Sepsis pp 237-264 | Cite as

Genetics in the Prevention and Treatment of Sepsis

  • John P. Reilly
  • Nuala J. Meyer
  • Jason D. ChristieEmail author
Part of the Respiratory Medicine book series (RM)


Sepsis, the systemic response to acute infection, continues to be a leading cause of hospitalization, intensive care unit admission, and mortality in the United States despite significant advances in our understanding of sepsis pathogenesis and improvements in hospital-provided medical care [1, 2]. Modern hospital and intensive care unit practices, including early administration of antibiotics, fluid resuscitation, hemodynamic support, and mechanical ventilation, appear to be improving outcomes among patients with sepsis and septic shock [2, 3]. However, despite decades of research, the majority of clinic trials evaluating pharmacologic therapies targeting the host response to infection have demonstrated inconsistent or negative results [4–14]. The potential of genetics to improve the prevention and treatment of sepsis lies in furthering our understanding of the heterogeneity in host responses to infection, identifying those infected individuals at highest risk of incident sepsis, multi-organ system failure, or death, and selecting patients most likely to benefit from therapies targeted at sepsis pathogenesis.


Sepsis Septic shock Sepsis treatment Sepsis genetics Critical care Systemic inflammatory response syndrome 


  1. 1.
    Walkey AJ, Wiener RS, Lindenauer PK. Utilization patterns and outcomes associated with central venous catheter in septic shock: a population-based study. Crit Care Med. 2013;41(6):1450–7.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA. 2014;311(13):1308–16.PubMedCrossRefGoogle Scholar
  3. 3.
    Miller III RR, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR, et al. Multicenter implementation of a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care Med. 2013;188(1):77–82.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862–71.PubMedCrossRefGoogle Scholar
  5. 5.
    Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699–709.PubMedCrossRefGoogle Scholar
  6. 6.
    Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111–24.PubMedCrossRefGoogle Scholar
  7. 7.
    Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366(22):2055–64.PubMedCrossRefGoogle Scholar
  8. 8.
    Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R, et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet. 1998;351(9107):929–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Abraham E, Laterre PF, Garbino J, Pingleton S, Butler T, Dugernier T, et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med. 2001;29(3):503–10.PubMedCrossRefGoogle Scholar
  10. 10.
    Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA. 1995;273(12):934–41.PubMedCrossRefGoogle Scholar
  11. 11.
    Opal SM, Fisher Jr CJ, Dhainaut JF, Vincent JL, Brase R, Lowry SF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med. 1997;25(7):1115–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Szakmany T, Hauser B, Radermacher P. N-Acetylcysteine for sepsis and systemic inflammatory response in adults. Cochrane Database Syst Rev. 2012;9:CD006616.Google Scholar
  13. 13.
    Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290(2):238–47.PubMedCrossRefGoogle Scholar
  14. 14.
    Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med. 2010;38(8):1685–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Shorr AF, Tabak YP, Killian AD, Gupta V, Liu LZ, Kollef MH. Healthcare-associated bloodstream infection: a distinct entity? Insights from a large U.S. database. Crit Care Med. 2006;34(10):2588–95.PubMedCrossRefGoogle Scholar
  16. 16.
    Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006;34(1):15–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, et al. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA. 1997;278(3):234–40.PubMedCrossRefGoogle Scholar
  18. 18.
    Girard TD, Opal SM, Ely EW. Insights into severe sepsis in older patients: from epidemiology to evidence-based management. Clin Infect Dis. 2005;40(5):719–27.PubMedCrossRefGoogle Scholar
  19. 19.
    Krieger JN, Kaiser DL, Wenzel RP. Urinary tract etiology of bloodstream infections in hospitalized patients. J Infect Dis. 1983;148(1):57–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Sorensen TI, Nielsen GG, Andersen PK, Teasdale TW. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med. 1988;318(12):727–32.PubMedCrossRefGoogle Scholar
  21. 21.
    Finch CE. Evolution in health and medicine Sackler colloquium: evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Proc Natl Acad Sci U S A. 2010;107(Suppl 1):1718–24.PubMedCrossRefGoogle Scholar
  22. 22.
    Akey JM. Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res. 2009;19(5):711–22.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Murphy PM. Molecular mimicry and the generation of host defense protein diversity. Cell. 1993;72(6):823–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, et al. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet. 2002;359(9314):1311–2.PubMedCrossRefGoogle Scholar
  25. 25.
    Miller LH, Mason SJ, Clyde DF, McGinniss MH. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N Engl J Med. 1976;295(6):302–4.PubMedCrossRefGoogle Scholar
  26. 26.
    Kangelaris KN, Sapru A, Calfee CS, Liu KD, Pawlikowska L, Witte JS, et al. The association between a Darc gene polymorphism and clinical outcomes in African American patients with acute lung injury. Chest. 2012;141(5):1160–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet. 1997;349(9046):170–3.PubMedCrossRefGoogle Scholar
  28. 28.
    Burgner D, Jamieson SE, Blackwell JM. Genetic susceptibility to infectious diseases: big is beautiful, but will bigger be even better? Lancet Infect Dis. 2006;6(10):653–63.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Bellamy R, Hill AV. Genetic susceptibility to mycobacteria and other infectious pathogens in humans. Curr Opin Immunol. 1998;10(4):483–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Hattori M. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931–45.CrossRefGoogle Scholar
  31. 31.
