameron JE, Yin Q, Fewell C, et al. Epstein-Barr virus latent membrane protein 1 induces cellular MicroRNA miR-146a, a modulator of lymphocyte signaling pathways[J]. J Virol,2008, 82(4):1946-1958.
[35]Wang JF, Yu ML, Yu G, et al. Serum miR-146a and miR-223 as potential new biomarkers for sepsis[J]. Biochem Biophys Res Commun,2010, 394(1):184-188.
[36]Segura M F, Hanniford D, Menendez S, et al. Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor[J]. Proc Natl Acad Sci U S A, 2009,106(6):1814-1819.
[37]Sonkoly E, Wei T, Janson PC, et al. MicroRNAs:novel regulators involved in the pathogenesis of psoriasis?[J]. PLoS One,2007,2(7):e610.
[38]Lena AM, Shalom-Feuerstein R, Rivetti di Val Cervo P, et al. miR-203 represses 'sternness' by repressing DeltaNp63.[J]. Cell Death Differ,2008, 15(7):1187-1195.
[39]Yang H, Kong W, He L, et al. MicroRNA expression profiling in human ovarian cancer:miR-214 induces cell survival and cisplatin resistance by targeting PTEN[J]. Cancer Res,2008, 68(2):425-433.
[40]Fazi F, Rosa A, Fatica A, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis[J]. Cell,2005, 123(5):819-831.
[41]Zhuang G, Meng C, Guo X, et al. A Novel Regulator of Macrophage Activation:miR-223 in Obesity-Associated Adipose Tissue Inflammation[J]. Circulation,2012, 125(23):2892-2903.
[42]Ballabio E, Mitchell T, van Kester MS, et al. MicroRNA expression in Sezary syndrome:identification, function, and diagnostic potential[J]. Blood,2010, 116(7):1105-1113.
[43]Small EM, O'Rourke JR, Moresi V, et al. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486[J]. Proc Natl Acad Sci U S A,2010, 107(9):4218-4223.
2 Martin, G. S., Mannino, D. M., Eaton, S., and Moss, M., The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348 (16),1546 (2003).
3 Ming, Wang, Peng, Wei, Cai, Min, and Ji, Gang, Investigation on epidemiology in 645 cases with sepsis in surgical intensive care unit. Chin Crit Care Med 18 (2),74 (2006).
4 Angus, D. C. et al., Epidemiology of severe sepsis in the United States:analysis of incidence, outcome, and associated costs of care. Crit Care Med 29 (7),1303 (2001).
5 Comstock, G. W., Tuberculosis in twins:a re-analysis of the Prophit survey. Am Rev Respir Dis 117 (4),621 (1978).
6 Burgner, D., Jamieson, S. E. and Blackwell, J. M., Genetic susceptibility to infectious diseases:big is beautiful, but will bigger be even better? Lancet Infect Dis 6 (10),653 (2006).
7 Sorensen, T. I., Nielsen, G. G., Andersen, P. K., and Teasdale, T. W., Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 318 (12),727 (1988).
8 Sassi, F., Bejaoui, M. and Ayed, K., [A congenital deficiency of the C3 fraction of complement. A familial study]. Tunis Med 81 (5),354 (2003).
9 Gu, W. et al., Identification of interleukin-6 promoter polymorphisms in the Chinese Han population and their functional significance. Crit Care Med 36 (5),1437 (2008).
10 Westendorp, R. G., Hottenga, J. J. and Slagboom, P. E., Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 354(9178),561(1999).
11 Menges, T. et al., Plasminogen-activator-inhibitor-14G/5G promoter polymorphism and prognosis of severely injured patients. Lancet 357 (9262),1096 (2001).
12 Guo, R. F. et al., Altered neutrophil trafficking during sepsis. J Immunol 169 (1), 307 (2002).
13 Czermak, B. J. et al., Protective effects of C5a blockade in sepsis. Nat Med 5 (7), 788 (1999).
14 Rafiei, A. et al., Association between the Phe206Leu polymorphism of L-selectin and brucellosis. J Med Microbiol 55 (Pt 5),511 (2006).
15 Levi, M. and Ten, Cate H., Disseminated intravascular coagulation. N Engl J Med 341 (8),586(1999).
16 Aird, W. C., The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101 (10),3765 (2003).
17 Matsuda, N. and Hattori, Y., Vascular biology in sepsis:pathophysiological and therapeutic significance of vascular dysfunction. J Smooth Muscle Res 43 (4),117 (2007).
18 Vigorito, E. et al, microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27 (6),847 (2007).
19 Rodriguez, A. et al., Requirement of bic/microRNA-155 for normal immune function. Science 316 (5824),608 (2007).
20 Cheng, B. et al., Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med 35 (11),2538 (2007).
21 Tsokos, M., Fehlauer, F. and Puschel, K., Immunohistochemical expression of E-selectin in sepsis-induced lung injury. Int J Legal Med 113 (6),338 (2000).
