Abstract
The systemic inflammatory response syndrome (SIRS) is associated with activation of innate immunity. We studied the association between mortality and measures of disease severity in the intensive care unit (ICU) and functional polymorphisms in genes coding for Toll-like receptor 4 (TLR4), macrophage migratory inhibitory factor (MIF), tumour necrosis factor (TNF) and lymphotoxin-alpha (LTA). Two hundred thirty-three patients with severe SIRS were recruited from one general adult ICU in a tertiary centre in the UK. DNA from patients underwent genotyping by 5′ nuclease assay. Genotype was compared to phenotype. Primary outcome was mortality in ICU. Minor allele frequencies were TLR4 +896G 7%, MIF 173C 16%, TNF −238A 10% and LTA +252G 34%. The frequency of the hypoimmune minor allele TNF −238A was significantly higher in patients who died in ICU compared to those who survived (p = 0.0063) as was the frequency of the two haplotypes LTA +252G, TNF −1031T, TNF −308G, TNF −238A and LTA +252G, TNF−1031T, TNF−308A and TNF−238A (p = 0.0120 and 0.0098, respectively). These findings re-enforce the view that a balanced inflammatory/anti-inflammatory response is the most important determinant of outcome in sepsis. Genotypes that either favour inflammation or its counter-regulatory anti-inflammatory response are likely to influence mortality and morbidity.
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Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191
Bayley JP, Ottenhoff TH, Verweij CL (2004) Is there a future for TNF promoter polymorphisms? Genes Immun 5:315–329
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (1992) 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 101:1644–1655
Bosshart H, Heinzelmann M (2007) Targeting bacterial endotoxin: two sides of a coin. Ann NY Acad Sci 1096:1–17
Brun-Buisson C (2000) The epidemiology of the systemic inflammatory response. Intensive Care Med 26(Suppl 1):S64–S74
Child NJ, Yang IA, Pulletz MC, de Courcy-Golder K, Andrews AL, Pappachan VJ, Holloway JW (2003) Polymorphisms in Toll-like receptor 4 and the systemic inflammatory response syndrome. Biochem Soc Trans 31:652–653
De Benedetti F, Meazza C, Vivarelli M, Rossi F, Pistorio A, Lamb R, Lunt M, Thomson W, Ravelli A, Donn R, Martini A (2003) Functional and prognostic relevance of the −173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 48:1398–1407
de Kok JB, Wiegerinck ET, Giesendorf BA, Swinkels DW (2002) Rapid genotyping of single nucleotide polymorphisms using novel minor groove binding DNA oligonucleotides (MGB probes). Hum Mutat 19:554–559
Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W (1997) Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 3:678–681
Donn R, Alourfi Z, De Benedetti F, Meazza C, Zeggini E, Lunt M, Stevens A, Shelley E, Lamb R, Ollier WE, Thomson W, Ray D (2002) Mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. Arthritis Rheum 46:2402–2409
Donn RP, Shelley E, Ollier WE, Thomson W (2001) A novel 5′-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 44:1782–1785
Dupont WD, Plummer WD Jr (1990) Power and sample size calculations. A review and computer program. Control Clin Trials 11:116–128
Ertel W, Kremer JP, Kenney J, Steckholzer U, Jarrar D, Trentz O, Schildberg FW (1995) Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood 85:1341–1347
Fong CW, Siddiqui AH, Mark DF (1995) Characterization of protein complexes formed on the repressor elements of the human tumor necrosis factor alpha gene. J Interferon Cytokine Res 15:887–895
Gordon AC, Lagan AL, Aganna E, Cheung L, Peters CJ, McDermott MF, Millo JL, Welsh KI, Holloway P, Hitman GA, Piper RD, Garrard CS, Hinds CJ (2004) TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study. Genes Immun 5:631–640
Harrison DA, Welch CA, Eddleston JM (2006) The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care 10:R42
Holmes CL, Russell JA, Walley KR (2003) Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy. Chest 124:1103–1115
Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE (1999) Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 27:1230–1251
Kaluza W, Reuss E, Grossmann S, Hug R, Schopf RE, Galle PR, Maerker-Hermann E, Hoehler T (2000) Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism. J Invest Dermatol 114:1180–1183
Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829
Knight JC, Keating BJ, Kwiatkowski DP (2004) Allele-specific repression of lymphotoxin-alpha by activated B cell factor-1. Nat Genet 36:394–399
Leaver SK, Finney SJ, Burke-Gaffney A, Evans TW (2007) Sepsis since the discovery of Toll-like receptors: disease concepts and therapeutic opportunities. Crit Care Med 35:1404–1410
Lederer JA, Rodrick ML, Mannick JA (1999) The effects of injury on the adaptive immune response. Shock 11:153–159
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 29:530–538
Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 14:143–149
Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487–501
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
O’Sullivan ST, Lederer JA, Horgan AF, Chin DH, Mannick JA, Rodrick ML (1995) Major injury leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin-12 production associated with decreased resistance to infection. Ann Surg 222:482–490 discussion 490-2
Osuchowski MF, Welch K, Siddiqui J, Remick DG (2006) Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol 177:1967–1974
Rahman P, Siannis F, Butt C, Farewell V, Peddle L, Pellett F, Gladman D (2006) TNFalpha polymorphisms and risk of psoriatic arthritis. Ann Rheum Dis 65:919–923
Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP (1995) The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. Jama 273:117–123
Reilly BM, Evans AT, Schaider JJ, Das K, Calvin JE, Moran LA, Roberts RR, Martinez E (2002) Impact of a clinical decision rule on hospital triage of patients with suspected acute cardiac ischemia in the emergency department. Jama 288:342–350
Renner P, Roger T, Calandra T (2005) Macrophage migration inhibitory factor: gene polymorphisms and susceptibility to inflammatory diseases. Clin Infect Dis 41(Suppl 7):S513–S519
Roger T, David J, Glauser MP, Calandra T (2001) MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414:920–924
Sutherland AM, Russell JA (2005) Issues with polymorphism analysis in sepsis. Clin Infect Dis 41(Suppl 7):S396–S402
Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis- Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707–710
Ware CF (2005) Network communications: lymphotoxins, LIGHT, and TNF. Annu Rev Immunol 23:787–819
Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI, Vandenbroucke JP (1997) Genetic influence on cytokine production and fatal meningococcal disease. Lancet 349:170–173
Acknowledgements
The authors would like to acknowledge the patients and staff of the General Intensive Care unit, Southampton General Hospital.
Conflict of interest statement
The authors declare that they have no conflict of interest.
Contributions
VJP, IAY and JWH designed the study. TC, NJAC, DKM, SMN, MCKP and KdeCG recruited patients. TC, NJAC, DKM, SNM, MR-Z and IAY performed genotyping. VJP, TC, SB and IAY undertook statistical analysis. VJP, TC and JWH drafted the manuscript.
Sources of support
IAY was supported by an Allen+Hanburys/Thoracic Society of Australia and New Zealand Respiratory Research Fellowship. JWH was supported by a Medical Research Council (MRC) Research Training Fellowship. This study was supported by the University of Southampton. The sources of funding had no role in the study design, study performance or decision to publish the results.
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Pappachan, J.V., Coulson, T.G., Child, N.J.A. et al. Mortality in adult intensive care patients with severe systemic inflammatory response syndromes is strongly associated with the hypo-immune TNF −238A polymorphism. Immunogenetics 61, 657–662 (2009). https://doi.org/10.1007/s00251-009-0395-6
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DOI: https://doi.org/10.1007/s00251-009-0395-6