Genetic Susceptibility to Infection and Sepsis

  • Bradley D. Freeman
  • Barbara A. Zehnbauer
Part of the Perspectives on Critical Care Infectious Diseases book series (CCID, volume 2)


It is well accepted that an individual’s genetic background plays an influential role in determining the susceptibility to, and outcome from, a variety of chronic illnesses. This is particularly true of many malignancies in which the precise relationships between genetic abnormalities and clinical manifestations have been abundantly described. In contrast, while intensivists have long appreciated that acutely ill individuals display enormous inter-patient variability in response to uniform insults, the possibility that genetic differences may be responsible for these individualized responses has largely been ignored. In this review, we will discuss recent studies that examine the clinical manifestations of acute illness in the context of genetic variants of the inflammatory and coagulation cascades. Ultimately, this gene-based approach will be essential to furthering our understanding of critical illness, identifying new therapeutic targets, and developing novel treatment strategies.


Tumor Necrosis Factor Septic Shock Severe Sepsis Cerebral Malaria Meningococcal Disease 
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  1. 1.
    Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265:2037–2048.PubMedCrossRefGoogle Scholar
  2. 2.
    Zehnbauer BA, Romkes M, Carcillo JA. Textbook of Critical Care. In: Ayres SM, Grenvick A, Holbrook PR, Shoemaker WC, eds. Textbook of Critical Care. 4th ed. Philadelphia: W.B. Saunders Company; 1999.Google Scholar
  3. 3.
    Sorensen TIA, Nielsen GG, Anderson PK, Teasdale TW. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med. 1988;318:727–732.PubMedCrossRefGoogle Scholar
  4. 4.
    Winkler C, Modi W, Smith MW, et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science. 1998;279:389–393.PubMedCrossRefGoogle Scholar
  5. 5.
    Hohler T, Kruger A, Gerken G, Schneider PM, Buschenfelde KHMZ, Rittner C. A tumor necrosis factor-_ promotor polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol. 1998;111:579–582.PubMedCrossRefGoogle Scholar
  6. 6.
    Cabrera M, Shaw MA, Sharpies C, et al. Polymorphism in tumor necrosis factor genes associated with mucocutaneous Leishmaniasis. J Exp Med. 1995; 182:1259–1264.PubMedCrossRefGoogle Scholar
  7. 7.
    Natanson C, Hoffman WD, Suffredini AF, Eichacker PQ, Danner RL. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann Int Med. 1994;120:771–783.PubMedGoogle Scholar
  8. 8.
    Nedwin GE, Naylor SL, Sakaguchi AY. Human lymphotoxin and tumor necrosis factor genes: structure, homology, and chromosomal localization. Nuc Acid Res. 1985;13:6351–6373.CrossRefGoogle Scholar
  9. 9.
    Pociot F, Briant L, Jongeneel CV. Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol. 1993;23:224–231.PubMedCrossRefGoogle Scholar
  10. 10.
    McGuire W, Hill AVS, Allsopp CEM, Greenwood BM, Kwiatkowski D. Variation in the TNF promotor region associated with susceptibility to cerebral malaria. Nature. 1994;371:508–511.PubMedCrossRefGoogle Scholar
  11. 11.
    Nadel S, Newport MJ, Booy R, Levin M. Variation in the tumor necrosis factor gene promotor region may be associated with death from meningococcal disease. J Infect Dis. 2000;174:878–880.CrossRefGoogle Scholar
  12. 12.
    Stuber F, Peterson M, Bokelmann F, Schade U. A genomic polymorphism with in the tumor necrosis factor locus influences plasma tumor necrosis factor concentrations and outcome of patients with severe sepsis. Crit Care Med. 1996;24:381–384.PubMedCrossRefGoogle Scholar
  13. 13.
    Mira, J. P., Cariou, A., Grall, F., Delclaux, C., Losser, M. R., Heshmati, F., Cheval, C., Monchi, M., Teboul, J. L., Riche, F., Leleu, G., Arbibe, L., Mignon, A., Delpech, M., and Dhainaut, J. P. Association of TNF2, a TNF promotor polymorphism, with septic shock susceptibility and mortality — a multicenter study. JAMA 282(6), 561–568. 8-11-1999.Google Scholar
  14. 14.
    Majetschak M, Flohe S, Obertacke U, et al. Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg. 1999;230:207–214.PubMedCrossRefGoogle Scholar
  15. 15.
    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;27:1330–1334.PubMedCrossRefGoogle Scholar
  16. 16.
    Dinarello CA. Is there an interleukin-1 genetic predisposition to developing severe sepsis? Crit Care Med. 1999;27:1397–1398.PubMedCrossRefGoogle Scholar
  17. 17.
    Hirsch E, Irikura VM, Paul SM. Functions of interleukin-1 receptor antagonist in gene knock-out and over-producing mice. PNAS 1996;93:11008–11013.PubMedCrossRefGoogle Scholar
  18. 18.
    Clay FE, Cork MJ, Tarlow JK. Interleukin-1 receptor antagonist gene polymorphism association with lichen sclerosis. Hum Genet. 1994;94:407–410.PubMedCrossRefGoogle Scholar
  19. 19.
    Blakemore AI, Tarlow JK, Cork MJ. Interleukin-1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus. Arthrit Rheum. 1994;37:1380–1385.CrossRefGoogle Scholar
  20. 20.
    Mansfield JC, Holden H, Tarlow JK. Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist. Crit Care Med. 1994;106:637–642.Google Scholar
  21. 21.
    Hermans PWM, Hibberd ML, Booy R, et al. 4G/5G promotor polymorphism in the plasminogen-activator inhibitor-1 gene and outcome of meningococcal disease. Lancet. 1999;354:556–600.PubMedCrossRefGoogle Scholar
  22. 22.
    Westendorp RGJ, Hottenga JJ, Slagboom PE. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet. 1999;354:561–563.PubMedCrossRefGoogle Scholar
  23. 23.
    Pannekoek H, Veerman H, Lambers H. Endothelial plasminogen activator-1: a new member of the serpin gene family. EMBO J. 1986;5:2539–2544.PubMedGoogle Scholar
  24. 24.
    Kornelisse RF, Hazelzet JA, Savelkoul HFJ. The relationship between plasminogen activator-1 and pro-inflammatory and counter-inflammatory mediators in children with meningococcal septic shock. J Infect Dis. 1996; 173:1148–1156.PubMedCrossRefGoogle Scholar
  25. 25.
    Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promotor of the plasminogen activoator-1 (PAI-1) gene respond differently to interleukin-1 in HEPG2 cells. J Biol Chem. 1993;268:10739–10745.PubMedGoogle Scholar
  26. 26.
    Service RF. Microchip arrays put DNA on the spot. Science. 1998;282:396–399.PubMedCrossRefGoogle Scholar
  27. 27.
    Chen X, Zehnbauer B, Gnirke A, Kwok P-Y. Fluorescence energy transfer detection as a homogeneous DNA diagnostic method. PNAS. 1997;94:10756–10761.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Bradley D. Freeman
    • 1
  • Barbara A. Zehnbauer
    • 2
  1. 1.Departments of SurgeryWashington University School of MedicineSt. LouisUSA
  2. 2.Departments of PathologyWashington University School of MedicineSt. LouisUSA

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