    Casanova JL, Fieschi C, Bustamante J, Reichenbach J, Remus N, von Bernuth H, et al. From idiopathic infectious diseases to novel primary immunodeficiencies. J Allergy Clin Immunol. 2005;116(2):426–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Casanova JL, Abel L. Inborn errors of immunity to infection: the rule rather than the exception. J Exp Med. 2005;202(2):197–201.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–55.PubMedCrossRefGoogle Scholar
  34. 34.
    Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013;381(9868):774–5.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296(5576):2225–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273(5281):1516–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Vink JM, Boomsma DI. Gene finding strategies. Biol Psychol. 2002;61(1–2):53–71.PubMedCrossRefGoogle Scholar
  38. 38.
    Clark MF, Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med. 2006;32(11):1706–12.PubMedCrossRefGoogle Scholar
  39. 39.
    Chapman SJ, Hill AV. Human genetic susceptibility to infectious disease. Nat Rev Genet. 2012;13(3):175–88.PubMedGoogle Scholar
  40. 40.
    Marchini J, Cardon LR, Phillips MS, Donnelly P. The effects of human population structure on large genetic association studies. Nat Genet. 2004;36(5):512–7.PubMedCrossRefGoogle Scholar
  41. 41.
    McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008;9(5):356–69.PubMedCrossRefGoogle Scholar
  42. 42.
    ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74.CrossRefGoogle Scholar
  43. 43.
    Chung LP, Waterer GW. Genetic predisposition to respiratory infection and sepsis. Crit Rev Clin Lab Sci. 2011;48(5–6):250–68.PubMedCrossRefGoogle Scholar
  44. 44.
    Sutherland AM, Walley KR. Bench-to-bedside review: association of genetic variation with sepsis. Crit Care. 2009;13(2):210.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Wong HR. Genetics and genomics in pediatric septic shock. Crit Care Med. 2012;40(5):1618–26.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Namath A, Patterson AJ. Genetic polymorphisms in sepsis. Crit Care Clin. 2009;25(4):835–56. xPubMedCrossRefGoogle Scholar
  47. 47.
    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.PubMedCrossRefGoogle Scholar
  48. 48.
    Netea MG, van der Meer JW. Immunodeficiency and genetic defects of pattern-recognition receptors. N Engl J Med. 2011;364(1):60–70.PubMedCrossRefGoogle Scholar
  49. 49.
    Jack DL, Turner MW. Anti-microbial activities of mannose-binding lectin. Biochem Soc Trans. 2003;31(Pt 4):753–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Rantala A, Lajunen T, Juvonen R, Bloigu A, Silvennoinen-Kassinen S, Peitso A, et al. Mannose-binding lectin concentrations, MBL2 polymorphisms, and susceptibility to respiratory tract infections in young men. J Infect Dis. 2008;198(8):1247–53.PubMedCrossRefGoogle Scholar
  51. 51.
    Huh JW, Song K, Yum JS, Hong SB, Lim CM, Koh Y. Association of mannose-binding lectin-2 genotype and serum levels with prognosis of sepsis. Crit Care. 2009;13(6):R176.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Eisen DP, Dean MM, Boermeester MA, Fidler KJ, Gordon AC, Kronborg G, et al. Low serum mannose-binding lectin level increases the risk of death due to pneumococcal infection. Clin Infect Dis. 2008;47(4):510–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Eisen DP, Minchinton RM. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin Infect Dis. 2003;37(11):1496–505.PubMedCrossRefGoogle Scholar
  54. 54.
    Garred P, Larsen F, Seyfarth J, Fujita R, Madsen HO. Mannose-binding lectin and its genetic variants. Genes Immun. 2006;7(2):85–94.PubMedCrossRefGoogle Scholar
  55. 55.
    Gordon AC, Waheed U, Hansen TK, Hitman GA, Garrard CS, Turner MW, et al. Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome. Shock. 2006;25(1):88–93.PubMedCrossRefGoogle Scholar
  56. 56.
    Horiuchi T, Gondo H, Miyagawa H, Otsuka J, Inaba S, Nagafuji K, et al. Association of MBL gene polymorphisms with major bacterial infection in patients treated with high-dose chemotherapy and autologous PBSCT. Genes Immun. 2005;6(2):162–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Summerfield JA, Ryder S, Sumiya M, Thursz M, Gorchein A, Monteil MA, et al. Mannose binding protein gene mutations associated with unusual and severe infections in adults. Lancet. 1995;345(8954):886–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Garnacho-Montero J, Garcia-Cabrera E, Jimenez-Alvarez R, Diaz-Martin A, Revuelto-Rey J, Aznar-Martin J, et al. Genetic variants of the MBL2 gene are associated with mortality in pneumococcal sepsis. Diagn Microbiol Infect Dis. 2012;73(1):39–44.PubMedCrossRefGoogle Scholar
  59. 59.
    Garred P, Strom JJ, Quist L, Taaning E, Madsen HO: Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome. J Infect Dis 2003, 188(9):1394–1403.Google Scholar
  60. 60.
    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(3):638–44.PubMedCrossRefGoogle Scholar
  61. 61.
    Klostergaard A, Steffensen R, Moller JK, Peterslund N, Juhl-Christensen C, Molle I. Sepsis in acute myeloid leukaemia patients receiving high-dose chemotherapy: no impact of chitotriosidase and mannose-binding lectin polymorphisms. Eur J Haematol. 2010;85(1):58–64.PubMedGoogle Scholar
  62. 62.
    Kronborg G, Weis N, Madsen HO, Pedersen SS, Wejse C, Nielsen H, et al. Variant mannose-binding lectin alleles are not associated with susceptibility to or outcome of invasive pneumococcal infection in randomly included patients. J Infect Dis. 2002;185(10):1517–20.PubMedCrossRefGoogle Scholar
  63. 63.
