title: 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.
authors.affiliation: Critical 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
authors.forename: Ainsley M
authors.initials: AM
authors.lastname: Sutherland
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
authors.forename: Taka-Aki
authors.initials: TA
authors.lastname: Nakada
authors.forename: Andy H P
authors.initials: AH
authors.lastname: Sham
authors.forename: Mark M
authors.initials: MM
authors.lastname: Wurfel
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
mesh_terms: D000328:Adult; D002460:Cell Line; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D016908:Gram-Positive Bacterial Infections / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007114:Immunization; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012306:Risk; D018746:Systemic Inflammatory Response Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
chemical_list: D015850:Interleukin-6; D051193:Toll-Like Receptors; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases