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

Rationale: The IL-1 receptor–associated kinase (IRAK-1) plays a central role in TLR2- and TLR4-induced activation of nuclear factor (NF)-κB, 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. Objectives: To examine the functional significance of the IRAK-1 variant haplotype in modifying nuclear translocation of NF-κB 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-κB 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-κB, more severe organ dysfunction, and higher mortality.