Mutations in IRAK4 have been associated with recurrent Gram-positive infections in children. Given the central role of IRAK4 in innate immunity signaling, we hypothesized that common genetic variants of IRAK4 may be associated with prevalence of Gram-positive infection in critically ill adults. Haplotype clade tag single nucleotide polymorphisms (SNPs) of the IRAK4 gene were selected and genotyped in a cohort of 1,029 critically ill patients with systemic inflammatory response syndrome (SIRS). We found that a haplotype clade tagged by the A allele of the htSNP G29429A (Ala428Thr) was associated with increased relative risk of Gram-positive infection at admission to ICU (RR = 1.2, p < 0.05). Furthermore, the 29429A allele was associated with decreased lymphoblastoid cell response to CpG (as measured by IL-6 production) (raw values ± 95% CI 40.3 ± 32.3 vs. 85.8 ± 29.4 pg/ml; log-transformed values ± 95% CI 1.13 ± 0.37 vs. 1.55 ± 0.18, p < 0.04). We also found that IRAK4-deficient fibroblasts transfected with an IRAK4 expression plasmid containing the 29429A allele produced less IL-6 in response to lipopolysaccharide (p = 0.07). Our data suggest that the IRAK4 haplotype clade marked by 29429A (428Thr) alters susceptibility to Gram-positive bacteria, by decreasing cellular response to TLR ligands.
© 2011 S. Karger AG, Basel
- Bacterial infections
- Protein kinase
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Dr. Ainsley M. Sutherland
Critical Care Research Laboratories, Providence Heart and Lung Institute at
St. Paul’s Hospital, University of British Columbia
1081 Burrard Street, Vancouver, BC V6Z 1Y6 (Canada)
Tel. +1 416 728 2301, E-Mail firstname.lastname@example.org
Received: October 3, 2010
Accepted after revision: December 23, 2010
Published online: May 14, 2011
Number of Print Pages : 12
Number of Figures : 4, Number of Tables : 6, Number of References : 50
Journal of Innate Immunity
Vol. 3, No. 5, Year 2011 (Cover Date: August 2011)
Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)
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