    Zhang AQ, Yue CL, Pan W, Gao JW, Zeng L, Gu W, et al. Mannose-binding lectin polymorphisms and the risk of sepsis: evidence from a meta-analysis. Epidemiol Infect. 2014;1-12Google Scholar
  64. 64.
    Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature. 2004;430(6996):257–63.PubMedCrossRefGoogle Scholar
  65. 65.
    Casanova JL, Abel L, Quintana-Murci L. Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics. Annu Rev Immunol. 2011;29:447–91.PubMedCrossRefGoogle Scholar
  66. 66.
    Misch EA, Hawn TR. Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci (Lond). 2008;114(5):347–60.CrossRefGoogle Scholar
  67. 67.
    Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410(6832):1099–103.PubMedCrossRefGoogle Scholar
  68. 68.
    Wurfel MM, Gordon AC, Holden TD, Radella F, Strout J, Kajikawa O, et al. Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med. 2008;178(7):710–20.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Pino-Yanes M, Corrales A, Casula M, Blanco J, Muriel A, Espinosa E, et al. Common variants of TLR1 associate with organ dysfunction and sustained pro-inflammatory responses during sepsis. PLoS One. 2010;5(10):e13759.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun. 2000;68(11):6398–401.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Abu-Maziad A, Schaa K, Bell EF, Dagle JM, Cooper M, Marazita ML, et al. Role of polymorphic variants as genetic modulators of infection in neonatal sepsis. Pediatr Res. 2010;68(4):323–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25(2):187–91.PubMedCrossRefGoogle Scholar
  73. 73.
    Michel O, LeVan TD, Stern D, Dentener M, Thorn J, Gnat D, et al. Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. J Allergy Clin Immunol. 2003;112(5):923–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med. 2002;162(9):1028–32.PubMedCrossRefGoogle Scholar
  75. 75.
    Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis. 2002;186(10):1522–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Faber J, Henninger N, Finn A, Zenz W, Zepp F, Knuf M. A toll-like receptor 4 variant is associated with fatal outcome in children with invasive meningococcal disease. Acta Paediatr. 2009;98(3):548–52.PubMedCrossRefGoogle Scholar
  77. 77.
    Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, Laws RJ, et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J Exp Med. 2003;198(10):1563–72.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321(5889):691–6.CrossRefGoogle Scholar
  79. 79.
    Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, et al. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007;204(10):2407–22.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci U S A. 1998;95(2):588–93.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Moore CE, Segal S, Berendt AR, Hill AV, Day NP. Lack of association between Toll-like receptor 2 polymorphisms and susceptibility to severe disease caused by Staphylococcus aureus. Clin Diagn Lab Immunol. 2004;11(6):1194–7.PubMedPubMedCentralGoogle Scholar
  82. 82.
    von Aulock S, Schroder NW, Traub S, Gueinzius K, Lorenz E, Hartung T, et al. Heterozygous toll-like receptor 2 polymorphism does not affect lipoteichoic acid-induced chemokine and inflammatory responses. Infect Immun. 2004;72(3):1828–31.CrossRefGoogle Scholar
  83. 83.
    Everett B, Cameron B, Li H, Vollmer-Conna U, Davenport T, Hickie I, et al. Polymorphisms in Toll-like receptors-2 and -4 are not associated with disease manifestations in acute Q fever. Genes Immun. 2007;8(8):699–702.PubMedCrossRefGoogle Scholar
  84. 84.
    Read RC, Pullin J, Gregory S, Borrow R, Kaczmarski EB, di Giovine FS, et al. A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis. 2001;184(5):640–2.PubMedCrossRefGoogle Scholar
  85. 85.
    Allen A, Obaro S, Bojang K, Awomoyi AA, Greenwood BM, Whittle H, et al. Variation in Toll-like receptor 4 and susceptibility to group A meningococcal meningitis in Gambian children. Pediatr Infect Dis J. 2003;22(11):1018–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Arcaroli J, Silva E, Maloney JP, He Q, Svetkauskaite D, Murphy JR, et al. Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis. Am J Respir Crit Care Med. 2006;173(12):1335–41.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Schutt C. Cd14. Int J Biochem Cell Biol. 1999;31(5):545–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Landmann R, Reber AM, Sansano S, Zimmerli W. Function of soluble CD14 in serum from patients with septic shock. J Infect Dis. 1996;173(3):661–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Brunialti MK, Martins PS, de Barbosa Carvalho H, Machado FR, Barbosa LM, et al. TLR2, TLR4, CD14, CD11B, and CD11C expressions on monocytes surface and cytokine production in patients with sepsis, severe sepsis, and septic shock. Shock. 2006;25(4):351–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Burgmann H, Winkler S, Locker GJ, Presterl E, Laczika K, Staudinger T, et al. Increased serum concentration of soluble CD14 is a prognostic marker in gram-positive sepsis. Clin Immunol Immunopathol. 1996;80(3 Pt 1):307–10.PubMedCrossRefGoogle Scholar
  91. 91.
    Carrillo EH, Gordon L, Goode E, Davis E, Polk Jr HC. Early elevation of soluble CD14 may help identify trauma patients at high risk for infection. J Trauma. 2001;50(5):810–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Landmann R, Zimmerli W, Sansano S, Link S, Hahn A, Glauser MP, et al. Increased circulating soluble CD14 is associated with high mortality in gram-negative septic shock. J Infect Dis. 1995;171(3):639–44.PubMedCrossRefGoogle Scholar
  93. 93.
    Gibot S, Cariou A, Drouet L, Rossignol M, Ripoll L. Association between a genomic polymorphism within the CD14 locus and septic shock susceptibility and mortality rate. Crit Care Med. 2002;30(5):969–73.PubMedCrossRefGoogle Scholar
  94. 94.
    de Aguiar BB, Girardi I, Paskulin DD, de Franca E, Dornelles C, Dias FS, et al. CD14 expression in the first 24 h of sepsis: effect of -260C>T CD14 SNP. Immunol Invest. 2008;37(8):752–69.PubMedCrossRefGoogle Scholar
  95. 95.
    Barber RC, Aragaki CC, Chang LY, Purdue GF, Hunt JL, Arnoldo BD, et al. CD14-159 C allele is associated with increased risk of mortality after burn injury. Shock. 2007;27(3):232–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Barber RC, Chang LY, Arnoldo BD, Purdue GF, Hunt JL, Horton JW, et al. Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res. 2006;4(4):250–5.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Heesen M, Bloemeke B, Schade U, Obertacke U, Majetschak M. The −260 C–>T promoter polymorphism of the lipopolysaccharide receptor CD14 and severe sepsis in trauma patients. Intensive Care Med. 2002;28(8):1161–3.PubMedCrossRefGoogle Scholar
  98. 98.
    Hubacek JA, Stuber F, Frohlich D, Book M, Wetegrove S, Rothe G, et al. The common functional C(−159)T polymorphism within the promoter region of the lipopolysaccharide receptor CD14 is not associated with sepsis development or mortality. Genes Immun. 2000;1(6):405–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Weiss J. Bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP): structure, function and regulation in host defence against Gram-negative bacteria. Biochem Soc Trans. 2003;31(Pt 4):785–90.PubMedCrossRefGoogle Scholar
  100. 100.
    Hubacek JA, Stuber F, Frohlich D, Book M, Wetegrove S, Ritter M, et al. Gene variants of the bactericidal/permeability increasing protein and lipopolysaccharide binding protein in sepsis patients: gender-specific genetic predisposition to sepsis. Crit Care Med. 2001;29(3):557–61.PubMedCrossRefGoogle Scholar
  101. 101.
    Barber RC, O'Keefe GE. Characterization of a single nucleotide polymorphism in the lipopolysaccharide binding protein and its association with sepsis. Am J Respir Crit Care Med. 2003;167(10):1316–20.PubMedCrossRefGoogle Scholar
  102. 102.
    Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, et al. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999;282(6):561–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Beutler B. TNF, immunity and inflammatory disease: lessons of the past decade. J Invest Med. 1995;43(3):227–35.Google Scholar
  104. 104.
    Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987;330(6149):662–4.PubMedCrossRefGoogle Scholar
  105. 105.
    Opal SM, Cross AS, Kelly NM, Sadoff JC, Bodmer MW, Palardy JE, et al. Efficacy of a monoclonal antibody directed against tumor necrosis factor in protecting neutropenic rats from lethal infection with Pseudomonas aeruginosa. J Infect Dis. 1990;161(6):1148–52.PubMedCrossRefGoogle Scholar
  106. 106.
    Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A. 1997;94(7):3195–9.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Nadel S, Newport MJ, Booy R, Levin M. Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease. J Infect Dis. 1996;174(4):878–80.PubMedCrossRefGoogle Scholar
  108. 108.
    Stuber F, Udalova IA, Book M, Drutskaya LN, Kuprash DV, Turetskaya RL, et al. 308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J Inflamm. 1995;46(1):42–50.PubMedGoogle Scholar
  109. 109.
    Read RC, Teare DM, Pridmore AC, Naylor SC, Timms JM, Kaczmarski EB, et al. The tumor necrosis factor polymorphism TNF (−308) is associated with susceptibility to meningococcal sepsis, but not with lethality. Crit Care Med. 2009;37(4):1237–43.PubMedCrossRefGoogle Scholar
  110. 110.
    Pfeffer K. Biological functions of tumor necrosis factor cytokines and their receptors. Cytokine Growth Factor Rev. 2003;14(3–4):185–91.PubMedCrossRefGoogle Scholar
  111. 111.
    Waterer GW, Quasney MW, Cantor RM, Wunderink RG. Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations. Am J Respir Crit Care Med. 2001;163(7):1599–604.PubMedCrossRefGoogle Scholar
  112. 112.
    Majetschak M, Flohe S, Obertacke U, Schroder J, Staubach K, Nast-Kolb D, et al. Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg. 1999;230(2):207–14.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Henckaerts L, Nielsen KR, Steffensen R, Van Steen K, Mathieu C, Giulietti A, et al. Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med. 2009;37(1):192–201. e191-193PubMedCrossRefGoogle Scholar
  114. 114.
    Sole-Violan J, de Castro F, Garcia-Laorden MI, Blanquer J, Aspa J, Borderias L, et al. Genetic variability in the severity and outcome of community-acquired pneumonia. Respir Med. 2010;104(3):440–7.PubMedCrossRefGoogle Scholar
  115. 115.
    Temple SE, Cheong KY, Ardlie KG, Sayer D, Waterer GW. The septic shock associated HSPA1B1267 polymorphism influences production of HSPA1A and HSPA1B. Intensive Care Med. 2004;30(9):1761–7.PubMedCrossRefGoogle Scholar
  116. 116.
    Pruitt JH, Copeland III EM, Moldawer LL. Interleukin-1 and interleukin-1 antagonism in sepsis, systemic inflammatory response syndrome, and septic shock. Shock. 1995;3(4):235–51.PubMedCrossRefGoogle Scholar
  117. 117.
