Genetic Epidemiology of Sepsis and Septic Shock

ABSTRACT

Sepsis affects more than 750,000 people each year in the United States alone, with a mortality rate of over 35% making it one of the leading causes of death in developed countries. Recent genetic analysis has provided us with several candidate genes, which have become the focus of genetic research in sepsis. The analysis of single nucleotide polymorphisms among various genes, such as those coding for pro- and antiinflammatory mediators, in the septic response has the potential to develop into prediction tools that will permit the clinician to more precisely determine the type of therapy that a particular patient should receive. However, unraveling the genetic variation in sepsis is complicated, and close attention must be paid to study design issues, including the selection of an appropriate study population and sample size and understanding gene-environment interactions. We must anticipate that future implementation of genetic information will lend itself to additional ethical dilemmas when we are faced with allocation of resources.

KEYWORDS

Sepsis - genetics - genomics - single nucleotide polymorphisms - gene expression - microarrays

REFERENCES

• 1 Angus D C, Linde-Zwirble W T, Lidicker J, Clermont G, Carcillo J, Pinsky M R. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.  Crit Care Med. 2001;  29 1303-1310
• 2 Sands K E, Bates D W, Lanken P N et al.. Epidemiology of sepsis syndrome in eight academic medical centers. Academic Medical Center Consortium Sepsis Project Working Group.  JAMA. 1997;  278 234-240
• 3 Rangel-Frausto M S, Pittet D, Costigan M, Hwang T, Davis C S, Wenzel R P. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study.  JAMA. 1995;  273 117-123
• 4 Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment.  Crit Care Med. 1997;  25 1095-1100
• 5 Esmon C T. Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?.  Blood. 2000;  95 1113-1116
• 6 Matthay M A. Severe sepsis: a new treatment with both anticoagulant and antiinflammatory properties [editorial].  N Engl J Med. 2001;  344 759-762
• 7 Annane D, Sebille V, Charpentier C et al.. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.  JAMA. 2002;  288 862-871
• 8 Bernard G R, Vincent J L, Laterre P F et al.. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709
• 9 Rivers E, Nguyen B, Havstad S et al.. Early goal-directed therapy in the treatment of severe sepsis and septic shock.  N Engl J Med. 2001;  345 1368-1377
• 10 Sorensen T I, Nielsen G G, Andersen P K, Teasdale T W. Genetic and environmental influences on premature death in adult adoptees.  N Engl J Med. 1988;  318 727-732
• 11 Collins F S. Shattuck lecture: medical and societal consequences of the Human Genome Project.  N Engl J Med. 1999;  341 28-37
• 12 Nadel S, Newport M J, 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;  174 878-880
• 13 Fang X M, 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
• 14 Stuber F, Udalova I A, Book M 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 42-50
• 15 Stuber F, Petersen M, Bokelmann F, Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis.  Crit Care Med. 1996;  24 381-384
• 16 Mira J P, Cariou A, Grall F et al.. Association of TNF2, a TNF-α promoter polymorphism, with septic shock susceptibility and mortality. A multicenter study.  JAMA. 1999;  282 561-568
• 17 Cohen J. The immunopathogenesis of sepsis.  Nature. 2002;  420 885-891
• 17a Cobb J P, Laramie J M, Stormo G D et al.. Sepsis gene expression profiling: murine splenic compared with hepatic responses determined by using complementary DNA microarrays.  Crit Care Med. 2002;  30 2711-2721
• 17b Samuel J E, Kiss K, Varghees S. Molecular pathogenesis of Coxiella burnetii in a genomics era.  Ann N Y Acad Sci. 2003;  990 653-663
• 17c Hopf H W. Molecular diagnostics of injury and repair responses in critical illness: what is the future of “monitoring” in the intensive care unit?.  Crit Care Med. 2003;  31 S518-S523
• 18 Stephens J C, Schneider J A, Tanguay D A et al.. Haplotype variation and linkage disequilibrium in 313 human genes.  Science. 2001;  293 489-493
• 19 Kumar A, Short J, Parrillo J E. Genetic factors in septic shock.  JAMA. 1999;  282 579-581
• 20 Kellum J A, Angus D C. Genetic variation and risk of sepsis.  Minerva Anestesiol. 2003;  69 245-253
• 21 Lowe P R, Galley H F, Abdel-Fattah A, Webster N R. Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in critically ill patients.  Crit Care Med. 2003;  31 34-38
• 22 Gallagher P M, Lowe G, Fitzgerald T et al.. Association of IL-10 polymorphism with severity of illness in community acquired pneumonia.  Thorax. 2003;  58 154-156
• 23 Wood K A, Kellum J A, Ferrell R et al.. The IL-10 - 819T polymorphism is associated with increased susceptibility to severe sepsis [abstract].  Crit Care. 2003;  7(Suppl 2) S21
• 23a Martin G S, Mannino D M, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000.  N Engl J Med. 2003;  348 1546-1554
• 24 Holmes C L, Russell J A, Walley K R. Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy.  Chest. 2003;  124 1103-1115
• 25 Risch N J. Searching for genetic determinants in the new millennium.  Nature. 2000;  405 847-856
• 26 Zhang S, Sha Q, Chen H S, Dong J, Jiang R. Transmission/disequilibrium test based on haplotype sharing for tightly linked markers.  Am J Hum Genet. 2003;  73 566-579
• 27 Iles M M. Linkage and association: the transmission/disequilibrium test for QTLs.  Methods Mol Biol. 2002;  195 101-138
• 28 Lee W C. Transmission/disequilibrium test when neither parent is available in some families: a noniterative approach.  J Cancer Epidemiol Prev. 2002;  7 97-103
• 29 Devlin B, Roeder K, Wasserman L. Genomic control, a new approach to genetic-based association studies.  Theor Popul Biol. 2001;  60 155-166
• 30 Bacanu S A, Devlin B, Roeder K. The power of genomic control.  Am J Hum Genet. 2000;  66 1933-1944
• 31 Brennan P. Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it?.  Carcinogenesis. 2002;  23 381-387
• 32 Lynch M, Walsh B. Genotype X environment interactions. In Genetics and Analysis of Quantitative Ttraits. Sunderland, MA; Sinauer Associates 1998: 657-685
• 33 Wood K A, Angus D C. Reducing variation and standardizing practice: the key to better ICU care?.  Curr Opin Crit Care. 2001;  7 281-283
• 34 Wood K A, Huang D, Angus D C. Improving clinical trial design in acute lung injury.  Crit Care Med. 2003;  31 S305-S311
• 35 Cooper R, Rotimi C, Ataman S et al.. The prevalence of hypertension in seven populations of west African origin.  Am J Public Health. 1997;  87 160-168
• 36 Hendrie H C, Ogunniyi A, Hall K S et al.. Incidence of dementia and Alzheimer disease in two communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana.  JAMA. 2001;  285 739-747
• 37 Cooper R S. Gene-environment interactions and the etiology of common complex disease.  Ann Intern Med. 2003;  139 437-440
• 38 Huang Q, Liu D, Majewski P et al.. The plasticity of dendritic cell responses to pathogens and their components.  Science. 2001;  294 870-875
• 39 Pinsky M R. Genetic testing: costs and access to intensive care unit care.  Crit Care Med. 2003;  31 S411-S415