A Nonsynonymous Polymorphism of IRAK4 Associated with Increased Prevalence of Gram-Positive Infection and Decreased Response to Toll-Like Receptor Ligands
Open Access
- 14 May 2011
- journal article
- research article
- Published by S. Karger AG in Journal of Innate Immunity
- Vol. 3 (5), 447-458
- https://doi.org/10.1159/000323880
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.Keywords
This publication has 50 references indexed in Scilit:
- Important Role for Toll-Like Receptor 9 in Host Defense against Meningococcal SepsisInfection and Immunity, 2008
- Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in SepsisAmerican Journal of Respiratory and Critical Care Medicine, 2008
- Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsisThe Journal of Experimental Medicine, 2008
- Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injuryAmerican Journal of Physiology-Renal Physiology, 2008
- Expression and function of Toll-like receptor 9 in severely injured patients prone to sepsisClinical and Experimental Immunology, 2006
- Interleukin receptor–associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responsesThe Journal of Pediatrics, 2004
- Primary Immunodeficiency to pneumococcal infection due to a defect in Toll-like receptor signalingThe Journal of Pediatrics, 2004
- Allelic discrimination using fluorogenic probes and the 5′ nuclease assayGenetic Analysis: Biomolecular Engineering, 1999
- Genetic and Environmental Influences on Premature Death in Adult AdopteesThe New England Journal of Medicine, 1988
- APACHE IICritical Care Medicine, 1985