Abstract
Introduction
Early prediction of postoperative sepsis remains an enormous clinical challenge. Association of TNF-α-308 G/A polymorphism with sepsis remains controversial. We, therefore, investigated this polymorphism with serum levels of cytokines TNF-α, IL-6, and IL-8 in relation to development of sepsis following major gastrointestinal surgery.
Methods
Two hundred and thirty-nine patients undergoing major gastrointestinal surgery were enrolled. Polymorphism was studied through the analysis of restriction fragments of Nco1-digested DNA with the polymerase chain reaction. All patients were followed for 1 month following surgery for evidence of sepsis. Levels of serum cytokines TNF-α, IL-6, and IL-8 were measured preoperatively and postoperatively by enzyme-linked immunosorbent assay (ELISA).
Results
Forty-seven (19.66 %) patients developed postoperative sepsis. Patients with postoperative sepsis were significantly (p = 0.002) more likely to possess AA homozygous genotype with higher capacity to produce cytokines TNF-α (p < 0.0001), IL-6 (p < 0.0001), and IL-8 (p < 0.0001) as compared to other genotypes. When compared with patients carrying at least one G allele, the AA genotype was associated with a significantly higher probability (odds ratio (OR) = 4.17; p = 0.003; 95 % confidence interval (CI) = 1.5–11.48) of developing sepsis. Compared with the GG genotype, AA was associated with a significantly higher probability (OR = 5.18; p = 0.0008; 95 % CI = 1.82–14.76) of sepsis development.
Conclusion
TNF-α-308 G/A polymorphism is significantly associated with the development of postoperative sepsis and with increased expression of cytokines TNF-α, IL-6, and IL-8.
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References
Faist E, Wichmann M, Kim C: Immunosuppression and immunomodulation in surgical patients. Curr Opin Crit Care 1997;3:293-298.
Beutler B, Grau GE: Tumor Necrosis Factor in the pathogenesis of infectious diseases. Crit Care Med 1993;21:S423-435.
Bazzoni F, Beutler B: The Tumor Necrosis Factor ligand and receptor families. N Engl J Med 1996;334:1717-1725.
Wheeler AP, Bernard GR: Treating patients with severe sepsis. N Engl J Med 1999;340:207-214.
Debets JM, Kampmeijer R, van der Linden MP, Buurman WA, van der Linden CJ: Plasma Tumor Necrosis Factor and mortality in critically ill septic patients. Crit Care Med 1989;17:489-494.
Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI, Vandenbroucke JP: Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997;349:170-173.
Rink L, Kirchner H: Recent progress in the tumor necrosis factor-alpha field. Int Arch Allergy Immunol 1996;111:199-209.
Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte LB, Duff GW: An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles. J Exp Med 1993;177:557-560.
Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riché 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.
Appoloni O, Dupont E, Vandercruys M, Andriens M, Duchateau J, Vincent JL: Association of tumor necrosis factor-2 allele with plasma tumor necrosis factor-alpha levels and mortality from septic shock. Am J Med 2001;110:486-488.
Stuber F, Udalova IA, Book M, Drutskaya LN, Kuprash DV, Turetskaya RL, Schade FU, Nedospasov SA: -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 1996;46:42-50.
O’Keefe GE, Hybki DL, Munford RS: The G-->A single nucleotide polymorphism at the -308 position in the tumor necrosis factor-alpha promoter increases the risk for severe sepsis after trauma. J Trauma 2002;52:817-825.
Tang GJ, Huang SL, Yien HW, Chen WS, Chi CW, Wu CW, Lui WY, Chiu JH, Lee TY: Tumor necrosis factor gene polymorphism and septic shock in surgical infection. Crit Care Med 2000;28:2733-2736.
Louis E, Franchimont D, Piron A, Gevaert Y, Schaaf-Lafontaine N, Roland S Mahieu P, Malaise M, De Groote D, Louis R, Belaiche J: Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 1998;113:401-406.
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 USA. 1997;94:3195-3199.
Kothari N, Bogra J, Abbas H, Kohli M, Malik A, Kothari D, Srivastava S, Singh PK: Tumor necrosis factor gene polymorphism results in high TNF level in sepsis and septic shock. Cytokine 2013;61:676-681.
Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL: Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation. J Inflamm 1996;46:32-41.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA Schein RM, Sibbald WJ: 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;101:1644-1655.
Allen RA, Lee EM, Roberts DH, Park BK, Pirmohamed M: Polymorphisms in the TNF-alpha and TNF-receptor genes in patients with coronary artery disease. Eur J Clin Invest 2001;31:843-851.
Majetschak M, Flohe S, Obertacke U, Schroder J, Staubach K, Nast-Kolb D, Schade FU, Stuber F: Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg 1999;230:207-214.
Duan ZX, Gu W, Zhang LY, Jiang DP, Zhou J, Du DY, Zen L, Chen KH, Liu Q, Jiang JX: Tumor necrosis factor alpha gene polymorphism is associated with the outcome of trauma patients in Chinese Han population. J Trauma 2011;70:954-958.
Bittar MN, Carey JA, Barnard JB, Pravica V, Deiraniya AK, Yonan N, Hutchinson IV: Tumor necrosis factor alpha influences the inflammatory response after coronary surgery. Ann Thorac Surg 2006;81:132-137.
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.
Read RC, Teare DM, Pridmore AC, Naylor SC, Timms JM, Kaczmarski EB, Borrow R, Wilson AG: The tumor necrosis factor polymorphism TNF (-308) is associated with susceptibility to meningococcal sepsis, but not with lethality. Crit Care Med 2009;37:1237-1243.
Strey CW, Marquez-Pinilla RM, Markiewski MM, Siegmund B, Oppermann E, John Lambris JD, Bechstein WO: Early post-operative measurement of cytokine plasma levels combined with pre-operative bilirubin levels identify high-risk patients after liver resection. Int J Mol Med 2011;27:447-454.
Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO: Heritable major histocompatibility complex class II–associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 1990;87:1233-1237.
Hack CE, De Groot ER, Felt-Bersma RJ, Nuijens JH, Strack Van Schijndel RJ, Eerenberg-Belmer AJ, Eerenberg-Belmer AJ, Thijs LG, Aarden LA: Increased plasma levels of interleukin-6 in sepsis. Blood 1989;74:1704-1710.
Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M: Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 1992;215:356-362.
Hack CE, Hart M, van Schijndel RJ, Eerenberg AJ, Nuijens JH, Thijs LG, Aarden LA: Interleukin-8 in sepsis: relation to shock and inflammatory mediators. Infect Immun 1992;60:2835-2842.
Giannoudis PV, Smith MR, Evans RT, Bellamy MC, Guillou PJ: Serum CRP and IL-6 levels after trauma. Not predictive of septic complications in 31 patients. Acta Orthop Scand 1998;69:184-188.
Majetschak M, Krehmeier U, Ostroverkh L, Blömeke B, Schäfer M: Alterations in leukocyte function following surgical trauma: differentiation of distinct reaction types and association with tumor necrosis factor gene polymorphisms. Clin Diagn Lab Immunol 2005;12:296-303.
Tang R, Chen HH, Wang YL, Changchien CR, Chen JS, Hsu KC, Chiang JM, Wang JY: Risk factors for surgical site infection after elective resection of the colon and rectum: a single-center prospective study of 2,809 consecutive patients. Ann Surg 2001;234:181-189.
Offner PJ, Moore EE, Biffl WL: Male gender is a risk factor for major infections after surgery. Arch Surg 1999;134:935-940.
Velasco E, Thuler LC, Martins CA, Dias LM, Conalves VM: Risk factors for infectious complications after abdominal surgery for malignant disease. Am J Infect Control 1996;24:1-6.
Schro ̈der J, Kahlke V, Staubach KH, Zabel P, Stüber F: Gender differences in human sepsis. Arch Surg 1998;133:1200-1205.
Eachempati SR, Hydo L, Barie PS: Gender-based differences in outcome in patients with sepsis. Arch Surg 1999;134:1342-1347.
Wichmann MW, Inthorn D, Andress HJ, Schildberg FW: Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome. Intensive Care Med 2000;26:167-172.
Ansari MZ, Collopy BT, Hart WG, Carson NJ, Chandraraj EJ: In-hospital mortality and associated complications after bowel surgery in Victorian public hospitals. Aust N Z J Surg 2000;70:6-10.
Vogel TR, Dombrovskiy VY, Carson JL, Graham AM, Lowry SF: Postoperative sepsis in the United States. Ann Surg 2010;252:1065-1071.
Hensler T, Heidecke CD, Hecker H, Heeg K, Bartels H, Zantl N, Wagner H, Siewert JR, Holzmann B: Increased Susceptibility to Postoperative Sepsis in Patients with Impaired Monocyte IL-12 Production. J Immunol 1998;161:2655-2659.
Acknowledgments
The authors are thankful to the Council of Science and Technology, Government of Uttar Pradesh, Lucknow, India, for financially supporting the study (grant letter no. CST/SERPD/D-783 dated 01-07-2011).
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The authors declare that they have no competing interests.
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Baghel, K., Srivastava, R.N., Chandra, A. et al. TNF-α, IL-6, and IL-8 Cytokines and Their Association with TNF-α-308 G/A Polymorphism and Postoperative Sepsis. J Gastrointest Surg 18, 1486–1494 (2014). https://doi.org/10.1007/s11605-014-2574-5
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DOI: https://doi.org/10.1007/s11605-014-2574-5