Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis.
BACKGROUND
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.


OBJECTIVE
To examine the functional significance of the IRAK-1 variant haplotype in modifying nuclear translocation of NF-kappaB and affecting outcomes from sepsis.


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-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.


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-kappaB, more severe organ dysfunction, and higher mortality.
Arcaroli
John
J
Intensive Care unit, Albert Einstein Hospital and Division of Applied Physiology, Heart Institute, University of Sao Paulo, Brazil.
Silva
Eliezer
E
Maloney
James P
JP
He
Qianbin
Q
Svetkauskaite
Daiva
D
Murphy
James R
JR
Abraham
Edward
E
D000293:Adolescent; D000328:Adult; D002423:Cause of Death; D002467:Cell Nucleus / Q000378:metabolism; D003596:Cytosine; D005091:Exons / Q000235:genetics; D005260:Female; D006239:Haplotypes / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D012121:Respiration, Artificial; D018805:Sepsis / Q000503:physiopathology*; D012772:Shock, Septic / Q000097:blood / Q000235:genetics; D013941:Thymine; D014158:Transcription, Genetic / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics
D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D003596:Cytosine; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases; D013941:Thymine