Variant IRAK-1 haplotype is associated with increased nuclear factor-κB activation and worse outcomes in sepsis
Variant IRAK-1 haplotype is associated with increased nuclear factor-κB activation and worse outcomes in sepsis
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DOI：
10.1164/rccm.200603-341oc
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发表时间：
2006-06-15
影响因子：
24.7
通讯作者：
Abraham, Edward
中科院分区：
文献类型：
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作者：
Arcaroli, John;Silva, Eliezer;Abraham, Edward
理论基础：IL-1受体相关激酶(IRAK-1)在TLR2和TLR4诱导的核因子-kappaB的激活中起核心作用，这是许多脓毒症相关的促炎介质转录调控的关键事件。IRAK-1基因在高加索人中有两种单倍型，其中变异型单倍型包括5个内含子单核苷酸多态(SNPs)和3个外显子SNPs。目的：探讨IRAK-1变异型单倍型在修饰核因子-kappaB核转位及影响败血症预后方面的功能意义。21例(14%)是IRAK-1变异单倍型的纯合子，由IRAK-1基因第12外显子第1,595位核苷酸T被C取代的SNP确定。与野生型IRAK-1单倍型患者相比，脓毒症患者的IRAK-1变异单倍型与脂多糖刺激的中性粒细胞中的核转录因子-kappaB水平升高相关(p=0.0009)。休克发生率增加(P=0.047.0 1)(优势比[OR]，2.9；95%可信区间[CI]，1.1-7.7)，需要更长时间的机械呼吸机支持(P=0.0 4)(OR，2.7；95%CI，1.0 5-6.9)，以及更高的60d死亡率(P=0.0 5)(OR，2.7；结论：IRAK-1变异单倍型在脓毒症患者中具有显著的功能意义，可能与核因子-kappaB核转位增加、器官功能障碍加重、病死率高有关。
Rationale: The IL-1 receptor-associated kinase (IRAK-1) plays a central role in TLR2- and TLR4-induced activation of nuclear factor (NF)-kappa B, a critical event in the transcriptional regulation of many sepsis-associated proinflammatory mediators. There are two haplo-types for the IRAK-1 gene in Caucasians, with the variant haplotype consisting of five intron single-nucleotide polymorphisms (SNPs) and three exon SNPs.Objectives: To examine the functional significance of the IRAK-1 variant haplotype in modifying nuclear translocation of NF-kappa B and affecting outcomes from sepsis.Measurements and Main Results: One hundred fifty-five Caucasian patients with sepsis were included. Twenty-one (14%) were homozygous for the IRAK-1 variant haplotype as determined by a SNP in which T is replaced with C at nucleotide 1,595 within exon 12 of the IRAK-1 gene. The IRAK-1 variant haplotype was associated with increased nuclear levels of NF-kappa B in LPS-stimulated peripheral blood neutrophils from patients with sepsis compared with that found in patients with wild-type IRAK-1 haplotype (p = 0.0009). There was an increased incidence of shock (p = 0.047) (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.1-7.7), greater requirement for more prolonged mechanical ventilator support (p = 0.04) (OR, 2.7; 95% CI, 1.05-6.9), and higher 60-d mortality (p = 0.05) (OR, 2.7; 95% CI, 1.0-6.8) in patients with the IRAK-1 variant haplotype compared with wild type.Conclusions: These results indicate that the IRAK-1 variant haplotype is functionally significant in patients with sepsis, being associated with increased nuclear translocation of NF-kappa B, more severe organ dysfunction, and higher mortality.