PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jmedgeneJournal of Medical GeneticsVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
 
J Med Genet. 2004 November; 41(11): 808–813.
PMCID: PMC1383768
NIHMSID: NIHMS7298

TLR4 and TNF-α polymorphisms are associated with an increased risk for severe sepsis following burn injury

Abstract

Context: Sepsis, organ failure, and shock remain common among patients with moderate to severe burn injuries. The inability of clinical factors to identify at-risk patients suggests that genetic variation may influence the risk for serious infection and the outcome from severe injury.

Objective: Resolution of genetic variants associated with severe sepsis following burn injury.

Patients: A total of 159 patients with burns [gt-or-equal, slanted]20% of their total body surface area or any smoke inhalation injury without significant non-burn related trauma (injury severity score (ISS)[gt-or-equal, slanted]16), traumatic or anoxic brain injury, or spinal cord injury and who survived more than 48 h post-admission.

Methods: Candidate single nucleotide polymorphisms (SNPs) within bacterial recognition (TLR4 +896, CD14 –159) and inflammatory response (TNF-α –308, IL-1ß –31, IL-6 –174) loci were evaluated for association with increased risk for severe sepsis (sepsis plus organ dysfunction or septic shock) and mortality.

Results: After adjustment for age, full-thickness burn size, ethnicity, and gender, carriage of the TLR4 +896 G-allele imparted at least a 1.8-fold increased risk of developing severe sepsis following a burn injury, relative to AA homozygotes (adjusted odds ratio (aOR) 6.4; 95% confidence interval (CI) 1.8 to 23.2). Carriage of the TNF-α –308 A-allele imparted a similarly increased risk, relative to GG homozygotes (aOR = 4.5; 95% CI 1.7 to 12.0). None of the SNPs examined were significantly associated with mortality.

Conclusions: The TLR4 +896 and TNF-α –308 polymorphisms were significantly associated with an increased risk for severe sepsis following burn trauma.

Full Text

The Full Text of this article is available as a PDF (192K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med. 2001 Jul;29(7 Suppl):S109–S116. [PubMed]
  • Bone RC. Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome) JAMA. 1992 Dec 23;268(24):3452–3455. [PubMed]
  • Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time. Crit Care Med. 1998 Dec;26(12):2078–2086. [PubMed]
  • O'Keefe GE, Hunt JL, Purdue GF. An evaluation of risk factors for mortality after burn trauma and the identification of gender-dependent differences in outcomes. J Am Coll Surg. 2001 Feb;192(2):153–160. [PubMed]
  • Abraham E, Matthay MA, Dinarello CA, Vincent JL, Cohen J, Opal SM, Glauser M, Parsons P, Fisher CJ, Jr, Repine JE. Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation. Crit Care Med. 2000 Jan;28(1):232–235. [PubMed]
  • Sørensen TI, Nielsen GG, Andersen PK, Teasdale TW. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med. 1988 Mar 24;318(12):727–732. [PubMed]
  • Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riché F, et al. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999 Aug 11;282(6):561–568. [PubMed]
  • O'Keefe Grant E, Hybki Dixie L, Munford Robert S. 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 May;52(5):817–826. [PubMed]
  • Knight JC, Kwiatkowski D. Inherited variability of tumor necrosis factor production and susceptibility to infectious disease. Proc Assoc Am Physicians. 1999 Jul-Aug;111(4):290–298. [PubMed]
  • Wang Yue, Kato Naoya, Hoshida Yujin, Yoshida Hideo, Taniguchi Hiroyoshi, Goto Tadashi, Moriyama Masaru, Otsuka Motoyuki, Shiina Shuichiro, Shiratori Yasushi, et al. Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology. 2003 Jan;37(1):65–71. [PubMed]
  • Brull DJ, Montgomery HE, Sanders J, Dhamrait S, Luong L, Rumley A, Lowe GD, Humphries SE. Interleukin-6 gene -174g>c and -572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1458–1463. [PubMed]
  • Schwartz David A. TLR4 and LPS hyporesponsiveness in humans. Int J Hyg Environ Health. 2002 Apr;205(3):221–227. [PubMed]
  • Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000 Jun;25(2):187–191. [PubMed]
  • Abraham LJ, Kroeger KM. Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol. 1999 Oct;66(4):562–566. [PubMed]
  • LeVan TD, Bloom JW, Bailey TJ, Karp CL, Halonen M, Martinez FD, Vercelli D. A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol. 2001 Nov 15;167(10):5838–5844. [PubMed]
  • Kroeger KM, Steer JH, Joyce DA, Abraham LJ. Effects of stimulus and cell type on the expression of the -308 tumour necrosis factor promoter polymorphism. Cytokine. 2000 Feb;12(2):110–119. [PubMed]
  • El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000 Mar 23;404(6776):398–402. [PubMed]
  • Baker SP, O'Neill B, Haddon W, Jr, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma. 1974 Mar;14(3):187–196. [PubMed]
  • Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. [PMC free article] [PubMed]
  • Alderborn A, Kristofferson A, Hammerling U. Determination of single-nucleotide polymorphisms by real-time pyrophosphate DNA sequencing. Genome Res. 2000 Aug;10(8):1249–1258. [PubMed]
  • Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995 Oct;23(10):1638–1652. [PubMed]
  • Fitzwater John, Purdue Gary F, Hunt John L, O'Keefe Grant E. The risk factors and time course of sepsis and organ dysfunction after burn trauma. J Trauma. 2003 May;54(5):959–966. [PubMed]
  • Cumming J, Purdue GF, Hunt JL, O'Keefe GE. Objective estimates of the incidence and consequences of multiple organ dysfunction and sepsis after burn trauma. J Trauma. 2001 Mar;50(3):510–515. [PubMed]
  • Chapes SK, Mosier DA, Wright AD, Hart ML. MHCII, Tlr4 and Nramp1 genes control host pulmonary resistance against the opportunistic bacterium Pasteurella pneumotropica. J Leukoc Biol. 2001 Mar;69(3):381–386. [PubMed]
  • Ingalls RR, Lien E, Golenbock DT. Differential roles of TLR2 and TLR4 in the host response to Gram-negative bacteria: lessons from a lipopolysaccharide-deficient mutant of Neisseria meningitidis. J Endotoxin Res. 2000;6(5):411–415. [PubMed]
  • Leveque Gary, Forgetta Vincenzo, Morroll Shaun, Smith Adrian L, Bumstead Nat, Barrow Paul, Loredo-Osti JC, Morgan Kenneth, Malo Danielle. Allelic variation in TLR4 is linked to susceptibility to Salmonella enterica serovar Typhimurium infection in chickens. Infect Immun. 2003 Mar;71(3):1116–1124. [PMC free article] [PubMed]
  • Lorenz Eva, Mira Jean Paul, Frees Kathy L, Schwartz David A. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med. 2002 May 13;162(9):1028–1032. [PubMed]
  • Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B. Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4). Genome Biol. 2000;1(1):RESEARCH002–RESEARCH002. [PMC free article] [PubMed]
  • Belvin MP, Anderson KV. A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol. 1996;12:393–416. [PubMed]
  • O'Neill LAJ. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr Top Microbiol Immunol. 2002;270:47–61. [PubMed]
  • Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001 Aug;2(8):675–680. [PubMed]
  • An Huazhang, Yu Yizhi, Zhang Minghui, Xu Hongmei, Qi Runzi, Yan Xiaoyi, Liu Shuxun, Wang Wenya, Guo Zhenghong, Guo Jun, et al. Involvement of ERK, p38 and NF-kappaB signal transduction in regulation of TLR2, TLR4 and TLR9 gene expression induced by lipopolysaccharide in mouse dendritic cells. Immunology. 2002 May;106(1):38–45. [PubMed]
  • Beutler B. Tlr4: central component of the sole mammalian LPS sensor. Curr Opin Immunol. 2000 Feb;12(1):20–26. [PubMed]
  • Agnese Doreen M, Calvano Jacqueline E, Hahm Sae J, Coyle Susette M, Corbett Siobhan A, Calvano Steve E, Lowry Stephen F. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis. 2002 Nov 15;186(10):1522–1525. [PubMed]
  • Ferrand Pedro E, Fujimoto Toshio, Chennathukuzhi Vargheese, Parry Samuel, Macones George A, Sammel Mary, Kuivaniemi Helena, Romero Roberto, Strauss Jerome F., 3rd The CARD15 2936insC mutation and TLR4 896 A>G polymorphism in African Americans and risk of preterm premature rupture of membranes (PPROM). Mol Hum Reprod. 2002 Nov;8(11):1031–1034. [PubMed]
  • Frantz S, Kobzik L, Kim YD, Fukazawa R, Medzhitov R, Lee RT, Kelly RA. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest. 1999 Aug;104(3):271–280. [PMC free article] [PubMed]
  • Marano MA, Fong Y, Moldawer LL, Wei H, Calvano SE, Tracey KJ, Barie PS, Manogue K, Cerami A, Shires GT, et al. Serum cachectin/tumor necrosis factor in critically ill patients with burns correlates with infection and mortality. Surg Gynecol Obstet. 1990 Jan;170(1):32–38. [PubMed]
  • Drost AC, Burleson DG, Cioffi WG, Jr, Jordan BS, Mason AD, Jr, Pruitt BA., Jr Plasma cytokines following thermal injury and their relationship with patient mortality, burn size, and time postburn. J Trauma. 1993 Sep;35(3):335–339. [PubMed]
  • Endo S, Inada K, Yamada Y, Kasai T, Takakuwa T, Nakae H, Kikuchi M, Hoshi S, Suzuki M, Yamashita H, et al. Plasma tumour necrosis factor-alpha (TNF-alpha) levels in patients with burns. Burns. 1993 Apr;19(2):124–127. [PubMed]
  • Arslan E, Yavuz M, Dalay C. The relationship between tumor necrosis factor (TNF)-alpha and survival following granulocyte-colony stimulating factor (G-CSF) administration in burn sepsis. Burns. 2000 Sep;26(6):521–524. [PubMed]
  • Knight JC, Udalova I, Hill AV, Greenwood BM, Peshu N, Marsh K, Kwiatkowski D. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet. 1999 Jun;22(2):145–150. [PubMed]
  • Sankaran D, Asderakis A, Ashraf S, Roberts IS, Short CD, Dyer PA, Sinnott PJ, Hutchinson IV. Cytokine gene polymorphisms predict acute graft rejection following renal transplantation. Kidney Int. 1999 Jul;56(1):281–288. [PubMed]
  • 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 Oct;174(4):878–880. [PubMed]
  • 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 Apr 1;94(7):3195–3199. [PubMed]
  • Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol. 1997 Apr;34(5):391–399. [PubMed]
  • Ninis VN, Kýlýnç MO, Kandemir M, Dadlý E, Tolun A. High frequency of T9 and CFTR mutations in children with idiopathic bronchiectasis. J Med Genet. 2003 Jul;40(7):530–535. [PMC free article] [PubMed]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group