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Table of Contents
Vol. 3, No. 5, 2011
Issue release date: August 2011
Section title: Research Article
Free Access
J Innate Immun 2011;3:447–458

A Nonsynonymous Polymorphism of IRAK4 Associated with Increased Prevalence of Gram-Positive Infection and Decreased Response to Toll-Like Receptor Ligands

Sutherland A.M. · Walley K.R. · Nakada T. · Sham A.H.P. · Wurfel M.M. · Russell J.A.
Critical Care Research Laboratories, Providence Heart and Lung Institute at St. Paul’s Hospital, University of British Columbia, Vancouver, B.C., Canada
email Corresponding Author

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 ainsley.sutherland@utoronto.ca

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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

Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: October 03, 2010
Accepted: December 23, 2010
Published online: May 14, 2011
Issue release date: August 2011

Number of Print Pages: 12
Number of Figures: 4
Number of Tables: 6

ISSN: 1662-811X (Print)
eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN

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