22 Engelberts, I. et al., Generalized inflammation during peritonitis evidenced by intracutaneous E-selectin expression. Clin Immunol Immunopathol 65 (3),330 (1992).
23 Newman, W. et al., Soluble E-selectin is found in supernatants of activated endothelial cells and is elevated in the serum of patients with septic shock. J Immunol 150(2),644(1993).
24 Cummings, C. J. et al., Soluble E-selectin levels in sepsis and critical illness. Correlation with infection and hemodynamic dysfunction. Am J Respir Crit Care Med 156 (2 Pt 1),431 (1997).
25 Cowley, H. C. et al., Increased circulating adhesion molecule concentrations in patients with the systemic inflammatory response syndrome:a prospective cohort study. Crit Care Med 22 (4),651 (1994).
26 Stavarachi, M. et al., Investigation of P213S SELL gene polymorphism in type 2 diabetes mellitus and related end stage renal disease. A case-control study. Rom J Morphol Embryol 52 (3 Suppl),995 (2011).
27 Chen, H. et al., The common variants of E-selectin gene in Graves'disease. Genes Immun 9 (2),182 (2008).
28 Chang, Y. P. et al., Multiple genes for essential-hypertension susceptibility on chromosome 1q. Am J Hum Genet 80 (2),253 (2007).
29 Wang, Z. et al., E-selectin gene polymorphisms are associated with essential hypertension:a case-control pilot study in a Chinese population. BMC Med Genet 11, 127 (2010).
30 Pacher, P., Beckman, J. S. and Liaudet, L., Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87 (1),315 (2007).
31 Petros, A., Bennett, D. and Vallance, P., Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 338 (8782-8783),1557 (1991).
32 Nava, E., Palmer, R. M. and Moncada, S., Inhibition of nitric oxide synthesis in septic shock:how much is beneficial? Lancet 338 (8782-8783),1555 (1991).
33 Qidwai, T. and Jamal, F., Inducible nitric oxide synthase (iNOS) gene polymorphism and disease prevalence. Scand J Immunol 72 (5),375 (2010).
34 Abraham, E., Alterations in cell signaling in sepsis. Clin Infect Dis 41 Suppl 7, S459 (2005).
35 Medvedev, A. E. et al, Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 198 (4),521 (2003).
[1]Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference[J]. Crit Care Med,2003, 31(4):1250-1256.
[2]Riedemann NC, Ward PA. Oxidized lipid protects against sepsis[J]. Nat Med,2002, 8(10):1084-1085.
[3]Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans[J]. J Immunol,2001,166(11):6952-6963.
[4]Shi M, Guo N. MicroRNA expression and its implications for the diagnosis and therapeutic strategies of breast cancer[J]. Cancer Treat Rev,2009,35(4):328-334.
[5]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function[J]. Cell,2004,116(2):281-297.
[6]Stern-Ginossar N, Elefant N, Zimmermann A, et al. Host immune system gene targeting by a viral miRNA[J]. Science,2007, 317(5836):376-381.
[7]Tili E, Michaille JJ, Cimino A, et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock[J]. J Immunol,2007, 179(8):5082-5089.
[8]Rodriguez A, Vigorito E, Clare S, et al. Requirement of bic/microRNA-155 for normal immune function[J]. Science, 2007,316(5824):608-611.
[9]Thai TH, Calado DP, Casola S, et al. Regulation of the germinal center response by microRNA-155[J]. Science, 2007,316(5824):604-608.
[10]Vasilescu C, Rossi S, Shimizu M, et al. MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis[J], PLoS One,2009, 4(10):e7405.
[11]Schmidt WM, Spiel AO, Jilma B, et al. In vivo profile of the human leukocyte microRNA response to endotoxemia[J]. Biochem Biophys Res Commun,2009, 380(3):437-441.
[12]Taganov KD, Boldin MP, Chang KJ, et al. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses[J]. Proc Natl Acad Sci U S A,2006,103(33):12481-12486.
[13]Nahid MA, Pauley KM, Satoh M, et al. miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY[J]. J Biol Chem,2009, 284(50):34590-34599.
[14]Baltimore D, Boldin MP, O'Connell RM, et al. MicroRNAs:new regulators of immune cell development and function[J]. Nat Immunol,2008,9(8):839-845.
[15]Chen XM, Splinter PL, O'Hara SP, et al. A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection[J]. J Biol Chem,2007, 282(39):28929-28938.
[16]Neilson JR, Zheng GX, Burge CB, et al. Dynamic regulation of miRNA expression in ordered stages of cellular development[J]. Genes Dev,2007, 21(5):578-589.
