Variant IRAK-1 Haplotype Is Associated with Increased Nuclear Factor–κB Activation and Worse Outcomes in Sepsis

• DOI: 10.1164/rccm.200603-341oc
• Publication Date: 2006-03-10T02:05:03Z
• Authors: John Arcaroli; Eliezer Silva; James P. Maloney; Qianbin He; Daiva Svetkauskaite; James R. Murphy; Edward Abraham
• Keywords: Adult; Cell Nucleus; Lipopolysaccharides; Male; 0303 health sciences; Polymorphism, Genetic; Adolescent; Neutrophils; Homozygote; Intracellular Signaling Peptides and Proteins; NF-kappa B; Exons; Middle Aged; Introns; 3. Good health; Cytosine; 03 medical and health sciences; Interleukin-1 Receptor-Associated Kinases; Haplotypes; Cause of Death; Humans; Female; Inflammation Mediators

The IL-1 receptor-associated kinase (IRAK-1) plays a central role in TLR2- and TLR4-induced activation of nuclear factor (NF)-kappaB, a critical event in the transcriptional regulation of many sepsis-associated proinflammatory mediators. There are two haplotypes for the IRAK-1 gene in Caucasians, with the variant haplotype consisting of five intron single-nucleotide polymorphisms (SNPs) and three exon SNPs.To examine the functional significance of the IRAK-1 variant haplotype in modifying nuclear translocation of NF-kappaB and affecting outcomes from sepsis.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-kappaB 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.These results indicate that the IRAK-1 variant haplotype is functionally significant in patients with sepsis, being associated with increased nuclear translocation of NF-kappaB, more severe organ dysfunction, and higher mortality.