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

Intensive Care Unit, Albert Einstein Hospital and Division of Applied Physiology, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, and Department of Biostatistics, National Jewish Medical and Research Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Edward Abraham, M.D., Department of Medicine, Chairman's Office, University of Alabama at Birmingham, 1530 3rd Avenue South, BDB 420, Birmingham, AL 35294-0012. E-mail: eabraham{at}uab.edu

Rationale: The IL-1 receptor–associated kinase (IRAK-1) plays a central role in TLR2- and TLR4-induced activation of nuclear factor (NF)-B, 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-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-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-B, more severe organ dysfunction, and higher mortality.

Key Words: acute lung injury • haplotype, inflammation • neutrophil • NF- • B • single nucleotide polymorphism

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