[17]Wu H, Neilson JR, Kumar P, et al. miRNA profiling of naive, effector and memory CD8 T cells[J]. PLoS One,2007, 2(10):e1020.
[18]Chen CZ, Li L, Lodish HF, et al. MicroRNAs modulate hematopoietic lineage differentiation[J]. Science,2004, 303(5654):83-86.
[19]Li QJ, Chau J, Ebert PJ, et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection[J]. Cell,2007, 129(1):147-161.
[20]Teng G, Hakimpour P, Landgraf P, et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase[J]. Immunity,2008,28(5):621-629.
[21]Vigorito E, Perks KL, Abreu-Goodger C, et al. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells[J]. Immunity, 2007,27(6):847-859.
[22]Turner M, Vigorito E. Regulation of B-and T-cell differentiation by a single microRNA[J]. Biochem Soc Trans,2008, 36(Pt3):531-533.
[23]Zhou B, Wang S, Mayr C, et al. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely[J]. Proc Natl Acad Sci U S A,2007, 104(17):7080-7085.
[24]Cheng AM, Byrom MW, Shelton J, et al. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis[J]. Nucleic Acids Res,2005, 33(4):1290-1297.
[25]Moschos SA, Williams AE, Perry MM, et al. Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids[J]. BMC Genomics,2007, 8:240.
[26]El G M, Church A, Liu T, et al. MicroRNA-146a regulates both transcription silencing and translation disruption of TNF-{alpha} during TLR4-induced gene reprogramming[J]. J Leukoc Biol,2011,90(3):509-519.
[27]Lagos D, Pollara G, Henderson S, et al. miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator [J]. Nat Cell Biol,2010,12(5):513-519.
[28]Jing Q, Huang S, Guth S, et al. Involvement of microRNA in AU-rich element-mediated mRNA instability[J]. Cell,2005,120(5):623-634.
[29]Sheedy F J, Palsson-Mcdermott E, Hennessy EJ, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21[J]. Nat Immunol,2010,11(2):141-147.
[30]Kim SW, Ramasamy K, Bouamar H, et al. MicroRNAs miR-125a and miR-125b constitutively activate the NF-kappaB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20)[J]. Proc Natl Acad Sci U S A,2012,109(20):7865-7870.
[31]Chaudhuri AA, So AY, Mehta A, et al. Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A[J]. Proc Natl Acad Sci U S A, 2012,109(11):4233-4238.
[32]Shaked I, Meerson A, Wolf Y, et al. MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase[J]. Immunity,2009, 31(6):965-973.
[33]Sun Y, Varambally S, Maher CA, et al. Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality[J]. Blood, 2011,117(23):6172-6183.
[34]Cameron JE, Yin Q, Fewell C, et al. Epstein-Barr virus latent membrane protein 1 induces cellular MicroRNA miR-146a, a modulator of lymphocyte signaling pathways[J]. J Virol,2008, 82(4):1946-1958.
[35]Wang JF, Yu ML, Yu G, et al. Serum miR-146a and miR-223 as potential new biomarkers for sepsis[J]. Biochem Biophys Res Commun,2010, 394(1):184-188.
[36]Segura M F, Hanniford D, Menendez S, et al. Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor[J]. Proc Natl Acad Sci U S A, 2009,106(6):1814-1819.
[37]Sonkoly E, Wei T, Janson PC, et al. MicroRNAs:novel regulators involved in the pathogenesis of psoriasis?[J]. PLoS One,2007,2(7):e610.
[38]Lena AM, Shalom-Feuerstein R, Rivetti di Val Cervo P, et al. miR-203 represses 'sternness' by repressing DeltaNp63.[J]. Cell Death Differ,2008, 15(7):1187-1195.
[39]Yang H, Kong W, He L, et al. MicroRNA expression profiling in human ovarian cancer:miR-214 induces cell survival and cisplatin resistance by targeting PTEN[J]. Cancer Res,2008, 68(2):425-433.
[40]Fazi F, Rosa A, Fatica A, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis[J]. Cell,2005, 123(5):819-831.
[41]Zhuang G, Meng C, Guo X, et al. A Novel Regulator of Macrophage Activation:miR-223 in Obesity-Associated Adipose Tissue Inflammation[J]. Circulation,2012, 125(23):2892-2903.
[42]Ballabio E, Mitchell T, van Kester MS, et al. MicroRNA expression in Sezary syndrome:identification, function, and diagnostic potential[J]. Blood,2010, 116(7):1105-1113.
[43]Small EM, O'Rourke JR, Moresi V, et al. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486[J]. Proc Natl Acad Sci U S A,2010, 107(9):4218-4223.