    Emonts M, Vermont CL, Houwing-Duistermaat JJ, Haralambous E, Gaast-de Jongh CE, Hazelzet JA, et al. Polymorphisms in PARP, IL1B, IL4, IL10, C1INH, DEFB1, and DEFA4 in meningococcal disease in three populations. Shock. 2010;34(1):17–22.PubMedCrossRefGoogle Scholar
  118. 118.
    Gu W, Zeng L, Zhou J, Jiang DP, Zhang L, Du DY, et al. Clinical relevance of 13 cytokine gene polymorphisms in Chinese major trauma patients. Intensive Care Med. 2010;36(7):1261–5.PubMedCrossRefGoogle Scholar
  119. 119.
    Shimada T, Oda S, Sadahiro T, Nakamura M, Hirayama Y, Watanabe E, et al. Outcome prediction in sepsis combined use of genetic polymorphisms – a study in Japanese population. Cytokine. 2011;54(1):79–84.PubMedCrossRefGoogle Scholar
  120. 120.
    Arnalich F, Lopez-Maderuelo D, Codoceo R, Lopez J, Solis-Garrido LM, Capiscol C, et al. Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. Clin Exp Immunol. 2002;127(2):331–6.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Fang XM, Schroder S, Hoeft A, Stuber F. Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Crit Care Med. 1999;27(7):1330–4.PubMedCrossRefGoogle Scholar
  122. 122.
    Ma P, Chen D, Pan J, Du B. Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients. Crit Care Med. 2002;30(5):1046–50.PubMedCrossRefGoogle Scholar
  123. 123.
    Wan QQ, Ye QF, Ma Y, Zhou JD. Genetic association of interleukin-1beta (−511C/T) and its receptor antagonist (86-bpVNTR) gene polymorphism with susceptibility to bacteremia in kidney transplant recipients. Transplant Proc. 2012;44(10):3026–8.PubMedCrossRefGoogle Scholar
  124. 124.
    Zhang AQ, Pan W, Gao JW, Yue CL, Zeng L, Gu W, et al. Associations between interleukin-1 gene polymorphisms and sepsis risk: a meta-analysis. BMC Med Genet. 2014;15:8.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Zapata-Tarres M, Arredondo-Garcia JL, Rivera-Luna R, Klunder-Klunder M, Mancilla-Ramirez J, Sanchez-Urbina R, et al. Interleukin-1 receptor antagonist gene polymorphism increases susceptibility to septic shock in children with acute lymphoblastic leukemia. Pediatr Infect Dis J. 2013;32(2):136–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Zhang DL, Zheng HM, Yu BJ, Jiang ZW, Li JS. Association of polymorphisms of IL and CD14 genes with acute severe pancreatitis and septic shock. World J Gastroenterol. 2005;11(28):4409–13.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Meyer NJ, Ferguson JF, Feng R, Wang F, Patel PN, Li M, et al. A functional synonymous coding variant in the IL1RN gene is associated with survival in septic shock. Am J Respir Crit Care Med. 2014;190(6):656–64.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Meyer NJ, Feng R, Li M, Zhao Y, Sheu CC, Tejera P, et al. IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist. Am J Respir Crit Care Med. 2013;187(9):950–9.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102(7):1369–76.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Gaudino M, Andreotti F, Zamparelli R, Di Castelnuovo A, Nasso G, Burzotta F, et al. The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation. 2003;108(Suppl 1):II195–9.PubMedGoogle Scholar
  131. 131.
    Schluter B, Raufhake C, Erren M, Schotte H, Kipp F, Rust S, et al. Effect of the interleukin-6 promoter polymorphism (−174G/C) on the incidence and outcome of sepsis. Crit Care Med. 2002;30(1):32–7.PubMedCrossRefGoogle Scholar
  132. 132.
    Roth-Isigkeit A, Hasselbach L, Ocklitz E, Bruckner S, Ros A, Gehring H, et al. Inter-individual differences in cytokine release in patients undergoing cardiac surgery with cardiopulmonary bypass. Clin Exp Immunol. 2001;125(1):80–8.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    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(1):75–82.PubMedCrossRefGoogle Scholar
  134. 134.
    Flores C, Ma SF, Maresso K, Wade MS, Villar J, Garcia JG. IL6 gene-wide haplotype is associated with susceptibility to acute lung injury. Transl Res. 2008;152(1):11–7.PubMedCrossRefGoogle Scholar
  135. 135.
    Moore KW, de Waal MR, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.PubMedCrossRefGoogle Scholar
  136. 136.
    Surbatovic M, Grujic K, Cikota B, Jevtic M, Filipovic N, Romic P, et al. Polymorphisms of genes encoding tumor necrosis factor-alpha, interleukin-10, cluster of differentiation-14 and interleukin-1ra in critically ill patients. J Crit Care. 2010;25(3):542. e541–548PubMedCrossRefGoogle Scholar
  137. 137.
    Stanilova SA, Miteva LD, Karakolev ZT, Stefanov CS. Interleukin-10-1082 promoter polymorphism in association with cytokine production and sepsis susceptibility. Intensive Care Med. 2006;32(2):260–6.PubMedCrossRefGoogle Scholar
  138. 138.
    Gallagher PM, Lowe G, Fitzgerald T, Bella A, Greene CM, McElvaney NG, et al. Association of IL-10 polymorphism with severity of illness in community acquired pneumonia. Thorax. 2003;58(2):154–6.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Schaaf BM, Boehmke F, Esnaashari H, Seitzer U, Kothe H, Maass M, et al. Pneumococcal septic shock is associated with the interleukin-10-1082 gene promoter polymorphism. Am J Respir Crit Care Med. 2003;168(4):476–80.PubMedCrossRefGoogle Scholar
  140. 140.
    Carregaro F, Carta A, Cordeiro JA, Lobo SM, Silva EH, Leopoldino AM. Polymorphisms IL10-819 and TLR-2 are potentially associated with sepsis in Brazilian patients. Mem Inst Oswaldo Cruz. 2010;105(5):649–56.PubMedCrossRefGoogle Scholar
  141. 141.
    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(3):1690–8.PubMedCrossRefGoogle Scholar
  142. 142.
    Aso Y. Plasminogen activator inhibitor (PAI)-1 in vascular inflammation and thrombosis. Front Biosci. 2007;12:2957–66.PubMedCrossRefGoogle Scholar
  143. 143.
    Song Y, Lynch SV, Flanagan J, Zhuo H, Tom W, Dotson RH, et al. Increased plasminogen activator inhibitor-1 concentrations in bronchoalveolar lavage fluids are associated with increased mortality in a cohort of patients with Pseudomonas aeruginosa. Anesthesiology. 2007;106(2):252–61.PubMedCrossRefGoogle Scholar
  144. 144.
    Ware LB, Matthay MA, Parsons PE, Thompson BT, Januzzi JL, Eisner MD. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med. 2007;35(8):1821–8.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Hermans PW, Hazelzet JA. Plasminogen activator inhibitor type 1 gene polymorphism and sepsis. Clin Infect Dis. 2005;41(Suppl 7):S453–8.PubMedCrossRefGoogle Scholar
  146. 146.
    Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem. 1993;268(15):10739–45.PubMedGoogle Scholar
  147. 147.
    Westendorp RG, Hottenga JJ, Slagboom PE. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet. 1999;354(9178):561–3.PubMedCrossRefGoogle Scholar
  148. 148.
    Menges T, Hermans PW, Little SG, Langefeld T, Boning O, Engel J, et al. Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet. 2001;357(9262):1096–7.PubMedCrossRefGoogle Scholar
  149. 149.
    Haralambous E, Hibberd ML, Hermans PW, Ninis N, Nadel S, Levin M. Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children. Crit Care Med. 2003;31(12):2788–93.PubMedCrossRefGoogle Scholar
  150. 150.
    Binder A, Endler G, Muller M, Mannhalter C, Zenz W. 4G4G genotype of the plasminogen activator inhibitor-1 promoter polymorphism associates with disseminated intravascular coagulation in children with systemic meningococcemia. J Thromb Haemost. 2007;5(10):2049–54.PubMedCrossRefGoogle Scholar
  151. 151.
    Garcia-Segarra G, Espinosa G, Tassies D, Oriola J, Aibar J, Bove A, et al. Increased mortality in septic shock with the 4G/4G genotype of plasminogen activator inhibitor 1 in patients of white descent. Intensive Care Med. 2007;33(8):1354–62.PubMedCrossRefGoogle Scholar
  152. 152.
    Sapru A, Hansen H, Ajayi T, Brown R, Garcia O, Zhuo H, et al. 4G/5G polymorphism of plasminogen activator inhibitor-1 gene is associated with mortality in intensive care unit patients with severe pneumonia. Anesthesiology. 2009;110(5):1086–91.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Madach K, Aladzsity I, Szilagyi A, Fust G, Gal J, Penzes I, et al. 4G/5G polymorphism of PAI-1 gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective, observational, genetic study. Crit Care. 2010;14(2):R79.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Yende S, Angus DC, Ding J, Newman AB, Kellum JA, Li R, et al. 4G/5G plasminogen activator inhibitor-1 polymorphisms and haplotypes are associated with pneumonia. Am J Respir Crit Care Med. 2007;176(11):1129–37.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Li L, Nie W, Zhou H, Yuan W, Li W, Huang W. Association between plasminogen activator inhibitor-1-675 4G/5G polymorphism and sepsis: a meta-analysis. PLoS One. 2013;8(1):e54883.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Chen QX, Wu SJ, Wang HH, Lv C, Cheng BL, Xie GH, et al. Protein C -1641A/−1654C haplotype is associated with organ dysfunction and the fatal outcome of severe sepsis in Chinese Han population. Hum Genet. 2008;123(3):281–7.PubMedCrossRefGoogle Scholar
  157. 157.
    Spek CA, Koster T, Rosendaal FR, Bertina RM, Reitsma PH. Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol. 1995;15(2):214–8.PubMedCrossRefGoogle Scholar
  158. 158.
    Walley KR, Russell JA. Protein C -1641 AA is associated with decreased survival and more organ dysfunction in severe sepsis. Crit Care Med. 2007;35(1):12–7.PubMedCrossRefGoogle Scholar
  159. 159.
    Russell JA, Wellman H, Walley KR. Protein C rs2069912 C allele is associated with increased mortality from severe sepsis in North Americans of East Asian ancestry. Hum Genet. 2008;123(6):661–3.PubMedCrossRefGoogle Scholar
  160. 160.
    Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA. 1997;277(16):1305–7.PubMedCrossRefGoogle Scholar
  161. 161.
    Kerlin BA, Yan SB, Isermann BH, Brandt JT, Sood R, Basson BR, et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood. 2003;102(9):3085–92.PubMedCrossRefGoogle Scholar
  162. 162.
    Benfield TL, Dahl M, Nordestgaard BG, Tybjaerg-Hansen A. Influence of the factor V Leiden mutation on infectious disease susceptibility and outcome: a population-based study. J Infect Dis. 2005;192(10):1851–7.PubMedCrossRefGoogle Scholar
  163. 163.
