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

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.

Interleukin-1β Regulates CXCL8 Release and Influences Disease Outcome in Response to Streptococcus pneumoniae, Defining Intercellular Cooperation between Pulmonary Epithelial Cells and Macrophages

“…Hyporesponsiveness in this system, as recently demonstrated for an association between IRAK4 polymorphisms and susceptibility to Gram-positive infections in patients with critical illness, limit the effectiveness of the innate immune responses (56). We show that direct exposure of A549 cells to pneumococci induces only low-level CXCL8 secretion.…”

The Meta-Genome of Sepsis: Host Genetics, Pathogens and the Acute Immune Response

“…A polymorphism in CD14, a key molecule in the innate immune response to Gram-negative endotoxin has been found to increase the risk of serious Gram-negative infections [34], while polymorphisms in the complement-activating mannose-binding lectin results in increased serious infections [34]. A functional polymorphism of IRAK4 increases the risk of Gram-positive infections in childhood and in adult septic shock [36]. …”

Editorial

“…ly ill patients with systemic inflammatory response syndrome, a haplotype clade tagged by the A allele of the htSNP G29429A (Ala428Thr) was associated with an increased relative risk of Gram-positive infection at admission to the ICU [4] . One effect of this genotype was a decreased IL-6 production in response to PAMPs.…”