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J Innate Immun. 2011;3(5):447-58. doi: 10.1159/000323880. Epub 2011 May 14.

A nonsynonymous polymorphism of IRAK4 associated with increased prevalence of gram-positive infection and decreased response to toll-like receptor ligands.

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  • 1Critical Care Research Laboratories, Providence Heart and Lung Institute at St. Paul's Hospital, University of British Columbia, Vancouver, B.C., Canada. ainsley.sutherland @ utoronto.ca

Abstract

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.

Copyright © 2011 S. Karger AG, Basel.

PMID:
21576904
[PubMed - indexed for MEDLINE]
PMCID:
PMC3186712
Free PMC Article

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