    Benfield T, Ejrnaes K, Juul K, Ostergaard C, Helweg-Larsen J, Weis N, et al. Influence of Factor V Leiden on susceptibility to and outcome from critical illness: a genetic association study. Crit Care. 2010;14(2):R28.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Bernard GR, Margolis BD, Shanies HM, Ely EW, Wheeler AP, Levy H, et al. Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest. 2004;125(6):2206–16.PubMedCrossRefGoogle Scholar
  165. 165.
    Tsantes AE, Tsangaris I, Bonovas S, Kopterides P, Rapti E, Dimopoulou I, et al. The effect of four hemostatic gene polymorphisms on the outcome of septic critically ill patients. Blood Coagul Fibrinolysis. 2010;21(2):175–81.PubMedCrossRefGoogle Scholar
  166. 166.
    Zhang J, He Y, Song W, Lu Y, Li P, Zou L, et al. Lack of association between factor V leiden and sepsis: a meta-analysis. Clin Appl Thromb Hemost. 2015;21(3):204–10.PubMedCrossRefGoogle Scholar
  167. 167.
    Nakada TA, Russell JA, Boyd JH, Aguirre-Hernandez R, Thain KR, Thair SA, et al. Beta2-adrenergic receptor gene polymorphism is associated with mortality in septic shock. Am J Respir Crit Care Med. 2010;181(2):143–9.PubMedCrossRefGoogle Scholar
  168. 168.
    Nakada TA, Russell JA, Wellman H, Boyd JH, Nakada E, Thain KR, et al. Leucyl/cystinyl aminopeptidase gene variants in septic shock. Chest. 2011;139(5):1042–9.PubMedCrossRefGoogle Scholar
  169. 169.
    Nakada TA, Russell JA, Boyd JH, McLaughlin L, Nakada E, Thair SA, et al. Association of angiotensin II type 1 receptor-associated protein gene polymorphism with increased mortality in septic shock. Crit Care Med. 2011;39(7):1641–8.PubMedCrossRefGoogle Scholar
  170. 170.
    Man M, Close SL, Shaw AD, Bernard GR, Douglas IS, Kaner RJ, et al. Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis. Pharmacogenomics J. 2013;13(3):218–26.PubMedCrossRefGoogle Scholar
  171. 171.
    Davila S, Wright VJ, Khor CC, Sim KS, Binder A, Breunis WB, et al. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet. 2010;42(9):772–6.PubMedCrossRefGoogle Scholar
  172. 172.
    Band G, Le QS, Jostins L, Pirinen M, Kivinen K, Jallow M, et al. Imputation-based meta-analysis of severe malaria in three African populations. PLoS Genet. 2013;9(5):e1003509.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Jallow M, Teo YY, Small KS, Rockett KA, Deloukas P, Clark TG, et al. Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet. 2009;41(6):657–65.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Timmann C, Thye T, Vens M, Evans J, May J, Ehmen C, et al. Genome-wide association study indicates two novel resistance loci for severe malaria. Nature. 2012;489(7416):443–6.PubMedCrossRefGoogle Scholar
  175. 175.
    Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Bresolin N, Clerici M, et al. Genome-wide identification of susceptibility alleles for viral infections through a population genetics approach. PLoS Genet. 2010;6(2):e1000849.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Fijen CA, Kuijper EJ, te Bulte MT, Daha MR, Dankert J. Assessment of complement deficiency in patients with meningococcal disease in The Netherlands. Clin Infect Dis. 1999;28(1):98–105.PubMedCrossRefGoogle Scholar
  177. 177.
    Fry AE, Griffiths MJ, Auburn S, Diakite M, Forton JT, Green A, et al. Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria. Hum Mol Genet. 2008;17(4):567–76.PubMedCrossRefGoogle Scholar
  178. 178.
    Reilly JP, Meyer NJ, Shashaty MG, Feng R, Lanken PN, Gallop R, et al. ABO blood type A is associated with increased risk of ARDS in whites following both major trauma and severe sepsis. Chest. 2014;145(4):753–61.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Mu J, Myers RA, Jiang H, Liu S, Ricklefs S, Waisberg M, et al. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs. Nat Genet. 2010;42(3):268–71.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Naitza S, Porcu E, Steri M, Taub DD, Mulas A, Xiao X, et al. A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation. PLoS Genet. 2012;8(1):e1002480.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Mikacenic C, Reiner AP, Holden TD, Nickerson DA, Wurfel MM. Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of interindividual difference in TLR1/2-mediated responses. Genes Immun. 2013;14(1):52–7.PubMedCrossRefGoogle Scholar
  182. 182.
    Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, Cho RJ, et al. A network-based analysis of systemic inflammation in humans. Nature. 2005;437(7061):1032–7.PubMedCrossRefGoogle Scholar
  183. 183.
    Johnson SB, Lissauer M, Bochicchio GV, Moore R, Cross AS, Scalea TM. Gene expression profiles differentiate between sterile SIRS and early sepsis. Ann Surg. 2007;245(4):611–21.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Payen D, Lukaszewicz AC, Belikova I, Faivre V, Gelin C, Russwurm S, et al. Gene profiling in human blood leucocytes during recovery from septic shock. Intensive Care Med. 2008;34(8):1371–6.PubMedCrossRefGoogle Scholar
  185. 185.
    Tang BM, Huang SJ, McLean AS. Genome-wide transcription profiling of human sepsis: a systematic review. Crit Care. 2010;14(6):R237.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Tang BM, McLean AS, Dawes IW, Huang SJ, Lin RC. The use of gene-expression profiling to identify candidate genes in human sepsis. Am J Respir Crit Care Med. 2007;176(7):676–84.PubMedCrossRefGoogle Scholar
  187. 187.
