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Published ahead of print on March 9, 2006, doi:10.1164/rccm.200603-341OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 12, June 2006, 1335-1341

A more recent version of this article appeared on June 15, 2006
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Submitted on September 16, 2005
Accepted on March 30, 2006

Variant IRAK-1 Haplotype is Associated with Increased NF-{kappa}B Activation and Worse Outcomes in Sepsis

John Arcaroli1, Eliezer Silva2, James P Maloney1, Qianbin He1, Daiva Svetkauskaite1, James R Murphy3, and Edward Abraham1*

1 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 2 Intensive Care Unit, Albert Einstein Hospital and Division of Applied Physiology, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil, 3 Department of Biostatistics, National Jewish Medical and Research Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: eabraham{at}uab.edu.

Rationale: The interleukin-1 receptor-associated kinase (IRAK-1) plays a central role in TLR2 and TLR4 induced activation of NF-{kappa}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 5 intron single nucleotide polymorphisms (SNPs) and 3 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 of which 21 (14%) were homozygous for the IRAK-1 variant haplotype, as determined by a SNP in which T is replaced with C at nucleotide 1595 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 to that found in patients with wild type IRAK1 haplotype (p=0.0009). There was an increased incidence of shock (p = 0.047, O.R. 2.9, 95% CI: 1.1 to 7.7), greater requirement for more prolonged mechanical ventilator support (p = 0.04, O.R. 2.7, 95% CI: 1.05 to 6.9), and higher 60-day mortality (p = 0.05, O.R. 2.7, 95% CI: 1.0 to 6.8) in patients with the IRAK-1 variant haplotype compared to 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.
Key words: acute lung injury, single nucleotide polymorphism, haplotype, NF-{kappa}B, neutrophil




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