Free Access
J Innate Immun 2011;3:447–458
(DOI:10.1159/000323880)

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


 goto top of outline Key Words

  • Bacterial infections
  • Protein kinase
  • Inflammation

 goto top of outline 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


 goto top of outline References
  1. Akira S, Takeda K, Kaisho T: Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001;2:675–680.
  2. Beutler B, Hoebe K, Du X, Ulevitch RJ: How we detect microbes and respond to them: the Toll-like receptors and their transducers. J Leukoc Biol 2003;74:479–485.
  3. Burgner D, Levin M: Genetic susceptibility to infectious diseases. Pediatr Infect Dis J 2003;22:1–6.
  4. Choi EH, Zimmerman PA, Foster CB, Zhu S, Kumaraswami V, Nutman TB, Chanock SJ: Genetic polymorphisms in molecules of innate immunity and susceptibility to infection with Wuchereria bancrofti in south India. Genes Immun 2001;2:248–253.
  5. Majetschak M, Obertacke U, Schade FU, Bardenheuer M, Voggenreiter G, Bloemeke B, Heesen M: Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma patients. Clin Diagn Lab Immunol 2002;9:1205–1211.
  6. Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riche F, Leleu G, Arbibe L, Mignon A, Delpech M, Dhainaut JF: Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA 1999;282:561–568.
  7. Sorensen TI, Nielsen GG, Andersen PK, Teasdale TW: Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 1988;318:727–732.
  8. Suzuki N, Suzuki S, Yeh WC: IRAK-4 as the central TIR signaling mediator in innate immunity. Trends Immunol 2002;23:503–506.
  9. Yang K, Puel A, Zhang S, Eidenschenk C, Ku CL, Casrouge A, Picard C, von Bernuth H, Senechal B, Plancoulaine S, Al-Hajjar S, Al-Ghonaium A, Marodi L, Davidson D, Speert D, Roifman C, Garty BZ, Ozinsky A, Barrat FJ, Coffman RL, Miller RL, Li X, Lebon P, Rodriguez-Gallego C, Chapel H, Geissmann F, Jouanguy E, Casanova JL: Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 2005;23:465–478.
  10. Currie AJ, Davidson DJ, Reid GS, Bharya S, MacDonald KL, Devon RS, Speert DP: Primary immunodeficiency to pneumococcal infection due to a defect in Toll-like receptor signaling. J Pediatr 2004;144:512–518.
  11. Chapel H, Puel A, von Bernuth H, Picard C, Casanova JL: Shigella sonnei meningitis due to interleukin-1 receptor-associated kinase-4 deficiency: first association with a primary immune deficiency. Clin Infect Dis 2005;40:1227–1231.
  12. Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN: Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 2003;198:521–531.
  13. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL: Pyogenic bacterial infections in humans with irak-4 deficiency. Science 2003;299:2076–2079.
  14. Davidson DJ, Currie AJ, Bowdish DM, Brown KL, Rosenberger CM, Ma RC, Bylund J, Campsall PA, Puel A, Picard C, Casanova JL, Turvey SE, Hancock RE, Devon RS, Speert DP: IRAK-4 mutation (q293x): rapid detection and characterization of defective post-transcriptional TLR/IL-1r responses in human myeloid and non-myeloid cells. J Immunol 2006;177:8202–8211.
  15. Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001;68:978–989.
  16. Templeton AR, Weiss KM, Nickerson DA, Boerwinkle E, Sing CF: Cladistic structure within the human lipoprotein lipase gene and its implications for phenotypic association studies. Genetics 2000;156:1259–1275.
  17. Cardon LR, Bell JI: Association study designs for complex diseases. Nat Rev Genet 2001;2:91–99.
  18. Bone RC: The sepsis syndrome: definition and general approach to management. Clin Chest Med 1996;17:175–181.
  19. Knaus WA, Wagner DP, Draper EA, et al: The apache iii prognostic system: risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991;100:1619–1636.
  20. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: Apache II: a severity of disease classification system. Crit Care Med 1985;13:818–829.
  21. Rieder M: IRAK-4 Sequence Variation, SeattleSNPs. NHLBI Program for Genomic Applications HL66682, 2002.
  22. Kumar S, Tamura K, Jakobsen IB, Nei M: Mega2: molecular evolutionary genetics analysis software. Bioinformatics 2001;17:1244–1245.
  23. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science 2002;296:2225–2229.
  24. Johnson GC, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G, Ueda H, Cordell HJ, Eaves IA, Dudbridge F, Twells RC, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SC, Clayton DG, Todd JA: Haplotype tagging for the identification of common disease genes. Nat Genet 2001;29:233–237.
  25. Livak KJ: Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 1999;14:143–149.
  26. Baiyee EE, Flohe S, Lendemans S, Bauer S, Mueller N, Kreuzfelder E, Grosse-Wilde H: Expression and function of Toll-like receptor 9 in severely injured patients prone to sepsis. Clin Exp Immunol 2006;145:456–462.
  27. Dasari P, Nicholson IC, Hodge G, Dandie GW, Zola H: Expression of Toll-like receptors on B lymphocytes. Cell Immunol 2005;236:140–145.
  28. Plitas G, Burt BM, Nguyen HM, Bamboat ZM, DeMatteo RP: Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis. J Exp Med 2008;205:1277–1283.
  29. Sjolinder H, Mogensen TH, Kilian M, Jonsson AB, Paludan SR: Important role for Toll-like receptor 9 in host defense against meningococcal sepsis. Infect Immun 2008;76:5421–5428.

    External Resources

  30. Yasuda H, Leelahavanichkul A, Tsunoda S, Dear JW, Takahashi Y, Ito S, Hu X, Zhou H, Doi K, Childs R, Klinman DM, Yuen PS, Star RA: Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury. Am J Physiol Renal Physiol 2008;294:F1050–F1058.
  31. Liu S, Stolz DB, Sappington PL, Macias CA, Killeen ME, Tenhunen JJ, Delude RL, Fink MP: Hmgb1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers. Am J Physiol Cell Physiol 2006;290:C990–C999.
  32. Farley KS, Wang L, Mehta S: Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase. Am J Physiol Lung Cell Mol Physiol 2009;296:L480–L488.
  33. Nakada TA, Russell JA, Boyd JH, Aguirre-Hernandez R, Thain KR, Thair SA, Nakada E, McConechy M, Walley KR: Beta2-adrenergic receptor gene polymorphism is associated with mortality in septic shock. Am J Respir Crit Care Med 2010;181:143–149.
  34. Long AD, Langley CH: The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Res 1999;9:720–731.
  35. Wang Z, Liu J, Sudom A, Ayres M, Li S, Wesche H, Powers JP, Walker NP: Crystal structures of irak-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper. Structure 2006;14:1835–1844.
  36. Sutherland AM, Walley KR, Russell JA: Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults. Crit Care Med 2005;33:638–644.
  37. Tasaka S, Ishizaka A, Yamada W, Shimizu M, Koh H, Hasegawa N, Adachi Y, Yamaguchi K: Effect of CD14 blockade on endotoxin-induced acute lung injury in mice. Am J Respir Cell Mol Biol 2003;29:252–258.
  38. Opal SM, Palardy JE, Parejo N, Jasman RL: Effect of anti-CD14 monoclonal antibody on clearance of Escherichia coli bacteremia and endotoxemia. Crit Care Med 2003;31:929–932.
  39. Echchannaoui H, Frei K, Schnell C, Leib SL, Zimmerli W, Landmann R: Toll-like receptor 2-deficient mice are highly susceptible to Streptococcus pneumoniae meningitis because of reduced bacterial clearing and enhanced inflammation. J Infect Dis 2002;186:798–806.
  40. Day N, Tangsinmankong N, Ochs H, Rucker R, Picard C, Casanova JL, Haraguchi S, Good R: Interleukin receptor-associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses. J Pediatr 2004;144:524–526.
  41. Enders A, Pannicke U, Berner R, Henneke P, Radlinger K, Schwarz K, Ehl S: Two siblings with lethal pneumococcal meningitis in a family with a mutation in interleukin-1 receptor-associated kinase 4. J Pediatr 2004;145:698–700.

    External Resources

  42. Akey J, Jin L, Xiong M: Haplotypes vs. single marker linkage disequilibrium tests: what do we gain? Eur J Hum Genet 2001;9:291–300.
  43. Zhang K, Calabrese P, Nordborg M, Sun F: Haplotype block structure and its applications to association studies: power and study designs. Am J Hum Genet 2002;71:1386–1394.
  44. Templeton AR, Crandall KA, Sing CF: A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping and DNA sequence data. III. Cladogram estimation. Genetics 1992;132:619–633.
  45. Templeton AR: A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping or DNA sequencing. V. Analysis of case/control sampling designs: Alzheimer’s disease and the apoprotein E locus. Genetics 1995;140:403–409.
  46. Braaten O, Rodningen OK, Nordal I, Leren TP: The genetic algorithm applied to haplotype data at the LDL receptor locus. Comput Methods Programs Biomed 2000;61:1–9.
  47. Weiss KM, Clark AG: Linkage disequilibrium and the mapping of complex human traits. Trends Genet 2002;18:19–24.
  48. Wurfel MM, Gordon AC, Holden TD, Radella F, Strout J, Kajikawa O, Ruzinski JT, Rona G, Black RA, Stratton S, Jarvik GP, Hajjar AM, Nickerson DA, Rieder M, Sevransky J, Maloney JP, Moss M, Martin G, Shanholtz C, Garcia JG, Gao L, Brower R, Barnes KC, Walley KR, Russell JA, Martin TR: Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 2008;178:710–720.
  49. Sutherland AM, Walley KR, Manocha S, Russell JA: The association of interleukin 6 haplotype clades with mortality in critically ill adults. Arch Intern Med 2005;165:75–82.
  50. Wattanathum A, Manocha S, Groshaus H, Russell JA, Walley KR: Interleukin-10 haplotype associated with increased mortality in critically ill patients with sepsis from pneumonia but not in patients with extrapulmonary sepsis. Chest 2005;128:1690–1698.

 goto top of outline Author Contacts

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


 goto top of outline Article Information

Received: October 3, 2010
Accepted after revision: December 23, 2010
Published online: May 14, 2011
Number of Print Pages : 12
Number of Figures : 4, Number of Tables : 6, Number of References : 50


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 3, No. 5, Year 2011 (Cover Date: August 2011)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

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


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