    Tang BM, McLean AS, Dawes IW, Huang SJ, Cowley MJ, Lin RC. Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients. Crit Care Med. 2008;36(4):1125–8.PubMedCrossRefGoogle Scholar
  188. 188.
    Wong HR, Cvijanovich NZ, Allen GL, Thomas NJ, Freishtat RJ, Anas N, et al. Corticosteroids are associated with repression of adaptive immunity gene programs in pediatric septic shock. Am J Respir Crit Care Med. 2014;189(8):940–6.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Wong HR, Cvijanovich N, Allen GL, Lin R, Anas N, Meyer K, et al. Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum. Crit Care Med. 2009;37(5):1558–66.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012;10(6):701–6.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Stengaard-Pedersen K, Thiel S, Gadjeva M, Moller-Kristensen M, Sorensen R, Jensen LT, et al. Inherited deficiency of mannan-binding lectin-associated serine protease 2. N Engl J Med. 2003;349(6):554–60.PubMedCrossRefGoogle Scholar
  192. 192.
    Brenmoehl J, Herfarth H, Gluck T, Audebert F, Barlage S, Schmitz G, et al. Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients. Intensive Care Med. 2007;33(9):1541–8.PubMedCrossRefGoogle Scholar
  193. 193.
    Yuan FF, Wong M, Pererva N, Keating J, Davis AR, Bryant JA, et al. FcgammaRIIA polymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol. 2003;81(3):192–5.PubMedCrossRefGoogle Scholar
  194. 194.
    Moens L, Van Hoeyveld E, Verhaegen J, De Boeck K, Peetermans WE, Bossuyt X. Fcgamma-receptor IIA genotype and invasive pneumococcal infection. Clin Immunol. 2006;118(1):20–3.PubMedCrossRefGoogle Scholar
  195. 195.
    Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, et al. A mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet. 2007;39(4):523–8.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Michalek J, Svetlikova P, Fedora M, Klimovic M, Klapacova L, Bartosova D, et al. Bactericidal permeability increasing protein gene variants in children with sepsis. Intensive Care Med. 2007;33(12):2158–64.PubMedCrossRefGoogle Scholar
  197. 197.
    Stassen NA, Breit CM, Norfleet LA, Polk Jr HC. IL-18 promoter polymorphisms correlate with the development of post-injury sepsis. Surgery. 2003;134(2):351–6.PubMedCrossRefGoogle Scholar
  198. 198.
    Yende S, Angus DC, Kong L, Kellum JA, Weissfeld L, Ferrell R, et al. The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia. FASEB J. 2009;23(8):2403–11.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Das R, Subrahmanyan L, Yang IV, van Duin D, Levy R, Piecychna M, et al. Functional polymorphisms in the gene encoding macrophage migration inhibitory factor are associated with Gram-negative bacteremia in older adults. J Infect Dis. 2014;209(5):764–8.PubMedCrossRefGoogle Scholar
  200. 200.
    Renner P, Roger T, Bochud PY, Sprong T, Sweep FC, Bochud M, et al. A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease. FASEB J. 2012;26(2):907–16.PubMedCrossRefGoogle Scholar
  201. 201.
    Lehmann LE, Book M, Hartmann W, Weber SU, Schewe JC, Klaschik S, et al. A MIF haplotype is associated with the outcome of patients with severe sepsis: a case control study. J Transl Med. 2009;7:100.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Stassen NA, Leslie-Norfleet LA, Robertson AM, Eichenberger MR, Polk Jr HC. Interferon-gamma gene polymorphisms and the development of sepsis in patients with trauma. Surgery. 2002;132(2):289–92.PubMedCrossRefGoogle Scholar
  203. 203.
    Flores C, Maca-Meyer N, Perez-Mendez L, Sanguesa R, Espinosa E, Muriel A, et al. A CXCL2 tandem repeat promoter polymorphism is associated with susceptibility to severe sepsis in the Spanish population. Genes Immun. 2006;7(2):141–9.PubMedCrossRefGoogle Scholar
  204. 204.
    Lorente L, Martin M, Plasencia F, Sole-Violan J, Blanquer J, Labarta L, et al. The 372 T/C genetic polymorphism of TIMP-1 is associated with serum levels of TIMP-1 and survival in patients with severe sepsis. Crit Care. 2013;17(3):R94.PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Moretti EW, Morris RW, Podgoreanu M, Schwinn DA, Newman MF, Bennett E, et al. APOE polymorphism is associated with risk of severe sepsis in surgical patients. Crit Care Med. 2005;33(11):2521–6.PubMedCrossRefGoogle Scholar
  206. 206.
    Nakada TA, Russell JA, Boyd JH, Thair SA, Walley KR. Identification of a nonsynonymous polymorphism in the SVEP1 gene associated with altered clinical outcomes in septic shock. Crit Care Med. 2015;43(1):101–8.PubMedCrossRefGoogle Scholar
  207. 207.
    Marshall RP, Webb S, Bellingan GJ, Montgomery HE, Chaudhari B, McAnulty RJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;166(5):646–50.PubMedCrossRefGoogle Scholar
  208. 208.
    Harding D, Baines PB, Brull D, Vassiliou V, Ellis I, Hart A, et al. Severity of meningococcal disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism. Am J Respir Crit Care Med. 2002;165(8):1103–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • John P. Reilly
    • 1
  • Nuala J. Meyer
    • 2
  • Jason D. Christie
    • 3
    Email author
  1. 1.Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Division of Pulmonary Allergy, and Critical Care Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations